CN102372653A - Diphenyl methanol derivative, preparation method thereof and application of diphenyl methanol derivative in medicine - Google Patents

Diphenyl methanol derivative, preparation method thereof and application of diphenyl methanol derivative in medicine Download PDF

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CN102372653A
CN102372653A CN2011101121688A CN201110112168A CN102372653A CN 102372653 A CN102372653 A CN 102372653A CN 2011101121688 A CN2011101121688 A CN 2011101121688A CN 201110112168 A CN201110112168 A CN 201110112168A CN 102372653 A CN102372653 A CN 102372653A
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methyl
phenyl
ethyl
chloro
compound
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邓炳初
吴清泉
吴晓
郑震
嵇雯浩
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to CN2011101121688A priority Critical patent/CN102372653A/en
Priority to PCT/CN2011/001252 priority patent/WO2012019428A1/en
Priority to CN201180005039.7A priority patent/CN102958912B/en
Priority to TW100141561A priority patent/TW201242594A/en
Publication of CN102372653A publication Critical patent/CN102372653A/en
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Abstract

The invention relates to a diphenyl methanol derivative, a preparation method thereof and an application of the diphenyl methanol derivative in medicine. Concretely, the invention relates to a new diphenyl methanol derivative shown as a general formula (I), a preparation method thereof, a medicine composition containing the derivative and an application of the diphenyl methanol derivative when being taken as a therapeutic agent, especially a rennin inhibitor, in preparation of medicines used for treating diseases related to rennin activity, such as antihypertensive drug, wherein substituent groups in the general formula (I) are the same with definition in the specification.

Description

Benzhydrol analog derivative, its preparation method and in pharmaceutically application
Technical field
The pharmaceutical composition that the present invention relates to a kind of new benzhydrol analog derivative, its preparation method and contain this verivate with and as therapeutical agent particularly as renin inhibitor with in the purposes with the medicine of RA diseases related such as preparation treatment hypertension.
Background technology
Aspartate protease (Aspartic Proteinase) is one type of important protein lytic enzyme, participates in the metabolism and the biological regulating and controlling effect of body.In general, their active site is made up of the catalytic asparagicacid residue of two high conservatives.Common aspartate protease comprises: stomach en-; Feritin (Renin); Beta-secretase (beta-amyloyd precursor protein lyase, β-site amyloid precursor protein cleaving enzyme, BACE); Hiv protease, human T-leukemia virus's proteolytic enzyme etc.Their its generations with numerous disease are relevant, as: at the essential hypertension philtrum, because the katalysis of feritin makes the angiotensin I level raise; Generally believe at present that in addition one of alzheimer's disease main pathogenesis is to form owing to abnormal deposition that BACE acts on the product amyloid beta behind the amyloid precursor protein.In addition, human immunodeficiency virus and human T-leukemia virus all need the participation of aspartate protease separately in its ripening process.
Feritin (Renin) is claimed Angiotensinogenase again, and it is synthetic and release by renal glomerulus; In blood, proangiotensin is cracked into decapeptide angiotensin I (angiotensin I subsequently; Ang I), (angiotensin converting enzyme is under effect ACE) at angiotensin-converting enzyme; AngI is cracked into octapeptide Angiotensin II (angiotensin II; Ang II), the AngII of high biological activity can shrink direct rising blood pressure through arteries, also can discharge the aldosterone blood pressure that raises indirectly through regulating suprarenal gland.This begins to the regulation mechanism that generates till the aldosterone from feritin, be called renin-angiotensin-aldosterone system (Renin-angiotension-aldosterone system, RAAS).
Renin-angiotensin-aldosterone system (RAAS) is keying action target spot (the Nature Reviews Drug Discovery 2002 such as Zaman M.A. of pharmacological agent cardiovascular system diseases; The generation and the blocking-up angiotensin-ii receptor of the secretion that 1:621-36), it can be through suppressing feritin, activity, prevention Angiotensin II are realized.At present, (AngiotensinAT1 receptor blockers's blocker of angiotensin-convertion enzyme inhibitor (ACEi) and angiotensin receptor ARBS) all goes on the market, and some medicine becomes an antihypertensive line medicine.But also there are some problems in current ACEi suppressor factor and ABRs, not exclusively block like the non-specific RAAS of the causing system of ACEi, cross high spinoff thereby produce like dry cough, headache, blood potassium.Because feritin is directly regulated the initial link in the RAAS system---AngI generates, and vasotonia have high degree of specificity for endogenous, is the research focus that acts on the RASS medicine therefore always.
In addition, through suppressing feritin blocking-up RASS except ability is hypotensive, can also reduce the trouble mellitus and other cardiovascular disease risk that cause because of hypertension.As block RAAS and can be used for treating liver, renal fibrosis (Contrib Nephrol.2001 such as Gaedeke J; 135:153-60, World JGastroenterol.2009 such as Regina M.P.; 15 (21): 2579-86), atherosclerosis, myocardial hypertrophy, myocardial fibrosis, diastolic dysfunction, diabetic complication diseases such as (like ephrosis, eye diseases).
First-generation renin inhibitor is a peptide class substrate analogue, and the body internal stability is poor, and action time is short, can only the enteron aisle external administration (people J.Biol.Chem such as Cumin F, 1985; 260 (16): 9154-57.).After this on its basis, carry out chemically modified, synthesized the oral plan peptide of s-generation class renin inhibitor, disclosed related patent U.S. Patent No. has: WO2005051895, WO2005070871, WO2007031557 etc.Allie Gillen (aliskiren) successfully goes on the market at present.In recent years, along with the development of medicament research and development technology, design the non-peptide micromolecular of third generation renin inhibitor.Disclosed patent has: WO2006042150, WO2008036216, WO2008156817.
Although disclose a series of Renin suppressor factor at present; But still need exploitation new have better drug effect, medicine a compound for result and bioavailability; Through continuous effort; The compound that the present invention's design has the structure shown in the general formula (I), and find that the compound with this class formation shows excellent effect and effect.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.
Figure BSA00000486338900021
Wherein:
R 1Be alkyl;
Each R 2Be selected from independently of one another Wasserstoffatoms, halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,, wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl optional independently of one another further by one or more be selected from halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9Substituting group replace;
R 3, R 4And R 5In one be selected from cyanic acid, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11The NR of ,-SO) 10R 11Or-S (O) mR 9, wherein said alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9Substituting group replace, two other is selected from Wasserstoffatoms;
Perhaps, R 3And R 4Or R 4And R 5Form a heterocyclic radical with the atom that is connected, wherein said heterocyclic radical contains one and is selected from N, O or S (O) mHeteroatoms, and said heterocyclic radical is optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 6Be Wasserstoffatoms, R 7For-(CH 2) p-R 12, perhaps R 6For-(CH 2) p-R 12, R 7Be Wasserstoffatoms;
R 8Be selected from Wasserstoffatoms or alkyl;
R 9Be selected from Wasserstoffatoms, alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl are optional independently of one another further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 10Or R 11Independently be selected from separately Wasserstoffatoms, alkyl, naphthenic base, heterocyclic radical, aryl, heteroaryl or-S (O) mR 9, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl are optional independently of one another further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
Perhaps, R 10And R 11Nitrogen-atoms with being connected forms heterocyclic radical, and wherein said heterocyclic radical contains one or more N of being selected from, O or S (O) mHeteroatoms, and said heterocyclic radical is optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 12Be selected from naphthenic base, heterocyclic radical, aryl or heteroaryl, wherein said naphthenic base, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
M is 0,1 or 2;
N is 1,2,3,4 or 5; And
P is 0,1,2 or 3;
Preferred version of the present invention, compound and enantiomorph thereof shown in a kind of general formula (I), diastereomer or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) and enantiomorph, diastereomer or its pharmaceutically useful salt:
Wherein n, R 1～R 8Definition such as general formula (I) described in.
Preferred version of the present invention, compound and enantiomorph thereof shown in a kind of general formula (I), diastereomer or its pharmaceutically useful salt, wherein said compound comprise general formula (III) and (IV) shown in compound and enantiomorph, diastereomer or its pharmaceutically useful salt:
Figure BSA00000486338900041
R wherein 1～R 5, R 8, R 12, n and p definition such as general formula (I) described in.
Preferred version of the present invention, compound and enantiomorph thereof shown in a kind of general formula (I), diastereomer or its pharmaceutically useful salt, wherein: R 4Be selected from cyanic acid, alkyl, alkoxyl group, heterocyclic radical, naphthenic base or aryl.
Preferred version of the present invention, compound and enantiomorph thereof shown in a kind of general formula (I), diastereomer or its pharmaceutically useful salt, wherein: R 3And R 4Or R 4And R 5Form 5～6 yuan of heterocyclic radicals with the atom that is connected, wherein said heterocyclic radical contains an O atom.
Preferred version of the present invention, compound and enantiomorph thereof shown in a kind of general formula (I), diastereomer or its pharmaceutically useful salt, wherein said compound comprise logical formula V with (VI) shown in compound and enantiomorph, diastereomer or its pharmaceutically useful salt:
Figure BSA00000486338900042
Wherein X is-CH 2-, Y is the O atom, or X is the O atom, Y is-CH 2-;
Q is 1 or 2;
R 1, R 2, R 6～R 8, n definition such as general formula (I) described in.
Preferred version of the present invention provides compound shown in a kind of general formula (I) and enantiomorph, diastereomer or its pharmaceutically useful salt, and wherein n is 1, R 2Be halogen.
Preferred version of the present invention provides compound shown in a kind of general formula (I) and enantiomorph, diastereomer or its pharmaceutically useful salt, and wherein p is 1, R 12Be selected from naphthenic base or heterocyclic radical, be preferably cyclohexyl or THP trtrahydropyranyl.
Typical compound of the present invention includes, but are not limited to:
Figure BSA00000486338900051
Figure BSA00000486338900061
Figure BSA00000486338900071
Figure BSA00000486338900081
Figure BSA00000486338900091
Figure BSA00000486338900101
Figure BSA00000486338900111
Figure BSA00000486338900121
Figure BSA00000486338900141
Or its pharmaceutically useful salt.
The present invention relates to the compound method of the said compound of a kind of preparation general formula (I) or its pharmaceutically useful salt, this method comprises:
Figure BSA00000486338900142
General formula (IA) compound optionally hydrolyse is become carboxylic acid and the reaction of general formula (IB) compound, and the protection base PG of optional further deaminize obtains general formula (I) compound;
Wherein: n, R 1～R 8Definition such as general formula (I) described in;
G is selected from hydroxyl, alkoxy or halogen;
PG is amino protection base, is preferably tert-butoxycarbonyl.
A kind of general formula (IA) compound and enantiomorph thereof, diastereomer or its pharmaceutically useful salt, wherein:
Figure BSA00000486338900143
Wherein: n, R 1～R 5Definition such as general formula (I) described in;
G is selected from hydroxyl, alkoxy or halogen.
The preparation method of a kind of general formula (IA) compound and enantiomorph, diastereomer or its pharmaceutically useful salt, this method comprises:
Figure BSA00000486338900151
The grignard reagent reaction of phenyl aldehyde compounds a and substituted benzene obtains benzhydrol compounds b
Compound b and compound c are carried out condensation reaction and are obtained general formula (IA) compound;
Wherein: n, R 1～R 5Definition such as general formula (I) described in;
G is selected from hydroxyl, alkoxy or halogen.
The preparation method of a kind of general formula (IA) compound and enantiomorph, diastereomer or its pharmaceutically useful salt, this method comprises:
Figure BSA00000486338900153
Bromobenzene compounds e and substituted benzoyl aldehyde reaction obtain benzhydrol compounds f;
Figure BSA00000486338900154
Benzhydrol compounds f changes into compound g;
Figure BSA00000486338900155
Compound g obtains compound h with the methylsulfonyl chloride reaction after being reduced into alcohol again;
Compound h carries out azido reaction and obtains compound i;
Figure BSA00000486338900162
The compound i reduction obtains ethylamine compounds j;
Figure BSA00000486338900163
Compound j changes into compound k;
Compound k sloughs hydroxyl protecting group M and obtains general formula (IA) compound;
Wherein: n, R 1～R 5Definition such as claim 1 described in;
G is selected from hydroxyl, alkoxy or halogen;
M is a hydroxyl protecting group, is preferably methyl or tertiary butyl hexichol is silica-based.
Another aspect of the present invention relate to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and the purposes of pharmaceutically useful salt in the medicine of preparation renin inhibitor.
Another aspect of the present invention relate to as the The compounds of this invention of the medicine of renin inhibitor or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt.
The invention still further relates to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt in the medicine of the preparation treatment disease relevant with feritin purposes, wherein relevant with feritin disease comprises: the restenosis of the complication that myocardosis, instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, mellitus cause after hypertension, atherosclerosis, instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, the infraction (like ephrosis, vascular disease and neuropathy), coronary artery disease, postangioplasty, the rising of eye-chamber pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dementia, anxiety state or cognitive disorders.
Another aspect of the present invention relate to as the The compounds of this invention of the medicine of the treatment disease relevant or its tautomer, racemic modification, enantiomer, diastereomer with feritin, and composition thereof form, reach pharmaceutically useful salt.Wherein with the RA diseases associated as stated.
The present invention relates to a kind of method that suppresses feritin, this method comprise the effective therapeutic dose of patient that needs treatment The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt.
Further; Another aspect of the present invention relates to a kind of pharmaceutical composition; Its contain the The compounds of this invention of treating effective dose or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, and pharmaceutically useful carrier or vehicle.This pharmaceutical composition is as the medicine of renin inhibitor.The purposes of this pharmaceutical composition in the medicine of preparation treatment renin inhibitor.The purposes of this pharmaceutical composition in the medicine of the preparation treatment disease relevant with feritin, wherein relevant with feritin disease comprises: the restenosis of the complication that myocardosis, instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, mellitus cause after hypertension, atherosclerosis, instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, the infraction (like ephrosis, vascular disease and neuropathy), coronary artery disease, postangioplasty, the rising of eye-chamber pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dementia, anxiety state and cognitive disorders.
Another aspect of the present invention relates to the method for a kind of treatment and RA diseases associated, this method comprise the effective therapeutic dose of patient that needs treatment The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, reach pharmaceutically useful salt or pharmaceutical composition.Wherein with the RA diseases associated as stated.
Detailed description of the invention
Only if the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 12 carbon atom, non-limiting example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1; 2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1; 2-trimethylammonium propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2; 2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2; 3-dimethyl-amyl group, 2,4-dimethyl-amyl group, 2,2-dimethyl-amyl group, 3; 3-dimethyl-amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2; 5-dimethyl-hexyl, 2; 2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2; 2-diethylammonium amyl group, positive decyl, 3; 3-diethylhexyl, 2, the 2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1; 2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1; 2-trimethylammonium propyl group, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1; 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc.Alkyl can be substituted or unsubstituted; When being substituted; Substituting group can be substituted on any spendable tie point; Be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" naphthenic base " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic naphthenic base." spiro cycloalkyl group " refers to 5 to 20 yuan, many cyclic groups of a shared carbon atom (title spiro atom) between the monocycle, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
Figure BSA00000486338900181
" condensed ring alkyl " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins; Wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises
" bridge ring alkyl " refers to 5 to 20 yuan, shared two the many cyclic groups of full carbon of direct-connected carbon atom not of any two rings, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Figure BSA00000486338900191
Said cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring that wherein links together with precursor structure is a naphthenic base, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Naphthenic base can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is an integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazinyl etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic heterocyclic radical." spiro heterocyclic radical " refers to 5 to 20 yuan, many rings heterocyclic group of a shared atom (title spiro atom) between the monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" fused heterocycle base " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared many rings heterocyclic group of a pair of atom that adjoins; One or more rings can contain one or more pairs of keys; But the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
" bridge heterocyclic radical " refers to 5 to 14 yuan; Shared two the many rings heterocyclic groups of direct-connected atom not of any two rings; These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Figure BSA00000486338900202
Said heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heterocyclic radical, and non-limiting example comprises:
Figure BSA00000486338900203
Deng.Heterocyclic radical can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, and many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system is preferably 6 to 10 yuan, for example phenyl and naphthyl.Said aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is an aryl rings, and non-limiting example comprises:
Figure BSA00000486338900211
Aryl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Said heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heteroaryl ring, and non-limiting example comprises:
Figure BSA00000486338900212
Heteroaryl can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted naphthenic base), wherein the definition of alkyl, naphthenic base is as stated.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2
" cyanic acid " refers to-CN.
" nitro " refers to-NO 2
" benzyl " refers to-CH 2-phenyl.
" oxo " refers to=O.
" carboxylic acid " refers to-C (O) OH.
" carboxylicesters " refers to-C (O) O (alkyl) or (naphthenic base).
" hydroxyl protecting group " refer in organic synthesis, contains the molecule of 2 or a plurality of functional groups, exempts from the destruction of reaction for making hydroxyl, and certain reagent commonly used is earlier with its protection, and question response is sloughed the protective material base after accomplishing again.Hydroxyl protecting group includes but not limited to that methyl, ethyl, tert-butyl diphenyl are silica-based, the tertiary butyl, benzyl, acetyl or benzoyl base.
" amino protecting group " refer in organic synthesis, contains the molecule of 2 or a plurality of functional groups, exempts from the destruction of reaction for making amino, and certain reagent commonly used is earlier with its protection, and question response is sloughed the protective material base after accomplishing again.Amino protecting group includes but not limited to tertbutyloxycarbonyl, carbobenzoxy-(Cbz), formyl radical or trifluoroacetyl group." choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " optional by the substituted heterocyclic group of alkyl " mean alkyl can but must not exist, this explanation comprise heterocyclic group by the substituted situation of alkyl and heterocyclic group not by the substituted situation of alkyl.
" substituted " refers to the one or more Wasserstoffatomss in the group, is preferably maximum 5, and more preferably 1～3 Wasserstoffatoms is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group only is in their possible chemical position, and those skilled in the art can confirm (through experiment or theoretical) possibility or impossible replacement under the situation of not paying too much effort.For example, amino or the hydroxyl that has a free hydrogen possibly be unsettled when combining with the carbon atom with unsaturated (like olefinic) key.
" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to the absorption and then the performance biological activity of activeconstituents.
M, n and R 9～R 11Definition such as general formula (I) compound described in.
The compound method of The compounds of this invention
In order to accomplish the object of the invention, the present invention adopts following technical scheme:
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
The grignard reagent reaction of phenyl aldehyde compounds a and substituted benzene obtains benzhydrol compounds b; Compound b and compound c are carried out condensation reaction and are obtained general formula (IA) compound; General formula (IA) compound optionally hydrolyse becomes carboxylic acid and the reaction of general formula (IB) compound; The protection base PG of optional further deaminize obtains general formula (I) compound.
Wherein: n, R 1～R 8Definition such as general formula (I) described in;
G is selected from hydroxyl, alkoxy or halogen;
PG is amino protection base, is preferably tert-butoxycarbonyl.
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
Figure BSA00000486338900232
Bromobenzene compounds e and substituted benzoyl aldehyde reaction obtain benzhydrol compounds f, and compound f and METHYL BROMOACETATE react under alkaline condition and obtain compound g, and compound g obtains compound h with the methylsulfonyl chloride reaction after being reduced into alcohol again; Compound h carries out azido reaction and obtains compound i; The compound i reduction obtains ethylamine compounds j, and compound j and haloformate reaction obtain compound k, and compound k sloughs hydroxyl protecting group M and obtains general formula (IA) compound; General formula (IA) compound oxidation obtains compound d; The reaction of compound d and general formula (IB) compound, the protection base PG of optional further deaminize obtains general formula (I) compound.
Wherein: n, R 1～R 5Definition such as general formula (I) described in;
G is selected from hydroxyl, alkoxy or halogen;
M is a hydroxyl protecting group, is preferably methyl or tertiary butyl hexichol is silica-based.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound is confirmed through nucleus magnetic resonance (NMR) or mass spectrum (MS).The mensuration of NMR is with Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and the mensuration solvent is deuterated dimethyl sulfoxide (d-DMSO), deuterochloroform (CDCl 3), deuterated methanol (CH 3OD), in be designated as TMS (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: FinniganLCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6mm chromatographic column).
Average inhibiting rate of kinases and IC 50The mensuration of value is with NovoStar ELIASA (German BMG company).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm silica-gel plate.
Column chromatography generally uses the Huanghai Sea 200～300 order silica gel in Yantai to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art; Maybe can buy Co.KG from ABCR GmbH &; Acros Organnics; Aldrich Chemical Company, reaches company such as auspicious chemical at splendid chemistry science and technology far away (Accela ChemBio Inc).
Like no specified otherwise, reaction is all carried out under argon atmospher or nitrogen atmosphere among the embodiment.
Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.
Parr 3916EKX type hydrogenation appearance and clear blue QL-500 type steam iron generator or HC2-SS type hydrogenation appearance are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactors.
Like no specified otherwise, the solution in the reaction is meant the aqueous solution among the embodiment.
Like no specified otherwise, the temperature of reaction is a room temperature among the embodiment.
Room temperature is optimum temperature of reaction, and TR is 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment; The system of reacting employed developping agent has: A: methylene dichloride and methanol system; B: normal hexane and ethyl acetate system; C: sherwood oil and ethyl acetate system, D: acetone, the volume ratio of solvent is according to different adjusting of polarity of compound.
The system of the system of the eluent of the column chromatography that purifying compounds adopts and the developping agent of tlc comprises: A: methylene dichloride and methanol system; B: normal hexane and ethyl acetate system; C: normal hexane and acetone system, D: normal hexane, E: ETHYLE ACETATE; The volume ratio of solvent also can add a spot of triethylamine and acidity or alkaline reagents etc. and regulate according to different adjusting of polarity of compound.
Embodiment 1
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-cyclopropyl-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900251
The first step
(2S)-2-amino-3-cyclohexyl-methyl propionate hydrochloride
Under the ice bath, (8.55g 0.050mol) is dissolved in the 70mL methyl alcohol, and (5.4mL, 0.075mol), refluxing and stirring was reacted 2 hours to drip thionyl chloride with (2S)-2-amino-3-cyclohexylpropionic acid 1a.The reaction solution concentrating under reduced pressure obtains bullion title product (2S)-2-amino-3-cyclohexyl-methyl propionate hydrochloride 1b (12.50g, white solid), and product is not purified directly to carry out next step reaction.
Second step
(2S)-3-cyclohexyl-2-(dibenzyl is amino) methyl propionate
(11.10g 0.050mol) is dissolved in 70mL N, in the dinethylformamide with bullion (2S)-2-amino-3-cyclohexyl-methyl propionate hydrochloride 1b; (24.15g 0.175mol), drips benzyl bromine (13.10mL to add salt of wormwood; 0.11mol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds less water, with ethyl acetate extraction (150mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product (2S)-3-cyclohexyl-2-(dibenzyl is amino) methyl propionate 1c (16.00g with silica gel column chromatography; Weak yellow liquid), productive rate: 88.8%.
The 3rd step
(2S)-3-cyclohexyl-2-(dibenzyl is amino)-N-methyl-propionic acid amide
(16.00g 0.044mol) is dissolved in the methylamine methanol solution of 100mL40% methyl propionate 1c, stirring reaction 16 hours with (2S)-3-cyclohexyl-2-(dibenzyl is amino).The reaction solution concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product (2S)-3-cyclohexyl-2-(dibenzyl is amino)-N-methyl-propionic acid amide 1d (6.60g, white solid), productive rate: 41.7% with silica gel column chromatography.
MS?m/z(ESI)：365[M+1]
The 4th step
(2S)-N 2, N 2-dibenzyl-3-cyclohexyl-N 1-methyl-propane-1, the 2-diamines
Under the ice bath, with (2S)-3-cyclohexyl-2-(dibenzyl amino)-N-methyl-propionic acid amide 1d (6.60g 0.018mol) is dissolved in the 40mL THF, add lithium aluminum hydride (1.72g, 0.045mol), 50 ℃ of following stirring reactions 4 hours.Ice bath drips 10% sodium hydroxide solution cancellation reaction down, filters, and filter cake washs with THF, merging filtrate, and concentrating under reduced pressure obtains bullion title product (2S)-N 2, N 2-dibenzyl-3-cyclohexyl-N 1-methyl-propane-1,2-diamines 1e (8.00g, weak yellow liquid), product is not purified directly to carry out next step reaction.
The 5th step
N-[(2S)-3-cyclohexyl-2-(dibenzyl is amino) propyl group]-N-methyl-carboxylamine tertiary butyl ester
Under the ice bath, with (2S)-N 2, N 2-dibenzyl-3-cyclohexyl-N 1-methyl-propane-1,2-diamines 1e (6.35g, (V/V=1: in the mixed solvent 2), (5.93g, 0.027mol), reacted 12 hours to add two dimethyl dicarbonate butyl esters 0.018mol) to be dissolved in 60mL methylene dichloride and saturated sodium bicarbonate solution by stirring at room.Reaction solution merges organic phase, anhydrous sodium sulfate drying with dichloromethane extraction (100mL * 3); Filter; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product N-[(2S)-3-cyclohexyl-2-(dibenzyl amino) propyl group]-N-methyl-carboxylamine tertiary butyl ester 1f (4.40g with silica gel column chromatography; Weak yellow liquid), productive rate: 54.0%.
The 6th step
N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester
(6.17g 0.014mol) is dissolved in the 50mL THF, adds palladium hydroxide (2.44g, 40%), hydrogen exchange three times, 50 ℃ of following stirring reactions 12 hours with N-[(2S)-3-cyclohexyl-2-(dibenzyl amino) propyl group]-N-methyl-carboxylamine tertiary butyl ester 1f.Reacting liquid filtering, filtrate decompression concentrate, and obtain title product N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester 1g (3.15g, light yellow oil), productive rate: 85.0%.
MS?m/z(ESI)：272[M+1]
The 7th step
5-(trifluoromethyl sulfonyl) benzene-1,3-dicarboxylicacid methyl esters
Under-30 ℃, with 5-phenol-1,3-dicarboxylicacid methyl esters 1h (9.50g, 45mmol) and pyridine (10.70g 135mmol) is dissolved in the 150mL toluene, add Trifluoromethanesulfonic anhydride 1i (25.5g, 90mmol), stirring at room reaction 12 hours.Reaction solution is poured in the 250mL mixture of ice and water, with ethyl acetate extraction (100mL * 3), merges organic phase; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 5-(trifluoromethyl sulfonyl) benzene-1 with silica gel column chromatography, 3-dicarboxylicacid methyl esters 1j (14.40g; White solid), productive rate: 93.0%.
1H?NMR(400MHz，CDCl 3)：δ8.72(s，1H)，8.12(s，2H)，3.99(s，6H)
The 8th step
5-cyclopropyl-phenyl-1,3-dicarboxylicacid methyl esters
With 5-(trifluoromethyl sulfonyl) benzene-1, (4.00g 45mmol) is dissolved in the 100mL THF 3-dicarboxylicacid methyl esters 1j, adds 50mL 2M sodium carbonate solution; Adding cyclopropylboronic acid 1k (1.20g, 14mmol), 1; 1 '-two (diphenylphosphine) ferrocene Palladous chloride (II) (0.25g, 0.35mmol), 1; 1 '-two (diphenylphosphine) ferrocene (0.19g, 0.35mmol), 50 ℃ of following stirring reactions 12 hours.Reaction solution is reduced to room temperature, with ethyl acetate extraction (50mL * 3), merges organic phase; With saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-cyclopropyl-phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 1m (14.40g, white solid), productive rate: 93.0%.
1H?NMR(400MHz，CDCl 3)：δ8.45(s，1H)，7.92(s，2H)，3.95(s，6H)，2.01(m，1H)，1.06(m，2H)，0.79(m，2H)
The 9th step
3-cyclopropyl-5-methoxycarbonyl-phenylformic acid
With 5-cyclopropyl-phenyl-1,3-dicarboxylicacid methyl esters 1m (1.00g 4.27mmo1) is dissolved in the 5mL methyl alcohol, add sodium hydroxide (171mg, 4.27mmol) with 10mL acetone, 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 20mL water, with ethyl acetate extraction (20mL * 3), merges organic phase; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-cyclopropyl-5-methoxycarbonyl-phenylformic acid 1n (540mg, white solid), productive rate: 53.0%.
The tenth step
3-cyclopropyl-5-(methylol) oil of Niobe
With 3-cyclopropyl-5-methoxycarbonyl-phenylformic acid 1n (540mg 2.45mmol) is dissolved in the 5mL THF, add the 1M borine tetrahydrofuran solution (3.7mL, 3.68mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-cyclopropyl-5-(methylol) oil of Niobe 1o (440mg, colorless oil), productive rate: 87.1%.
The 11 step
3-cyclopropyl-5-formyloxy-oil of Niobe
With 3-cyclopropyl-5-(methylol) oil of Niobe 1o (540mg 2.45mmol) is dissolved in the 15mL methylene dichloride, add pyridinium chloro-chromate (1.38g, 6.4mmol) and sodium acetate (700mg, 8.54mmol), stirring reaction 12 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-cyclopropyl-5-formyloxy-oil of Niobe 1p (240mg, white solid), productive rate: 55.2% with silica gel column chromatography.
The 12 step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopropyl-oil of Niobe
Under the ice bath, with 3-cyclopropyl-5-formyloxy-oil of Niobe 1p (240mg 1.18mmol) is dissolved in the 5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (1.2mL, 1.18mmol), stirring reaction 1 hour.Add the shrend reaction of going out, with ethyl acetate extraction (25mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopropyl-oil of Niobe 1q (280mg with tlc; Colourless viscous liquid), productive rate: 75.1%.
The 13 step
N-(2-hydroxyethyl) Urethylane
Under the ice bath, (15.00g 246mmol) is dissolved in the 200mL acetonitrile, and (101.80g, 738mmol), (50mL, 647mmol), stirring at room was reacted 1 hour to drip methyl-chloroformate 1s to add salt of wormwood with 2-monoethanolamine 1r.Add the shrend reaction of going out, filtration is with ethyl acetate extraction (100mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product N-(2-hydroxyethyl) Urethylane 1t (26.00g, colorless oil), productive rate: 90.1%.
MS?m/z(ESI)：120[M+1]
1H?NMR(400MHz，CDCl 3)：δ5.64(br.s，1H)，3.69(m，5H)，3.59(t，J＝5.6Hz，1H)，3.32(m，2H)
The 14 step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopropyl-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopropyl-oil of Niobe 1q (280mg; 0.89mmol) and N-(2-hydroxyethyl) Urethylane 1t (115mg 0.97mmol) is dissolved in the 25mL toluene, adds tosic acid (177mg; 0.93mmol), stirring reaction 1 hour.Add 100mL ETHYLE ACETATE, with saturated sodium bicarbonate solution washing (20mL * 2), anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopropyl-oil of Niobe 1u (200mg with silica gel column chromatography; Yellow oil), productive rate: 54.0%.
The 15 step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopropyl-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-oil of Niobe 1u (197mg 0.47mmol) is dissolved in the 1mL methyl alcohol, add sodium hydroxide (47mg, 1.18mmol), 50 ℃ of following stirring reactions 12 hours.Add the hydrochloric acid cancellation reaction of 1M, concentrating under reduced pressure is with dichloromethane extraction (20mL * 3); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-phenylformic acid 1v (190mg, white solid), product is not purified directly to carry out next step reaction.
The 16 step
N-[2-[[3-[[(1R)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopropyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-formic acid 1v (85mg, 0.21mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(75mg 0.27mmol) is dissolved in 2mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the N-NMF; The adding I-hydroxybenzotriazole (47mg, 1.18mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (106mg; 0.55mmol) and N; The N-diisopropylethylamine (143.6mg, 1.11mmol), stirring reaction 12 hours.Add the 50mL methylene dichloride; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[[3-[[(1R)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopropyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 1w (134mg, white solid), productive rate: 96.9%.
The 17 step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-cyclopropyl-phenyl] methoxyl group] ethyl] Urethylane
With N-[2-[[3-[[(1R)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopropyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 1w (134mg; 0.27mmol) be dissolved in the 1mL trifluoroacetic acid stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (20mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-cyclopropyl-phenyl] methoxyl group] ethyl] Urethylane 1 (62mg, white solid), productive rate: 54.8%.
MS?m/z(ESI)：556[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.00-7.12(m，7H)，5.34?and?5.33(2s，1H)，5.70(m，1H)，4.60(m，1H)，3.72-3.01(m，9H)，2.66?and?2.60(2s，3H)，1.90-0.75(m，18H)
Embodiment 2
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900301
The first step
5-p-methoxy-phenyl-1,3-dicarboxylicacid methyl esters
With 5-phenol-1,3-dicarboxylicacid methyl esters 1h (4.20g 20mmol) is dissolved in the 50mL acetone, add salt of wormwood (5.50g, 40mmol) and methyl tosylate (5.60g, 30mmol), 50 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure adds 100mL water, with ethyl acetate extraction (80mL * 3), merges organic phase; Water (15mL * 2) and saturated nacl aqueous solution washing (15mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system C purifying gained resistates, obtains bullion title product 5-p-methoxy-phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 2a (5.30g, white solid), product is not purified directly to carry out next step reaction.
Second step
3-methoxyl group-5-methoxycarbonyl-phenylformic acid
With 5-p-methoxy-phenyl-1, (4.48g 20mmol) is dissolved in the 50mL methyl alcohol 3-dicarboxylicacid methyl esters 2a, adds 25mL sodium hydroxide (800mg, methanol solution 20mmol), stirring reaction 24 hours.The reaction solution concentrating under reduced pressure adds 100mL water, with dichloromethane extraction (20mL * 3); It is 4～5 that water uses 4M hydrochloric acid to regulate pH, filters, and filter cake in vacuum is dry; Obtain title product 3-methoxyl group-5-methoxycarbonyl-phenylformic acid 2b (2.20g, white solid), productive rate: 52.0%.
The 3rd step
3-(methylol)-5-methoxyl group-oil of Niobe
Under the ice bath, (2.20g 10.5mmol) is dissolved in the 15mL THF with 3-methoxyl group-5-methoxycarbonyl-phenylformic acid 2b; Tetrahydrofuran solution (the 16mL that adds the 1M borine; 16mmol), 50 ℃ of following stirring reactions 12 hours rise to 70 ℃ and continued stirring reactions 4 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 100mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-(methylol)-5-methoxyl group-oil of Niobe 2c (1.7g, colorless oil), productive rate: 82.9%.
The 4th step
3-formyloxy-5-methoxyl group-oil of Niobe
With 3-(methylol)-5-methoxyl group-oil of Niobe 2c (1.7g 8.7mmol) is dissolved in the 20mL methylene dichloride, add pyridinium chloro-chromate (3.7g, 17.3mmol) and sodium acetate (2.14g, 26mmol), stirring reaction 12 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 3-formyloxy-5-methoxyl group-oil of Niobe 2d (1.1g, white solid), productive rate: 64.7% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxyl group-oil of Niobe
Under the ice bath, with 3-formyloxy-5-methoxyl group-oil of Niobe 2d (550mg 2.85mmol) is dissolved in the 5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (4.3mL, 4.30mmol), stirring reaction 1 hour.Add the shrend reaction of going out, with ethyl acetate extraction (25mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxyl group-oil of Niobe 2e (780mg with silica gel column chromatography; Faint yellow oily thing), productive rate: 90.1%.
1H?NMR(400MHz，CDCl 3)：δ7.63(s，1H)，7.47(m，1H)，7.38(s，1H)，7.25(m，3H)，7.13(m，1H)，5.81(s，1H)，3.90(s，3H)，3.84(s，3H)，2.38(br?s，1H)
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxyl group-oil of Niobe 2e (780mg; 2.55mmol) and N-(2-hydroxyethyl) Urethylane 1t (331mg; 2.81mmol) be dissolved in the 50mL toluene; (509mg, 2.68mmol), 130 ℃ were stirred dehydration reaction 2 hours down to add tosic acid.Add 2mL triethylamine cancellation reaction; Concentrating under reduced pressure; With tlc with developping agent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-oil of Niobe 2f (390mg, colorless oil), productive rate: 37.0%.
1H?NMR(400MHz，CDCl 3)：δ7.59(s，1H)，7.47(m，1H)，7.33(s，1H)，7.25(m，2H)，7.20(m，1H)，7.07(m，1H)，5.32(s，1H)，5.05(br.s，1H)，3.92(s，3H)，3.84(s，3H)，3.67(s，3H)，3.53(m，2H)，3.43(m，2H)
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methoxyl group-oil of Niobe 2f (390mg 0.96mmol) is dissolved in the 3mL methyl alcohol, add sodium hydroxide (96mg, 2.4mmol), 40 ℃ of following stirring reactions 36 hours.Add the hydrochloric acid cancellation reaction of 1M, concentrating under reduced pressure is with dichloromethane extraction (20mL * 3); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-phenylformic acid 2g (340mg, white solid), productive rate: 90.6%.
The 8th step
N-[2-[[3-[[(1R)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-phenylformic acid 2g (190mg; 0.48mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester 1g (130mg; 0.48mmol) be dissolved in 6mL N, dinethylformamide and N, N-diisopropylethylamine (V/V=5: in the mixed solvent 1); Add I-hydroxybenzotriazole (130mg; 0.96mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (184mg, 0.96mmol), stirring reaction 12 hours.Add the 50mL methylene dichloride; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[[3-[[(1R)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 2h (200mg, colorless oil), productive rate: 66.0%.
MS?m/z(ESI)：646[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1R)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 2h (210mg; 0.33mmol) be dissolved in the 10mL methylene dichloride; Add the 2.5mL trifluoroacetic acid, stirring reaction 1.5 hours.The reaction solution concentrating under reduced pressure; Add the 100mL methylene dichloride, organic phase is used saturated sodium bicarbonate solution (10mL * 2), water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying successively; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl with tlc] Urethylane 2 (80mg; Colorless oil), productive rate: 40.0%.
MS?m/z(ESI)：546[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.99-7.66(m，2H)，7.48(m，2H)，7.21(m，2H)，7.09-6.83(m，2H)，5.67?and?5.58(2br.s，1H)，5.30?and?5.26(2br.s，1H)，4.61(m，1H)，5.83?and?5.81(2s，3H)，3.64-3.02(m，10H)，2.68?and?2.67(2s，3H)，1.78-.087(m，13H)
Embodiment 3
N-[2-[(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopropyl-benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-phenylformic acid 1v (85mg, 0.21mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (57.4mg, 0.21mmol; Adopt known method " patent WO2007070201 " preparation and get) be dissolved in 6mL N, in the dinethylformamide, adding I-hydroxybenzotriazole (57mg; 0.42mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (81mg, 0.42mmol) and N, N-diisopropylethylamine (109mg; 0.84mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; Add 25mL ETHYLE ACETATE, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 3b (137mg with tlc; White solid), productive rate: 98.8%.
Second step
N-[2-[(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopropyl-benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 3b (137mg; 0.21mmol) be dissolved in the 3mL methylene dichloride; Add the 1mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane 3 (56mg, white solid), productive rate: 48.0%.
MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.37-6.67(m，8H)，5.29(m，2H)，3.85-3.04(m，16H)，2.62(m，3H)，2.05-1.22(m，7H)，0.97(m，2H)，0.72(m，2H)
Embodiment 4
N-[2-[(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900341
The first step
5-(3-methoxy propoxy) phenyl-1,3-dicarboxylicacid methyl esters
With 5-phenol-1, (4.20g 20mmol) is dissolved in the 100mL acetone 3-dicarboxylicacid methyl esters 1h; The adding potassiumiodide (200mg, 1.68mmol), salt of wormwood (4.15g; 30mmol) with 1-bromo-3-methoxyl group-propane 4a (3.37g, 22mmol), 80 ℃ of following stirring reactions 8 hours.Reacting liquid filtering adds less water, and filtrating merges organic phase with dichloromethane extraction (150mL * 3); Water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains bullion title product 5-(3-methoxy propoxy) phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 4b (5.60g, white solid), product is not purified directly to carry out next step reaction.
Second step
3-methoxycarbonyl-5-(3-methoxy propoxy) phenylformic acid
With 5-(3-methoxy propoxy) phenyl-1, (5.60g 20mmol) is dissolved in the 50mL methyl alcohol 3-dicarboxylicacid methyl esters 4b, adds 25mL sodium hydroxide (800mg, methanol solution 20mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure adds 100mL water, with dichloromethane extraction (20mL * 3); It is 3～4 that water uses 1M hydrochloric acid to regulate pH, filters, and filter cake in vacuum is dry; Obtain title product 3-methoxycarbonyl-5-(3-methoxy propoxy) phenylformic acid 4c (2.80g, white solid), productive rate: 52.8%.
The 3rd step
3-(methylol)-5-(3-methoxy propoxy) oil of Niobe
Under the ice bath, with 3-methoxycarbonyl-5-(3-methoxy propoxy) phenylformic acid 4c (2.80g 10.5mmol) is dissolved in the 30mL THF, add the 1M borine tetrahydrofuran solution (15mL, 15mmol), stirring reaction 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 100mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-(methylol)-5-(3-methoxy propoxy) oil of Niobe 4d (2.0g, colorless oil), productive rate: 74.9%.
The 4th step
3-formyloxy-5-(3-methoxy propoxy) oil of Niobe
Under the dry ice bath, (1.00g 13.6mmol) is dissolved in the 8mL methylene dichloride with methyl-sulphoxide; Drip oxalyl chloride (1.00g; 8.16mmol), stirring reaction 50 minutes, Dropwise 5 mL 3-(methylol)-5-(3-methoxy propoxy) oil of Niobe 4d (1.7g; 6.8mmol) dichloromethane solution, stirring reaction 2.5 hours.Add triethylamine cancellation reaction, stirred 0.5 hour, add 50mL water; With dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-formyloxy-5-(3-methoxy propoxy) oil of Niobe 4e (1.50g, faint yellow oily thing), productive rate: 88.0%.
1H?NMR(400MHz，CDCl 3)：δ10.02(s，1H)，8.10(s，1H)，7.83(s，1H)，7.59(s，1H)，4.17(t，J＝8.0Hz，2H)，3.96(s，3H)，3.57(t，J＝8.0Hz，2H)，3.36(s，3H)，2.10(m，2H)
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(3-methoxy propoxy) oil of Niobe
Under the ice bath, with 3-formyloxy-5-(3-methoxy propoxy) oil of Niobe 4e (1.50g 5.92mmol) is dissolved in the 5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (12.0mL, 12.0mmol), stirring reaction 20 minutes.Add the shrend reaction of going out, the reaction solution concentrating under reduced pressure is with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(3-methoxy propoxy) oil of Niobe 4f (1.5g, faint yellow oily thing), productive rate: 69.0%.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(3-methoxy propoxy) oil of Niobe 4f (1.50g; 4.12mmol) and N-(2-hydroxyethyl) Urethylane 1t (490mg; 4.12mmol) be dissolved in the 80mL toluene; (783mg, 4.12mmol), 130 ℃ were stirred dehydration reaction 2 hours down to add tosic acid.Add 100mL ETHYLE ACETATE; With saturated sodium bicarbonate solution washing (50mL); With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) oil of Niobe 4g (720mg, yellow oil), productive rate: 37.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) oil of Niobe 4g (720mg; 1.55mmol) be dissolved in the 5mL methyl alcohol; Add sodium hydroxide (124mg, 3.1mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, and the hydrochloric acid adjusting pH that adds 1M is 3～4; With dichloromethane extraction (20mL * 3), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) phenylformic acid 4h (580mg, faint yellow oily thing), productive rate: 83.0%.
The 8th step
N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) phenylformic acid 4h (90mg, 0.20mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-(55mg 0.20mmol) is dissolved in 6mL N to N-methyl-carboxylic acid tertiary butyl ester 3a; In the N-NMF; The adding I-hydroxybenzotriazole (54mg, 0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (76.4mg; 0.4mmol) and N; The N-diisopropylethylamine (77.5mg, 0.6mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 50mL ETHYLE ACETATE, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 4i (81mg; Colorless oil), productive rate: 57.0%.MS?m/z(ESI)：606[M-100+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 4i (109mg; 0.24mmol) be dissolved in the 12mL methylene dichloride; Add the 3mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 4 (25mg, white solid), productive rate: 36.7%.
MS?m/z(ESI)：606[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.55-8.35(m，1H)，7.90-7.75(m，1H)，7.49-6.90(m，6H)，5.70(s，1H)，5.32-5.29(m?1H)，4.10(br.s，2H)，3.89-3.14(m，18H)，2.77(s，3H)，2.05-1.30(m，9H)
Embodiment 5
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl] methoxyl group] ethyl] Urethylane
The first step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(3-methoxy propoxy) phenylformic acid 4h (109mg, 0.24mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(65mg 0.24mmol) is dissolved in 6mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (65mg, 0.48mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (92mg; 0.48mmol) and N; The N-diisopropylethylamine (93mg, 0.72mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 50mL ETHYLE ACETATE, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 5a (113mg; Colorless oil), productive rate: 67.0%.
MS?m/z(ESI)：704[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 5a (112mg; 0.19mmol) be dissolved in the 12mL methylene dichloride; Add the 3mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(3-methoxy propoxy) phenyl] methoxyl group] ethyl] Urethylane 5 (70mg, white solid), productive rate: 63.0%.
MS?m/z(ESI)：604[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.8-7.6(m，2H)，7.40(m，2H)，7.2(m，2H)，6.91(m，2H)，5.70?and?5.60(2s，1H)，5.30(m，1H)，4.59(m，1H)，4.06(t，J＝6.0Hz，2H)，3.64-3.41(m，8H)，3.34(s，3H)，3.05(m，1H)，2.71(s，3H)，2.02(m，3H)，1.75-0.87(m，14H)
Embodiment 6
N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900381
The first step
5-ethoxyl phenenyl-1,3-dicarboxylicacid methyl esters
With 5-phenol-1,3-dicarboxylicacid methyl esters 1h (5.00g 23mmol) is dissolved in the 50mL acetonitrile, add salt of wormwood (4.90g, 36mmol) with iodoethane 6a (4.30g, 28mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 50mL water, with ethyl acetate extraction (80mL * 3), merges organic phase; Water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-ethoxyl phenenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 6b (4.80g, white solid), productive rate: 84.8%.
1H?NMR(400MHz，CDCl 3)：δ8.26(s，1H)，7.74(s，2H)，4.23(q，J＝8.0Hz，2H)，3.94(s，3H)，1.44(t，J＝8.0Hz，3H)
Second step
3-methoxycarbonyl-5-ethoxybenzoic acid
With 5-ethoxyl phenenyl-1, (4.80g 20mmol) is dissolved in the 50mL methyl alcohol 3-dicarboxylicacid methyl esters 6b, adds 25mL sodium hydroxide (810mg, methanol solution 20mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure adds 150mL water, with dichloromethane extraction (20mL * 3); Water is regulated pH=4～5 with 1M hydrochloric acid, filters, and filter cake in vacuum is dry; Obtain title product 3-methoxycarbonyl-5-ethoxybenzoic acid 6c (3.50g, white solid), productive rate: 78.6%.
The 3rd step
3-(methylol)-5-ethoxy-benzoic acid methyl ester
Under the ice bath, with 3-methoxycarbonyl-5-ethoxybenzoic acid 6c (3.50g 15.6mmol) is dissolved in the 20mL THF, add the 1M borine tetrahydrofuran solution (23mL, 23mmol), stirring reaction 12 hours, 60 ℃ were continued stirring reaction 5 hours down.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 100mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-(methylol)-5-ethoxy-benzoic acid methyl ester 6d (2.9g, colorless oil), productive rate: 88.0%.
The 4th step
3-formyloxy-5-ethoxy-benzoic acid methyl ester
With 3-(methylol)-5-ethoxy-benzoic acid methyl ester 6d (2.90g 13.8mmol) is dissolved in the 60mL methylene dichloride, add pyridinium chloro-chromate (5.90g, 27.6mmol) and sodium acetate (3.40g, 41.4mmol), stirring reaction 12 hours.Add 3.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyloxy-5-ethoxy-benzoic acid methyl ester 6e (2.20g, yellow solid), productive rate: 76.0% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-ethoxy-benzoic acid methyl ester
Under the ice bath, with 3-formyloxy-5-ethoxy-benzoic acid methyl ester 6e (600mg 2.9mmol) is dissolved in the 9mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (6.0mL, 6.0mmol), stirring reaction 0.5 hour.Add the shrend reaction of going out, the reaction solution concentrating under reduced pressure is with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-ethoxy-benzoic acid methyl ester 6f (729mg, colorless oil), productive rate: 79.0%.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-ethoxy-benzoic acid methyl ester
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-ethoxy-benzoic acid methyl ester 6f (729mg; 2.27mmol) and N-(2-hydroxyethyl) Urethylane 1t (542mg; 4.56mmol) be dissolved in the 50mL toluene; (431mg, 2.27mmol), 130 ℃ were stirred dehydration reaction 1.2 hours down to add tosic acid.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-ethoxy-benzoic acid methyl ester 6g (567mg, colorless oil), productive rate: 59.1%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-ethoxybenzoic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-ethoxy-benzoic acid methyl ester 6g (567mg 1.34mmol) is dissolved in the 1.5mL methyl alcohol, add Pottasium Hydroxide (151mg, 2.7mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, and the hydrochloric acid adjusting pH that adds 1M is 3～4; With dichloromethane extraction (20mL * 3), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-ethoxybenzoic acid 6h (440mg, white solid), productive rate: 80.3%.
The 8th step
N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-the 5-ethoxyl phenenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-ethoxybenzoic acid 6h (81mg, 0.20mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(70mg 0.26mmol) is dissolved in 6mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (54mg, 0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (76mg; 0.4mmol) and N; The N-diisopropylethylamine (105mg, 0.8mmol), stirring reaction 18 hours.The reaction solution concentrating under reduced pressure adds the 50mL methylene dichloride, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-ethoxyl phenenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 6i (93mg; Colorless oil), productive rate: 71.0%.
MS?m/z(ESI)：660[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-ethoxyl phenenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 6i (93mg; 0.14mmol) be dissolved in the 8mL methylene dichloride; Add the 2mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 6 (60mg, white solid), productive rate: 76.0%.
MS?m/z(ESI)：560[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.04-6.78(m，8H)，5.74?and?5.65(2s，1H)，5.32(m，1H)，4.64-4.54(m，1H)，4.07(t，J＝6.0Hz，2H)，3.67-3.05(m，9H)，2.71(s，3H)，1.81-0.91(m，16H)
Embodiment 7
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-and 3-cyclohexyl-2-methylamino-propyl group] carbamyl] 5-oxyethyl group-phenyl] methoxyl group] ethyl] Urethylane
The first step
(2S)-2-amino-3-cyclohexyl-ethyl propionate hydrochloride
Under the ice bath, (8.55g 0.050mol) is dissolved in the 70mL methyl alcohol, and (5.5mL, 0.075mol), refluxing and stirring was reacted 2 hours to drip thionyl chloride with (2S)-2-amino-3-cyclohexylpropionic acid 1a.The reaction solution concentrating under reduced pressure obtains bullion title product (2S)-2-amino-3-cyclohexyl-ethyl propionate hydrochloride 7a (13.00g, white solid), and product is not purified directly to carry out next step reaction.
Second step
(2S)-2-(t-butoxycarbonyl amino)-3-cyclohexyl-ethyl propionate
Under the ice bath; With bullion (2S)-2-amino-3-cyclohexyl-ethyl propionate hydrochloride 7a (13g; 0.050mol) be dissolved in 50mL methylene dichloride and saturated sodium bicarbonate solution (V/V=1: in the mixed solvent 2); (16.35g, 0.075mol), stirring at room was reacted 12 hours to add two dimethyl dicarbonate butyl esters.Reaction solution is with dichloromethane extraction (100mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product (2S)-2-(t-butoxycarbonyl amino)-3-cyclohexyl-ethyl propionate 7b (17g, weak yellow liquid), product is not purified directly to carry out next step reaction.
The 3rd step
N-[(1S)-and 1-(cyclohexyl methyl)-2-hydroxyl-ethyl] t-butyl carbamate
Under the ice bath, (17g 0.050mol) is dissolved in the 80mL ethanol, and (9.50g, 0.25mol), stirring at room was reacted 12 hours to add Peng Qinghuana with bullion (2S)-2-(t-butoxycarbonyl amino)-3-cyclohexyl-ethyl propionate 7b.The reaction solution concentrating under reduced pressure adds 20mL water, with ethyl acetate extraction (150mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product N-[(1S)-1-(cyclohexyl methyl)-2-hydroxyl-ethyl] t-butyl carbamate 7c (11.20g with silica gel column chromatography; Colourless liquid), productive rate: 87.0%.
MS?m/z(ESI)：158[M-100+1]
The 4th step
[(2S)-and 2-(t-butoxycarbonyl amino)-3-cyclohexyl-propyl group] methanesulfonic
Under-15 ℃; With N-[(1S)-1-(cyclohexyl methyl)-2-hydroxyl-ethyl] t-butyl carbamate 7c (6.71g, 0.026mol) and triethylamine (9.05mL 0.065mol) is dissolved in the 50mL methylene dichloride; Add methylsulfonyl chloride (4.46mL; 0.057mol), stirring reaction 0.5 hour, 0 ℃ was continued stirring reaction 1 hour down.Add less water cancellation reaction, separatory, water is with dichloromethane extraction (100mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product [(2S)-2-(t-butoxycarbonyl amino)-3-cyclohexyl-propyl group] methanesulfonic 7d (9.50g, colourless liquid), product is not purified directly to carry out next step reaction.
The 5th step
N-[(1S)-and 1-(azido-methyl)-2-cyclohexyl-ethyl] t-butyl carbamate
With bullion [(2S)-2-(t-butoxycarbonyl amino)-3-cyclohexyl-propyl group] methanesulfonic 7d (9.50g 0.026mol) is dissolved in 50mL N, in the dinethylformamide, add sodiumazide (3.39g, 0.052mol), 80 ℃ of following stirring reactions 3 hours.Add 100mL ETHYLE ACETATE, organic phase is water (50mL) and saturated nacl aqueous solution washing (50mL) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product N-[(1S)-1-(azido-methyl)-2-cyclohexyl-ethyl] t-butyl carbamate 7e (2.89g with silica gel column chromatography; Colourless liquid), productive rate: 39.0%.
The 6th step
N-[(1S)-1-(azido-methyl)-2-cyclohexyl-ethyl]-N-methyl-t-butyl carbamate
With N-[(1S)-1-(azido-methyl)-2-cyclohexyl-ethyl] t-butyl carbamate 7e (2.89g; 0.010mol) be dissolved in the 10mL THF, the sodium hydride of adding 60% (615mg, 0.015mol); Stirring reaction 0.5 hour; The adding methyl iodide (1mL, 0.016mol), stirring reaction 12 hours.Add less water cancellation reaction,, merge organic phase with ethyl acetate extraction (50mL * 3); Water (30mL) and saturated nacl aqueous solution washing (30mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product N-[(1S)-1-(azido-methyl)-2-cyclohexyl-ethyl]-N-methyl-t-butyl carbamate 7f (2.68g with silica gel column chromatography; Colourless liquid), productive rate: 90.5%.
1H?NMR(400MHz，CDCl 3)：δ4.36(m，1H)，3.38-3.11(m，2H)，2.71(s，3H)，1.87(d，J＝11.2Hz，1H)，1.70-0.85(m，12H)，1.48(s，9H)
The 7th step
N-[(1S)-1-(amino methyl)-2-cyclohexyl-ethyl]-N-methyl-t-butyl carbamate
(2.00g 6.7mmol) is dissolved in the 50mL THF, adds palladium/carbon (400mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with N-[(1S)-1-(azido-methyl)-2-cyclohexyl-ethyl]-N-methyl-t-butyl carbamate 7f.Reacting liquid filtering, concentrating under reduced pressure obtains title product N-[(1S)-1-(amino methyl)-2-cyclohexyl-ethyl]-N-methyl-t-butyl carbamate 7g (1.63g, colorless oil), productive rate: 89.0%.
The 8th step
N-[2-[[3-[[(2S)-and 2-(tertbutyloxycarbonyl (methyl) amino)-3-cyclohexyl-propyl group] carbamyl]-5-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-ethoxybenzoic acid 6h (80mg, 0.20mmol) and N-[(1S)-1-(amino methyl)-2-cyclohexyl-ethyl]-(69mg 0.26mmol) is dissolved in 4mL N to N-methyl-t-butyl carbamate 7g; In the dinethylformamide; The adding I-hydroxybenzotriazole (53mg, 0.36mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (68mg; 0.36mmol) and N; The N-diisopropylethylamine (127mg, 0.98mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; Add the 50mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-cyclohexyl-propyl group] carbamyl]-5-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 7h (93mg; White solid), productive rate: 72.0%.MS?m/z(ESI)：660[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-and 3-cyclohexyl-2-methylamino-propyl group] carbamyl] 5-oxyethyl group-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-cyclohexyl-propyl group] carbamyl]-5-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 7h (93mg; 0.14mmol) be dissolved in the 8mL methylene dichloride; Add the 3mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-3-cyclohexyl-2-methylamino-propyl group] carbamyl] 5-oxyethyl group-phenyl] methoxyl group] ethyl] Urethylane 7 (62mg, white solid), productive rate: 79.0%.
MS?m/z(ESI)：560[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.70-8.40(m，1H)，7.94-7.78(m，1H)，7.49-6.87(m，6H)，5.77(br.s，1H)，5.32-5.29(m，1H)，4.06(t，J＝8.0Hz，2H)，4.01-3.25(m，11H)，2.71(s，3H)，1.88-0.91(m，16H)
Embodiment 8
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] propyl group] carbamyl]-5-phenyl-phenyl] methoxy ethyl] Urethylane
Figure BSA00000486338900441
The first step
Biphenyl-3, the 5-dimethyl dicarboxylate
With 5-(trifluoromethyl sulfonyloxy) benzene-1, (3.00g is 8.77mmol) with phenylo boric acid 8a (1.28g for 3-dimethyl dicarboxylate 1j; 10.50mmol) be dissolved in the 80mL THF, add 40mL 2M sodium carbonate solution, 1; 1 '-two (diphenylphosphine) ferrocene Palladous chloride (II) (0.19g, 0.26mmol) with 1,1 '-two (diphenylphosphine) ferrocene (0.14g; 0.26mmol), 50 ℃ of following stirring reactions 12 hours.Reaction solution is reduced to room temperature, with ethyl acetate extraction (50mL * 3), merges organic phase; With saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product biphenyl-3 with silica gel column chromatography; 5-dimethyl dicarboxylate 8b (1.90g, white solid), productive rate: 80.0%.
MS?m/z(ESI)：271[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.65(t，J＝1.6Hz，1H)，8.46(d，J＝1.6Hz，2H)，7.69(m，2H)，7.50-7.41(m，3H)，3.98(s，6H)
Second step
Biphenyl-3,5-dicarboxylicacid-3-methyl esters
With biphenyl-3,5-dimethyl dicarboxylate 8b (1.28g, (V/V=3: in the mixed solvent 2), (0.26g, 4.7mmol), reacted 5 hours to add Pottasium Hydroxide 4.7mmol) to be dissolved in 20mL methyl alcohol and THF by refluxing and stirring.The reaction solution concentrating under reduced pressure adds 150mL water and 50mL ETHYLE ACETATE, regulates pH=6; Separatory, organic phase is with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product biphenyl-3; 5-dicarboxylicacid-3-methyl esters 8c (1.30g, white solid), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：255[M-1]
The 3rd step
5-methylol-biphenyl-3-carboxylate methyl ester
Under the ice bath, with bullion biphenyl-3,5-dicarboxylicacid-3-methyl esters 8c (600mg 2.3mmol) is dissolved in the 10mL THF, add the 1M borine tetrahydrofuran solution (3.5mL, 3.5mmol), 50 ℃ of following stirring reactions 24 hours.Add less water cancellation reaction, concentrating under reduced pressure is with ethyl acetate extraction (50mL * 3); Water (20mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-methylol-biphenyl-3-carboxylate methyl ester 8d (310mg with silica gel column chromatography; White solid), productive rate: 55.0%.
The 4th step
5-formyl radical-biphenyl-3-carboxylate methyl ester
With 5-methylol-biphenyl-3-carboxylate methyl ester 8d (310mg 1.3mmol) is dissolved in the 8mL methylene dichloride, add pyridinium chloro-chromate (551mg, 2.6mmol) and sodium acetate (315mg, 3.8mmol), stirring reaction 12 hours.Add 3.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-formyl radical-biphenyl-3-carboxylate methyl ester 8e (250mg, white solid), productive rate: 81.0% with silica gel column chromatography.
The 5th step
5-[(3-chloro-phenyl-)-hydroxyl-methyl] biphenyl methyl esters
Under the ice bath, with 5-formyl radical-biphenyl-3-carboxylate methyl ester 8e (240mg 1mmol) is dissolved in the 5mL THF, drip 0.5M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (4mL, 2mmol), stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction, concentrating under reduced pressure is with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-phenyl-oil of Niobe 8f (320mg, white solid), productive rate: 91.0%.
MS?m/z(ESI)：335[M-15]
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-phenyl-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-phenyl-oil of Niobe 8f (200mg; 0.57mmol) and N-(2-hydroxyethyl) Urethylane 1t (136mg 1.1mmol) is dissolved in the 20mL toluene, adds tosic acid (109mg; 0.57mmol), 130 ℃ were stirred dehydration reaction 3 hours down.The reaction solution concentrating under reduced pressure; With tlc with developping agent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-phenyl-oil of Niobe 8g (110mg, colourless liquid), productive rate: 42.0%.
MS?m/z(ESI)：335[M-118]
1H?NMR(400MHz，CDCl 3)：δ8.19(d，J＝1.6Hz，1H)，7.96(d，J＝1.6Hz，1H)，7.72(s，1H)，7.59(d，J＝7.0Hz，2H)，7.45(m，2H)，7.37(m，2H)，7.25(m，3H)，5.42(s，1H)，5.09(br.s，1H)，3.94(s，3H)，3.65(s，3H)，3.57(m，2H)，3.46(m，2H)
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-phenyl-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-phenyl-oil of Niobe 8g (110mg 0.24mmo1) is dissolved in the 1.5mL methyl alcohol, add sodium hydroxide (19mg, 0.49mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 20mL ETHYLE ACETATE, and the hydrochloric acid adjusting pH that adds 1M is 3～4; With dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-phenyl-phenylformic acid 8h (107mg, white solid), productive rate: 97.0%.
The 8th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-phenyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath, with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-phenyl-phenylformic acid 8h (107mg, 0.24mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester 1g (85mg; 0.32mmol) be dissolved in 5mL N, in the dinethylformamide, add I-hydroxybenzotriazole (66mg; 0.49mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (93mg, 0.49mmol) and N, N-diisopropylethylamine (119mg; 0.9mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; With tlc with developping agent system B purifying gained resistates; Obtain title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-phenyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 8i (130mg; White solid), productive rate: 77.0%.
MS?m/z(ESI)：692[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] propyl group] carbamyl]-5-phenyl-phenyl] methoxy ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-phenyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 8i (130mg; 0.19mmol) be dissolved in the 8mL methylene dichloride; Add the 2mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] propyl group] carbamyl]-5-phenyl-phenyl] methoxy ethyl] Urethylane 8 (100mg, white solid), productive rate: 90.0%.
MS?m/z(ESI)：592[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.17-7.20(m，12H)，5.60(m，1H)，5.40(s，1H)，4.60(m，1H)，3.62-2.96(m，10H)，2.65?and?2.64(2s，3H)，2.05-0.81(m，13H)
Embodiment 9
N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxy ethyl] Urethylane
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-oxyethyl group-benzoyl] amino] methyl]-2-[(3R)-and THF-3-yl] ethyl]-N-methyl-t-butyl carbamate
With N-[2-[[3-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-cyclohexyl-propyl group] carbamyl]-5-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] and Urethylane 7h (70mg, 0.17mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-(70mg 0.26mmol) is dissolved in 3mL N to N-methyl-carboxylic acid tertiary butyl ester 3a; In the dinethylformamide; The adding I-hydroxybenzotriazole (48mg, 0.35mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (67mg; 0.35mmol) and N; The N-diisopropylethylamine (111mg, 0.86mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds the 50mL methylene dichloride, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-oxyethyl group-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 9a (72mg; Colorless oil), productive rate: 65.0%.
MS?m/z(ESI)：562[M-100+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxy ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-oxyethyl group-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 9a (72mg; 0.11mmol) be dissolved in the 8mL methylene dichloride; Add the 2mL trifluoroacetic acid, stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxy ethyl] Urethylane 9 (45mg, white solid), productive rate: 75.7%.
MS?m/z(ESI)：562[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.62-8.41(m，1H)，7.94-7.77(m，1H)，7.51-7.17(m，5H)，6.95-6.90(m，1H)，5.74(s，1H)，5.33?and?5.29(2s，1H)，4.09-3.14(m，16H)，2.76and?2.74(2s，3H)，2.05-1.27(m，10H)
Embodiment 10
N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900481
The first step
5-cyclohexyl phenyl-1,3-dicarboxylicacid methyl esters
With 5-(trifluoromethyl sulfonyl) benzene-1, (2.00g is 5.85mmol) with cyclohexyl boric acid 10a (0.90g for 3-dicarboxylicacid methyl esters 1j; 7mmol) be dissolved in the 30mL toluene; Add 5mL 2M cesium carbonate (3.00g, 9.36mmol) solution and 1,1 '-two (diphenylphosphine) ferrocene Palladous chloride (II) (347mg; 0.47mmol), 110 ℃ of following stirring reactions 5 hours.Reaction solution is reduced to room temperature, adds 50mL water, with ethyl acetate extraction (50mL * 3), merges organic phase; With saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-cyclohexyl phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 10b (1.20g, white solid), productive rate: 75.0%.
Second step
3-cyclohexyl-5-methoxycarbonyl-phenylformic acid
With 5-cyclohexyl phenyl-1, (1.73g 6.3mmol) is dissolved in the 20mL acetone 3-dicarboxylicacid methyl esters 10b, adds 20mL sodium hydroxide (250mg, methanol solution 6.3mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 50mL water, and with dichloromethane extraction (50mL * 3), regulating pH is 3～4; Separate out white solid, filter vacuum-drying; Obtain title product 3-cyclohexyl-5-methoxycarbonyl-phenylformic acid 10c (1.10g, white solid), productive rate: 67.0%.
The 3rd step
3-cyclohexyl-5-(methylol) oil of Niobe
Under the ice bath, with 3-cyclohexyl-5-methoxycarbonyl-phenylformic acid 10c (1.10g 4.2mmol) is dissolved in the 20mL THF, add the 1M borine tetrahydrofuran solution (6.3mL, 6.3mmol), 50 ℃ of following stirring reactions 12 hours.Add small amount of methanol cancellation reaction, concentrating under reduced pressure adds 20mL water; With ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-cyclohexyl-5-(methylol) oil of Niobe 10d (500mg, white solid), productive rate: 70.0%.
The 4th step
3-cyclohexyl-5-formyloxy-oil of Niobe
With 3-cyclohexyl-5-(methylol) oil of Niobe 10d (500mg 2mmol) is dissolved in the 8mL methylene dichloride, add pyridinium chloro-chromate (902mg, 5.2mmol) and sodium acetate (516mg, 6.3mmol), stirring reaction 12 hours.Add 3.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-cyclohexyl-5-formyloxy-oil of Niobe 10e (316mg, colorless oil), productive rate: 31.6% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclohexyl-oil of Niobe
Under the ice bath, with 3-cyclohexyl-5-formyloxy-oil of Niobe 10e (316mg 1.28mmol) is dissolved in the 5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (3mL, 3mmol), stirring reaction 20 minutes.Add the 20mL saturated sodium bicarbonate solution, concentrating under reduced pressure is with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclohexyl-oil of Niobe 10f (509mg, white solid), product is not purified directly to carry out next step reaction.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-oil of Niobe
With bullion 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclohexyl-oil of Niobe 10f (509mg; 1.42mmol) and N-(2-hydroxyethyl) Urethylane 1t (338mg; 2.84mmol) be dissolved in the 20mL toluene; (270mg, 1.42mmol), 130 ℃ were stirred dehydration reaction 3.5 hours down to add tosic acid.The reaction solution concentrating under reduced pressure adds saturated sodium bicarbonate solution, with dichloromethane extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-oil of Niobe 10g (373mg, colourless liquid), productive rate: 57.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclohexyl-oil of Niobe 10g (373mg 0.81mmol) is dissolved in the 10mL methyl alcohol, add sodium hydroxide (81mg, 2.03mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure, the hydrochloric acid that adds 1M is regulated pH=3～4, with dichloromethane extraction (20mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-phenylformic acid 10h (388mg; White solid), product is not purified directly carries out next step reaction.
The 8th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclohexyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath, with bullion 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclohexyl-phenylformic acid 10h (100mg, 0.22mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester 1g (61mg; 0.22mmol) be dissolved in 5mL N, in the dinethylformamide, add I-hydroxybenzotriazole (61mg; 0.45mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (86mg, 0.45mmol) and N, N-diisopropylethylamine (0.2mL; 0.9mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure adds entry, with dichloromethane extraction (20mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclohexyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 10i (148mg; White solid), productive rate: 99.0%.
MS?m/z(ESI)：698[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclohexyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 10i (195mg; 0.28mmol) be dissolved in the 8mL methylene dichloride; Add 12mL trifluoroacetic acid and methylene dichloride (V/V=1: mixing solutions 2), stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 10 (100mg, white solid), productive rate: 59.0%.
MS?m/z(ESI)：598[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.72-7.18(m，8H)，5.84?and?5.70(2s，1H)，5.32?and5.29(2s，1H)，4.59(m，1H)，3.62-3.26(m，8H)，3.00(m，1H)，2.60(s，3H)，2.49(m，1H)，1.81-0.88(m，13H)
Embodiment 11
N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900511
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-benzoyl] amino] methyl]-2-[(3R)-and THF-3-yl] ethyl]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclohexyl-phenylformic acid 10h (100mg, 0.12mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-(61mg 0.22mmol) is dissolved in 3mL N to N-methyl-carboxylic acid tertiary butyl ester 3a; In the dinethylformamide; The adding I-hydroxybenzotriazole (61mg, 0.45mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (86mg; 0.45mmol) and N; The N-diisopropylethylamine (116mg, 0.90mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure; With dichloromethane extraction (50mL * 3), merge organic phase, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclohexyl-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 11a (72mg; Colorless oil), productive rate: 65.0%.
MS?m/z(ESI)：700[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclohexyl-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 11a (138mg; 0.2mmol) be dissolved in the 6mL methylene dichloride; Add 9mL and methylene dichloride (V/V=1: mixing solutions 2), stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (30mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyclohexyl-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 11 (65mg, white solid), productive rate: 55.0%.
MS?m/z(ESI)：600[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.64-7.07(m，8H)，5.69(br.s，1H)，5.31(m，1H)，3.97-3.08(m，14H)，2.64(s，3H)，2.50(m，1H)，2.00-0.86(m，17H)
Embodiment 12
N-[2-[(3-chloro-phenyl-)-[2-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900521
The first step
3-formyl radical-4-methoxyl group-oil of Niobe
3-formyl radical-4-hydroxy-benzoic acid methyl esters 12a (2.00g, 11.1mmol adopt known method " chempharm bull 1983; 31 (5), 1752 " preparation and get) is dissolved in 20mL N, in the N-NMF; Add salt of wormwood (2.30g; 16.7mmol) and methyl iodide (3.20g, 22.2mmol), stirring reaction 12 hours.Reaction solution adds the less water cancellation, and concentrating under reduced pressure is with ethyl acetate extraction (50mL * 3); Merge organic phase, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-formyl radical-4-methoxyl group-oil of Niobe 12b (1.50g, faint yellow solid), productive rate: 68.0%.
Second step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-methoxyl group-oil of Niobe
Under the ice bath, with 3-formyl radical-4-methoxyl group-oil of Niobe 12b (300mg 1.6mmol) is dissolved in the 5mL ether, drip 0.5M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (3.4mL, 1.7mmol), stirring reaction 2 hours.Add saturated sodium bicarbonate solution cancellation reaction,, add 30mL water, with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-methoxyl group-oil of Niobe 12c (340mg, white solid), productive rate: 70.0%.
MS?m/z(ESI)：307[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.07(d，J＝4.0Hz，1H)，8.00(d，J＝8.0Hz，1H)，7.38(s，1H)，7.24(m，3H)，6.90(d，J＝12.0Hz，1H)，6.03(s，1H)，3.88(s，3H)，3.86(s，3H)
The 3rd step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-methoxyl group-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-methoxyl group-oil of Niobe 12c (270mg; 0.88mmol) and N-(2-hydroxyethyl) Urethylane 1t (105mg 0.88mmol) is dissolved in the 20mL toluene, adds tosic acid (167mg; 0.88mmol), reflux water-dividing reaction 1 hour.The reaction solution concentrating under reduced pressure adds 100mL ETHYLE ACETATE, with saturated sodium bicarbonate solution washing (20mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-methoxyl group-oil of Niobe 12d (280mg, yellow oil), productive rate: 78.0%.
MS?m/z(ESI)：430[M+23]
1H?NMR(400MHz，CDCl 3)：δ8.07(s，1H)，7.97(d，J＝9.2Hz，1H)，7.36(s，1H)，7.23(m，2H)，6.89(d，J＝8.8Hz，1H)，5.71(s，1H)，5.16(s，1H)，3.89(s，3H)，3.88(s，3H)，3.66(s，3H)，3.54-3.43(m，4H)
The 4th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-methoxyl group-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-4-methoxyl group-oil of Niobe 12d (280mg 0.69mmol) is dissolved in the 1mL methyl alcohol, add sodium hydroxide (55mg, 1.38mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure, the hydrochloric acid adjusting pH that adds 1M is 3, with dichloromethane extraction (20mL * 3); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-methoxyl group-phenylformic acid 12e (270mg; Yellow oil), slightly product is directly thrown next step.
MS?m/z(ESI)：392[M-1]
The 5th step
N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath, with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-4-methoxyl group-phenylformic acid 12e (270mg, 0.69mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (186mg; 0.69mmol) be dissolved in 6mL N, in the dinethylformamide, add I-hydroxybenzotriazole (185mg; 1.4mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (263mg, 1.4mmol) and N, N-diisopropylethylamine (337mg; 2.6mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with ethyl acetate extraction (50mL * 3), merges organic phase; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system B purifying gained resistates; Obtain title product N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 12f (350mg, white solid), productive rate: 79.0%.
MS?m/z(ESI)：648[M+1]
The 6th step
N-[2-[(3-chloro-phenyl-)-[2-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2-methoxyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 12f (350mg; 0.54mmol) be dissolved in the 7.5mL methylene dichloride; Add the 2.5mL trifluoroacetic acid, stirring reaction 1 hour.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (30mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[2-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 12 (150mg, white solid), productive rate: 51.0%.
MS?m/z(ESI)：548[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.12(d，J＝4.0Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.78(br.s，1H)，7.35(s，1H)，7.18(m，3H)，6.85(d，J＝8.0Hz，1H)，5.99(s，1H)，5.30(s，1H)，3.83-3.71(m，7H)，3.48-3.34(m，3H)，3.10(m，2H)，2.54(s，3H)，2.54(s，3H)，1.91(1H)，1.79(1H)，1.60-1.48(m，4H)
Embodiment 13
N-[2-[(3-chloro-phenyl-)-[2-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900551
The first step
4-oxyethyl group-3-formyl radical-oil of Niobe
With 3-formyl radical-4-hydroxy-benzoic acid methyl esters 12a (3.50g 19.4mmol) is dissolved in 150mL N, in the dinethylformamide, add salt of wormwood (4.00g, 29.1mmol) and iodoethane (6.06g, 38.9mmol), stirring reaction 12 hours.Reaction solution adds the less water cancellation, and concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 4-oxyethyl group-3-formyl radical-oil of Niobe 13a (1.30g, white solid), productive rate: 32.2% with silica gel column chromatography.
Second step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-oxyethyl group-oil of Niobe
Under the ice bath, with 4-oxyethyl group-3-formyl radical-oil of Niobe 13a (500mg 2.4mmol) is dissolved in the 10mL THF, drip 0.5M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (5.3mL, 2.65mmol), stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction,, add 30mL water, with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-oxyethyl group-oil of Niobe 13b (360mg, white solid), productive rate: 47.0%.
1H?NMR(400MHz，CDCl 3)：δ8.10(d，J＝2.3Hz，1H)，7.95(dd，J＝2.3Hz，8.4Hz，1H)，7.39(s，1H)，7.21(m，3H)，6.85(d，J＝8.4Hz，1H)，5.98(s，1H)，4.05(m，2H)，3.87(s，3H)，1.36(t，J＝7.0Hz，3H)
The 3rd step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-oxyethyl group-oil of Niobe is with 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-4-oxyethyl group-oil of Niobe 13b (360mg; 1.13mmol) and N-(2-hydroxyethyl) Urethylane 1t (105mg; 0.88mmol) be dissolved in the 20mL toluene; (119mg, 1.13mmol), reflux water-dividing reacted 1 hour to add tosic acid.Add 100mL ETHYLE ACETATE, with saturated sodium bicarbonate solution washing (20mL * 2), anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-oxyethyl group-oil of Niobe 13c (250mg with tlc; Colorless oil), productive rate: 53.0%.
1H?NMR(400MHz，CDCl 3)：δ8.11(d，J＝2.4Hz，1H)，7.95(m，1H)，7.39(s，1H)，7.37(s，1H)，7.22(m，3H)，6.83(d，J＝8.4Hz，1H)，5.67(s，1H)，5.10(br.s，1H)，4.11(m，2H)，3.89(s，3H)，3.66(s，3H)，3.52(m，2H)，3.43(m，2H)，1.39(t，J＝7.0Hz，3H)
The 4th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-oxyethyl group-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-4-oxyethyl group-oil of Niobe 13c (250mg 0.60mmol) is dissolved in the 3mL methyl alcohol, add sodium hydroxide (196mg, 4.9mmol), 50 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, the hydrochloric acid adjusting pH that adds 1M is 2, with dichloromethane extraction (20mL * 3); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-4-oxyethyl group-phenylformic acid 13d (135mg; White solid), productive rate: 56.0%.
MS?m/z(ESI)：406[M-1]
1H?NMR(400MHz，CDCl 3)：δ8.24(s，1H)，8.05(d，J＝8.0Hz，1H)，7.42(s，1H)，7.27(m，3H)，6.90(d，J＝8.4Hz，1H)，5.72(s，1H)，5.20(br.s，1H)，4.15(m，2H)，3.71(s，3H)，3.57(m，2H)，3.48(m，2H)，1.48(t，J＝7.2Hz，3H)
The 5th step
N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath, with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-4-oxyethyl group-phenylformic acid 13d (135mg, 0.33mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (90mg; 0.33mmol) be dissolved in 6mL N, in the N-NMF, add I-hydroxybenzotriazole (90mg; 0.66mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (127mg, 0.66mmol) and N, N-diisopropylethylamine (163mg; 1.26mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with ethyl acetate extraction (50mL * 3), merges organic phase; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system B purifying gained resistates; Obtain title product N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 13e (100mg, colorless oil), productive rate: 46.0%.
MS?m/z(ESI)：662[M+1]
The 6th step
N-[2-[(3-chloro-phenyl-)-[2-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[5-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2-oxyethyl group-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 13e (100mg; 0.15mmol) be dissolved in the 6mL methylene dichloride; Add the 2mL trifluoroacetic acid, stirring reaction 1 hour.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (30mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[2-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 13 (60mg, white solid), productive rate: 71.0%.
MS?m/z(ESI)：562[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.35(br.s，1H)，8.26(s，1H)，7.88(m，1H)，7.37-7.13(m，4H)，6.79(m，1H)，5.98(s，1H)，3.99(m，2H)，3.86-3.09(m，13H)，2.63(s，3H)，1.99-1.22(m，11H)
Embodiment 14
N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900571
The first step
5-cyclopentyl phenyl-1,3-dicarboxylicacid methyl esters
With 5-(trifluoromethyl sulfonyl) benzene-1, (0.64g is 1.87mmol) with cyclopentyl boric acid 14a (256mg for 3-dicarboxylicacid methyl esters 1j; 2.24mmol) be dissolved in the 20mL toluene; Add 5mL 2M cesium carbonate (960mg, 2.94mmol) solution and 1,1 '-two (diphenylphosphine) ferrocene Palladous chloride (II) (112mg; 0.15mmol), 110 ℃ of following stirring reactions 5 hours.Reaction solution is reduced to room temperature, adds 50mL water, with ethyl acetate extraction (50mL * 3), merges organic phase; With saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-cyclopentyl phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 14b (334mg, white solid), productive rate: 68.0%.
Second step
3-cyclopentyl-5-methoxycarbonyl-phenylformic acid
With 5-cyclopentyl phenyl-1, (334mg 1.27mmol) is dissolved in the 10mL acetone 3-dicarboxylicacid methyl esters 14b, adds 10mL sodium hydroxide (51mg, methanol solution 1.27mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 30mL water, and with dichloromethane extraction (20mL * 3), regulating pH is 3～4; Separate out white solid, filter vacuum-drying; Obtain title product 3-cyclopentyl-5-methoxycarbonyl-phenylformic acid 14c (275mg, white solid), productive rate: 87.0%.
The 3rd step
3-cyclopentyl-5-(methylol) oil of Niobe
Under the ice bath, with 3-cyclopentyl-5-methoxycarbonyl-phenylformic acid 14c (275mg 1.1mmol) is dissolved in the 5mL THF, add the 1M borine tetrahydrofuran solution (2.2mL, 2.2mmol), 50 ℃ of following stirring reactions 12 hours.Add small amount of methanol cancellation reaction, concentrating under reduced pressure adds 20mL water; With ethyl acetate extraction (20mL * 3), with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-cyclopentyl-5-(methylol) oil of Niobe 14d, product is not purified directly to carry out next step reaction.
The 4th step
3-cyclopentyl-5-formyloxy-oil of Niobe
14d is dissolved in the 8mL methylene dichloride with bullion 3-cyclopentyl-5-(methylol) oil of Niobe, add pyridinium chloro-chromate (477mg, 2.2mmol) and sodium acetate (272mg, 3.3mmol), stirring reaction 12 hours.Add 3.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-cyclopentyl-5-formyloxy-oil of Niobe 14e (158mg, colorless oil), productive rate: 61.0% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopentyl-oil of Niobe
Under the ice bath, with 3-cyclopentyl-5-formyloxy-oil of Niobe 14e (158mg 0.68mmol) is dissolved in the 5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (1.36mL, 1.36mmol), stirring reaction 20 minutes.Add the 20mL saturated sodium bicarbonate solution, concentrating under reduced pressure is with ethyl acetate extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopentyl-oil of Niobe 14f (265mg, white solid), product is not purified directly to carry out next step reaction.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-oil of Niobe is with 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-cyclopentyl-oil of Niobe 14f (265mg; 0.77mmol) and N-(2-hydroxyethyl) Urethylane 1t (183mg; 1.54mmol) be dissolved in the 20mL toluene; (147mg, 0.77mmol), 130 ℃ were stirred dehydration reaction 3.5 hours down to add tosic acid.The reaction solution concentrating under reduced pressure adds saturated sodium bicarbonate solution, with dichloromethane extraction (25mL * 3); Merge organic phase, water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-oil of Niobe 14g (177mg, white solid), productive rate: 52.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-phenylformic acid is with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-oil of Niobe 14g (177mg; 0.40mmol) be dissolved in the 7mL methyl alcohol; Add sodium hydroxide (40mg; 1mmol), 50 ℃ of following stirring reactions are 12 hours.The reaction solution concentrating under reduced pressure, the hydrochloric acid adjusting pH that adds 1M is 3～4, with dichloromethane extraction (20mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-phenylformic acid 14h (257mg; White solid), bullion is directly cast the step reaction.
The 8th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopentyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath, with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopentyl-phenylformic acid 14h (100mg, 0.23mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-carboxylamine tertiary butyl ester 1g (63mg; 0.23mmol) be dissolved in 5mL N, in the dinethylformamide, under the argon atmospher; The adding I-hydroxybenzotriazole (63mg, 0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (88mg; 0.46mmol) and N; The N-diisopropylethylamine (0.2mL, 0.92mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure adds entry, with dichloromethane extraction (20mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopentyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 14i (111mg; White solid), productive rate: 71.0%.
MS?m/z(ESI)：684[M+1]
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-cyclopentyl-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 14i (111mg; 0.16mmol) be dissolved in the 10mL methylene dichloride; Add 7.5mL trifluoroacetic acid and methylene dichloride (V/V=1: mixing solutions 2), stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (50mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 14 (72mg, white solid), productive rate: 80.0%.
MS?m/z(ESI)：584[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.09-7.77(m，3H)，7.49-7.19(m，5H)，5.87?and?5.74(2s，1H)，5.32?and?5.29(2s，1H)，4.62(m，1H)，3.66(s，3H)，3.63-3.40(m，4H)，3.00-2.94(m，2H)，2.62(s，3H)，2.03(m，2H)，1.79-0.86(m，21H)
Embodiment 15
N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900601
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-benzoyl] amino] methyl]-2-[(3R)-and THF-3-yl] ethyl]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopentyl-phenylformic acid 14h (100mg, 0.23mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-(63mg 0.23mmol) is dissolved in 3mL N to N-methyl-carboxylic acid tertiary butyl ester 3a; In the dinethylformamide; The adding I-hydroxybenzotriazole (63mg, 0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (88mg; 0.46mmol) and N; The N-diisopropylethylamine (119mg, 0.92mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure; With dichloromethane extraction (50mL * 3), merge organic phase, successively water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyclopentyl-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 15a (103mg; White solid), productive rate: 71.0%.
MS?m/z(ESI)：686[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyclopentyl-benzoyl] amino] methyl]-2-[(3R)-THF-3-yl] ethyl]-N-methyl-t-butyl carbamate 15a (103mg; 0.15mmol) be dissolved in the 8mL methylene dichloride; Add 6mL and methylene dichloride (V/V=1: mixing solutions 2), stirring reaction 1.5 hours.Reaction solution is regulated pH＞7 with saturated sodium bicarbonate solution, with dichloromethane extraction (30mL * 3), merges organic phase; Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyclopentyl-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 15 (65mg, white solid), productive rate: 75.0%.
MS?m/z(ESI)：586[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.63-7.15(m，8H)，5.71(s，1H)，5.31(s，1H)，3.85-3.11(m，14H)，2.65(s，3H)，2.03-0.87(m，16H)
Embodiment 16,17
N-[2-[(R)-(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane
N-[2-[(S)-(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane
Figure BSA00000486338900611
With N-[2-[(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane 3 (200mg; 0.36mmol) carry out chiral separation; Adopt the HPLC method; With chiral column chiral isomer is separated (separation condition: chiral column Chiralcel ODH with preparation equipment; Moving phase: normal hexane: Virahol: diethylolamine=60: 40: 0.1; Flow velocity: 1.0mL/ minute); Collect its respective components, rotary evaporation removes and to desolvate, and obtains title product N-[2-[(R)-(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane 16 (95.5mg; 0.17mmol) and N-[2-[(S)-(3-chloro-phenyl-)-[3-cyclopropyl-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] oxyethyl group] Urethylane 17 (89.7mg, 0.16mmol).
16MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.16-7.07(m，8H)，5.40(s，1H)，5.30(s，1H)，3.83(m，2H)，3.64-2.98(m，12H)，2.52(s，3H)，1.91-1.19(m，8H)，0.96(m，2H)，0.73(m，2H)17MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.69-7.09(m，8H)，5.41(s，1H)，5.31(s，1H)，4.03-2.98(m，11H)，2.54(s，3H)，1.91-0.96(m，8H)，0.96(m，2H)，0.73(m，2H)
Embodiment 18
N-[2-[[3-butoxy-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Figure BSA00000486338900621
The first step
5-butyl phenyl ether-1,3-dicarboxylicacid methyl esters
Under the ice-water bath, with 5-phenol-1,3-dicarboxylicacid methyl esters 1h (2.50g, 12mmol); The 1-butanols (1.30g, 18mmol) and triphenylphosphate (4.70g 18mmol) is dissolved in 40mL1, in the 4-dioxane; (3.10g, 18mmol), stirring at room was reacted 12 hours to drip diethyl azodiformate.The reaction solution concentrating under reduced pressure, with ETHYLE ACETATE (50mL), water (50mL) and saturated nacl aqueous solution washing (50mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 5-butyl phenyl ether-1 with silica gel column chromatography, 3-dicarboxylicacid methyl esters 18a (2.90g; Yellow liquid), productive rate: 93.0%.
Second step
3-butoxy-5-methoxycarbonyl-phenylformic acid
With 5-butyl phenyl ether-1,3-dicarboxylicacid methyl esters 18a (2.90g 11.40mmol) is dissolved in the 15mL methyl alcohol, add sodium hydroxide (456mg, 11.40mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 150mL water, and with dichloromethane extraction (20mL * 3), it is 3～4 that water uses 1M hydrochloric acid to regulate pH, filters and obtains title product 3-butoxy-5-methoxycarbonyl-phenylformic acid 18b (2.03g, white solid), productive rate: 75.0%.
The 3rd step
3-butoxy-5-(methylol) oil of Niobe
Under the ice bath, with 3-butoxy-5-methoxycarbonyl-phenylformic acid 18b (2g 7.96mmol) is dissolved in the 12mL THF, add the 1M borine tetrahydrofuran solution (12mL, 12mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-butoxy-5-(methylol) oil of Niobe 18c (2g, colorless oil), product is not purified directly to carry out next step reaction.
The 4th step
3-butoxy-5-formyloxy-oil of Niobe
With bullion 3-butoxy-5-(methylol) oil of Niobe 18c (2g 8.40mmol) is dissolved in the 40mL methylene dichloride, add pyridinium chloro-chromate (5.42g, 25.20mmol) and sodium acetate (2.10g, 25.20mmol), stirring reaction 18 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-butoxy-5-formyloxy-oil of Niobe 18d (1.60g, colorless oil), productive rate: 80.8% with silica gel column chromatography.
The 5th step
3-butoxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe
Under the ice bath, with 3-butoxy-5-formyloxy-oil of Niobe 18d (1.60g 6.78mmol) is dissolved in the 14mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (14mL, 14mmol), stirring reaction 0.5 hour.Add the shrend reaction of going out, with ethyl acetate extraction (50mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product 3-butoxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe 18e (1.90g with silica gel column chromatography; Colourless liquid), productive rate: 81.0%.
The 6th step
3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe
With 3-butoxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe 18e (1.90g; 4.90mmol) and N-(2-hydroxyethyl) Urethylane 1t (1.20g 10mmol) is dissolved in the 50mL toluene, adds tosic acid (931mg; 4.90mmol), refluxing and stirring reaction 1 hour.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 18f (1.10g, colorless oil), productive rate: 50.0%.
The 7th step
3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] phenylformic acid
With 3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] oil of Niobe 18f (1.10g 2.40mmol) is dissolved in the 50mL methyl alcohol, add sodium hydroxide (200mg, 4.80mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds ETHYLE ACETATE (50mL) and water (50mL), and it is 3～4 that the hydrochloric acid soln of 6M is regulated pH; With ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] phenylformic acid 18g (810mg, white wax shape), productive rate: 81.0%.
The 8th step
N-[2-[[3-butoxy-5-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-butoxy-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] phenylformic acid 18g (104mg, 0.24mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(60mg 0.22mmol) is dissolved in 5mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (60mg, 0.44mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (84mg; 0.44mmol) and N; The N-diisopropylethylamine (142mg, 1.10mmol), stirring reaction 12 hours.Concentrating under reduced pressure; Add the 50mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[[3-butoxy-5-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 18h (118mg; Faint yellow oily thing), productive rate: 77.0%.
The 9th step
N-[2-[[3-butoxy-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-butoxy-5-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 18h (118mg; 0.17mmol) be dissolved in the 6mL methylene dichloride; Dropping 6mL contains the dichloromethane solution of 3mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (20mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[[3-butoxy-5-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 18 (46mg, white solid), productive rate: 45.0%.MS?m/z(ESI)：558.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.96-6.94(m，8H)，5.75?and?5.65(2s，1H)，5.34?and5.29(2s，1H)，4.60(m，1H)，4.01(t，J＝6.4Hz，2H)，3.67(s，3H)，3.57-3.06(m，7H)，2.72(s，3H)，1.75-0.87(m，22H)
Embodiment 19
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl] methoxyl group] ethyl] Urethylane
The first step
5-(2-methoxy ethoxy) benzene-1,3-dicarboxylicacid methyl esters
With 5-phenol-1, and 3-dicarboxylicacid methyl esters 1h (2.50g, 12mmol), 1-bromo-2-methoxyl group-ethane (2.50g; 18mmol), and salt of wormwood (3.30g, 24mmol) and potassiumiodide (0.30g; 1.8mmol) be dissolved in the 50mL acetonitrile, 50 ℃ of following stirring reactions 12 hours, 75 ℃ are continued reaction 5 hours down.Concentrating under reduced pressure obtains bullion title product 5-(2-methoxy ethoxy) benzene-1,3-dicarboxylicacid methyl esters 19a (3.05g, white solid), and product is not purified directly to carry out next step reaction.
Second step
3-methoxycarbonyl-5-(2-methoxy ethoxy) phenylformic acid
With bullion 5-(2-methoxy ethoxy) benzene-1,3-dicarboxylicacid methyl esters 19a (3g 11.20mmol) is dissolved in the 15mL methyl alcohol, add sodium hydroxide (448mg, 11.20mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 150mL water, with dichloromethane extraction (20mL * 3); It is 3～4 that water uses 1M hydrochloric acid to regulate pH, filters vacuum-drying; Obtain title product 3-methoxycarbonyl-5-(2-methoxy ethoxy) phenylformic acid 19b (2.16g, white solid), productive rate: 76.0%.
The 3rd step
3-(methylol)-5-(2-methoxy ethoxy) oil of Niobe
Under the ice bath, with 3-methoxycarbonyl-5-(2-methoxy ethoxy) phenylformic acid 19b (2.10g 8.26mmol) is dissolved in the 12mL THF, add the 1M borine tetrahydrofuran solution (12.5mL, 12.50mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-(methylol)-5-(2-methoxy ethoxy) oil of Niobe 19c (1.87g, colorless oil), product is not purified directly to carry out next step reaction.
The 4th step
3-formyloxy-5-(2-methoxy ethoxy) oil of Niobe
With bullion 3-(methylol)-5-(2-methoxy ethoxy) oil of Niobe 19c (1.87g; 7.80mmol) be dissolved in the 40mL methylene dichloride, add pyridinium chloro-chromate (5.10g, 23.60mmol) and sodium acetate (1.95g; 23.60mmol), stirring reaction 18 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyloxy-5-(2-methoxy ethoxy) oil of Niobe 19d (1.40g, colorless oil), productive rate: 76.0% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2-methoxy ethoxy) oil of Niobe
Under the ice bath, with 3-formyloxy-5-(2-methoxy ethoxy) oil of Niobe 19d (1.40g 6mmol) is dissolved in the 12mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (12mL, 12mmol), stirring reaction 0.5 hour.Add the shrend reaction of going out, with ethyl acetate extraction (50mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2-methoxy ethoxy) oil of Niobe 19e (1.80g with silica gel column chromatography; White solid), productive rate: 89.0%.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2-methoxy ethoxy) oil of Niobe 19e (1.80g; 5.17mmol) and N-(2-hydroxyethyl) Urethylane 1t (1.22g; 10.30mmol) be dissolved in the 50mL toluene; (980mg, 5.17mmol), refluxing and stirring was reacted 1 hour to add tosic acid.Concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) oil of Niobe 19f (1.20g, colorless oil), productive rate: 52.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) oil of Niobe 19f (1.20g; 2.67mmol) be dissolved in the 40mL methyl alcohol; Add sodium hydroxide (214mg, 5.35mmol), 50 ℃ of following stirring reactions 12 hours.Concentrating under reduced pressure adds methylene dichloride (50mL), and it is 3～4 that the hydrochloric acid soln of 1M is regulated pH; With dichloromethane extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains crude product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) phenylformic acid 19g (870mg; Faint yellow thick), productive rate: 75.0%.
The 8th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) phenylformic acid 19g (106mg, 0.24mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(60mg 0.22mmol) is dissolved in 5mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the N-NMF; The adding I-hydroxybenzotriazole (60mg, 0.44mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (84mg; 0.44mmol) and N; The N-diisopropylethylamine (142mg, 1.10mmol), stirring reaction 12 hours.Concentrating under reduced pressure; Add the 50mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 19h (121mg; Faint yellow oily thing), productive rate: 79.0%.
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 19h (121mg; 0.18mmol) be dissolved in the 6mL methylene dichloride; Dropping 6mL contains the dichloromethane solution of 3mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (20mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-methoxy ethoxy) phenyl] methoxyl group] ethyl] Urethylane 19 (56mg, colorless solid), productive rate: 54.0%.
MS?m/z(ESI)：590.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.91-6.88(m，8H)，5.75?and?5.65(2s，1H)，5.29?and5.24(2s，1H)，4.60(m，1H)，4.15(s，2H)，3.69-3.28(m，14H)，3.08(m，1H)，2.67(s，3H)，1.79-0.83(m，13H)
Embodiment 20
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900681
The first step
5-(cyclo propyl methoxy) benzene-1,3-dicarboxylicacid methyl esters
With 5-phenol-1, and 3-dicarboxylicacid methyl esters 1h (2.50g, 12mmol), brooethyl Trimetylene (2.40g; 17.80mmol), salt of wormwood (3.30g, 24mmol) and potassiumiodide (0.30g; 24mmol) be dissolved in the 50mL acetonitrile, 50 ℃ of stirring reactions 12 hours, 75 ℃ of reactions are 5 hours again.Concentrating under reduced pressure obtains bullion title product 5-(cyclo propyl methoxy) benzene-1,3-dicarboxylicacid methyl esters 20a (2.90g, white solid), and product is not purified directly to carry out next step reaction.
Second step
3-(cyclo propyl methoxy)-5-methoxycarbonyl-phenylformic acid
With bullion 5-(cyclo propyl methoxy) benzene-1,3-dicarboxylicacid methyl esters 20a (2.90g 11mmol) is dissolved in the 15mL methyl alcohol, add sodium hydroxide (440mg, 11mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 150mL water, with dichloromethane extraction (20mL * 3); It is 3～4 that water uses 1M salt acid for adjusting pH value; Filtration obtains title product 3-(cyclo propyl methoxy)-5-methoxycarbonyl-phenylformic acid 20b (2.20g, white solid), productive rate: 80%.
The 3rd step
3-(cyclo propyl methoxy)-5-(methylol) oil of Niobe
Under the ice bath, with 3-(cyclo propyl methoxy)-5-methoxycarbonyl-phenylformic acid 20b (2.20g 8.80mmol) is dissolved in the 13mL THF, add the 1M borine tetrahydrofuran solution (13.5mL, 13.20mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and saturated nacl aqueous solution (20mL) washing of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-(cyclo propyl methoxy)-5-(methylol) oil of Niobe 20c (1.90g, colorless oil), product is not purified directly to carry out next step reaction.
The 4th step
3-(cyclo propyl methoxy)-5-formyloxy-oil of Niobe
With bullion 3-(cyclo propyl methoxy)-5-(methylol) oil of Niobe 20c (1.90g 8mmol) is dissolved in the 40mL methylene dichloride, add pyridinium chloro-chromate (5.20g, 24mmol) and sodium acetate (1.95g, 24mmol), stirring reaction 18 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-(cyclo propyl methoxy)-5-formyloxy-oil of Niobe 20d (1.60g, colorless oil), productive rate: 85.0% with silica gel column chromatography.
The 5th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(cyclo propyl methoxy) oil of Niobe
Under the ice bath, with 3-(cyclo propyl methoxy)-5-formyloxy-oil of Niobe 20d (1.60g 6.80mmol) is dissolved in the 14mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (14mL, 14mmol), stirring reaction 0.5 hour.Add the shrend reaction of going out, with ethyl acetate extraction (50mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution (20mL) washing successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(cyclo propyl methoxy) oil of Niobe 20e (1.85g with silica gel column chromatography; Colorless oil), productive rate: 78.0%.
The 6th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(cyclo propyl methoxy) oil of Niobe 20e (1.85g; 5.30mmol) and N-(2-hydroxyethyl) Urethylane 1t (1.26g; 10.70mmol) be dissolved in the 50mL toluene; (1g, 5.30mmol), refluxing and stirring was reacted 1 hour to add tosic acid.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) oil of Niobe 20f (950mg, colorless oil), productive rate: 41.3%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) oil of Niobe 20f (950mg; 2.10mmol) be dissolved in the 30mL methyl alcohol; Add sodium hydroxide (168mg, 4.20mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds methylene dichloride (50mL), and it is 3～4 that the hydrochloric acid soln of 1M is regulated the pH value; Extraction merges organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) phenylformic acid 20g (750mg; Faint yellow thick), productive rate: 81.0%.
The 8th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(cyclo propyl methoxy) phenylformic acid 20g (100mg, 0.23mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(81mg 0.30mmol) is dissolved in 5mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (62.50mg, 0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (88.70mg; 0.46mmol) and N; The N-diisopropylethylamine (114mg, 0.88mmol), stirring reaction 12 hours.Concentrating under reduced pressure; Add 50mL ETHYLE ACETATE, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 20h (107mg; White solid), productive rate: 67.0%.
The 9th step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 20h (107mg; 0.16mmol) be dissolved in the 4mL methylene dichloride; Drip the 1mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (20mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclo propyl methoxy) phenyl] methoxyl group] ethyl] Urethylane 20 (65mg, white solid), productive rate: 71.0%.
MS?m/z(ESI)：586.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.11-6.94(m，8H)，5.75?and?5.65(2s，1H)，5.30?and5.25(2s，1H)，4.61(m，1H)，3.82(d，J＝6.8Hz，2H)，3.64-3.01(m，10H)，2.68(s，3H)，1.79-0.89(m，14H)，0.61(m，2H)，0.33(m，2H)
Embodiment 21
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-isobutoxy-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900701
Figure BSA00000486338900711
The first step
2-methyl-third-1-alcohol
Under the ice bath, with 2 methyl propanal 21a (3g 41mmol) is dissolved in the 30mL THF, add in batches Peng Qinghuana (3.10g, 82mmol), stirring reaction 4 hours.Filter, filtrate decompression concentrates, and obtains bullion title product 2-methyl-third-1-alcohol 21b (2.10g, colorless oil), and product is not purified directly to carry out next step reaction.
Second step
5-isobutyl phenyl ether-1,3-dicarboxylicacid methyl esters
Under the ice-water bath, with 5-phenol-1,3-dicarboxylicacid methyl esters 1h (2.50g; 12mmol), and bullion 2-methyl-third-1-alcohol 21b (1.30g, 18mmol) and triphenylphosphate (4.70g; 18mmol) be dissolved in 40mL1, in the 4-dioxane, drip diethyl azodiformate (3.10g; 18mmol), the stirring at room reaction is 12 hours.Concentrating under reduced pressure adds ETHYLE ACETATE (50mL), water (50mL) and saturated nacl aqueous solution washing (50mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 5-isobutyl phenyl ether-1 with silica gel column chromatography, 3-dicarboxylicacid methyl esters 21c (3g; Yellow liquid), productive rate: 94.0%.
The 3rd step
3-isobutoxy-5-methoxycarbonyl-phenylformic acid
With 5-isobutyl phenyl ether-1,3-dicarboxylicacid methyl esters 21c (3g 11.32mmol) is dissolved in the 15mL methyl alcohol, add sodium hydroxide (452mg, 11.32mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 150mL water, and with dichloromethane extraction (20mL * 3), it is 3～4 that water uses 1M salt acid for adjusting pH value, filters and obtains title product 3-isobutoxy-5-methoxycarbonyl-phenylformic acid 21d (2.20g, white solid), productive rate: 76%.
The 4th step
3-(methylol)-5-isobutoxy-oil of Niobe
Under the ice bath, with 3-isobutoxy-5-methoxycarbonyl-phenylformic acid 21d (2.20g 8.70mmol) is dissolved in the 13mL THF, add the 1M borine tetrahydrofuran solution (13mL, 13mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and saturated nacl aqueous solution (20mL) washing of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-(methylol)-5-isobutoxy-oil of Niobe 21e (2g, colorless oil), product is not purified directly to carry out next step reaction.
The 5th step
3-formyloxy-5-isobutoxy-oil of Niobe
With bullion 3-(methylol)-5-isobutoxy-oil of Niobe 21e (2g 8.40mmol) is dissolved in the 40mL methylene dichloride, add pyridinium chloro-chromate (5.40g, 25.20mmol) and sodium acetate (2.10g, 25.20mmol), stirring reaction 18 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyloxy-5-isobutoxy-oil of Niobe 21f (1.50g, colorless oil), productive rate: 76.0% with silica gel column chromatography.
The 6th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-isobutoxy-oil of Niobe
Under the ice bath, with 3-formyloxy-5-isobutoxy-oil of Niobe 21f (1.50g 6.35mmol) is dissolved in the 13mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (13mL, 12.70mmol), stirring reaction 0.5 hour.Add the shrend reaction of going out, with ethyl acetate extraction (50mL * 3), the merging organic phase; Water (15mL) and saturated nacl aqueous solution (20mL) washing successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-isobutoxy-oil of Niobe 21g (1.70g with silica gel column chromatography; Colorless oil), productive rate: 79.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-isobutoxy-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-isobutoxy-oil of Niobe 21g (1.70g; 4.90mmol) and N-(2-hydroxyethyl) Urethylane 1t (1.20g 10mmol) is dissolved in the 50mL toluene, adds tosic acid (0.93g; 4.90mmol), refluxing and stirring reaction 1 hour.Concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-isobutoxy-oil of Niobe 21h (1.20g, colorless oil), productive rate: 54.0%.
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-isobutoxy-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-isobutoxy-oil of Niobe 21h (1.40g 3.10mmol) is dissolved in the 10mL methyl alcohol, add sodium hydroxide (250mg, 6.30mmol), 50 ℃ of following stirring reactions 48 hours.Concentrating under reduced pressure adds methylene dichloride (50mL), and it is 3～4 that the hydrochloric acid soln of 1M is regulated the pH value; Extraction, the organic phase anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain crude product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-isobutoxy-phenylformic acid 21i (1.20g, faint yellow solid), productive rate: 88.0%.
The 9th step
N-[2-[[3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-isobutoxy-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-isobutoxy-phenylformic acid 21i (100mg, 0.23mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(81mg 0.30mmol) is dissolved in 5mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (62.50mg, 0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (88.70mg; 0.46mmol) and N; The N-diisopropylethylamine (114mg, 0.88mmol), stirring reaction 12 hours.Concentrating under reduced pressure; Add 50mL ETHYLE ACETATE, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-isobutoxy-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl with tlc] Urethylane 21j (116mg; White solid), productive rate: 73.4%.
The tenth step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-isobutoxy-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-isobutoxy-phenyl]-(3-chloro-phenyl-) methoxyl group] ethyl] Urethylane 21j (116mg; 0.17mmol) be dissolved in the 4mL methylene dichloride; Drip the 1mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (20mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-isobutoxy-phenyl] methoxyl group] ethyl] Urethylane 21 (95mg, white solid), productive rate: 96.0%.
MS?m/z(ESI)：588[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.05-6.82(m，8H)，5.82?and?5.69(2s，1H)，5.30?and5.25(2s，1H)，4.65(m，1H)，3.77-3.00(m，12H)，2.67(s，3H)，2.04(m，1H)，1.86-0.86(m，20H)
Embodiment 22
N-[2-[(3-chlorophenyl)-[5-[[(1S)-and (cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-7-yl]-methoxyl group] ethyl] methyl-formiate
Figure BSA00000486338900731
Figure BSA00000486338900741
The first step
7-bromo-2,3-Dihydrobenzofuranes-5-formaldehyde
Under the ice bath, with 2, (1.00g 6.76mmol) is dissolved in the 15mL acetate 3-Dihydrobenzofuranes-5-formaldehyde 22a, and (665mg, 8.1mmol), slowly dripping bromine (0.7mL, 13.5mmol), reacted 3 hours by stirring at room to add sodium acetate.Add 10mL saturated sodium thiosulfate solution and 20mL saturated sodium bicarbonate solution,, merge organic phase with ethyl acetate extraction (30mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; Obtain bullion title product 7-bromo-2; 3-Dihydrobenzofuranes-5-formaldehyde 22b (2.16g, yellow oil), product is not purified directly to carry out next step reaction.
Second step
(7-bromo-2,3-Dihydrobenzofuranes-5-yl) methyl alcohol
Under the ice bath, with bullion 7-bromo-2, (1.54g 6.76mmol) is dissolved in the 20mL ethanol 3-Dihydrobenzofuranes-5-formaldehyde 22b, and add Peng Qinghuana (257mg, 6.76mmol), stirring at room was reacted 3 hours in batches.The reaction solution concentrating under reduced pressure adds 20mL water, with ethyl acetate extraction (20mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains bullion title product (7-bromo-2,3-Dihydrobenzofuranes-5-yl) methyl alcohol 22c (1.89g; Yellow oil), product is not purified directly carries out next step reaction.
The 3rd step
(7-bromo-2,3-Dihydrobenzofuranes-5-yl) methoxyl group-tert-butyl diphenyl silane
Under the ice bath, with bullion (7-bromo-2,3-Dihydrobenzofuranes-5-yl) methyl alcohol 22c (1.89g; 8.2mmol) be dissolved in the 20mL methylene dichloride, the adding imidazoles (559mg, 8.2mmol); (2.56mL, 9.85mmol), stirring at room was reacted 12 hours slowly to drip tert-butyl diphenyl chlorosilane.Add 30mL water,, merge organic phase with dichloromethane extraction (20mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product (7-bromo-2,3-Dihydrobenzofuranes-5-yl) methoxyl group-tert-butyl diphenyl silane 22d (3.69g with silica gel column chromatography; Colorless oil), productive rate: 95.8%.
1H?NMR(400MHz，CDCl 3)：δ7.76-7.73(m，4H)，7.50-7.43(m，6H)，7.25(s，1H)，7.12(s，1H)，4.75-4.69(m，4H)，3.34(t，J＝8.8Hz，2H)，1.15(s，9H)
The 4th step
[5-[(tert-butyl diphenyl is silica-based) oxygen Ji Jia]-2,3-Dihydrobenzofuranes-7-yl]-(3-chloro-phenyl-) methyl alcohol
Under the dry ice bath, with (7-bromo-2,3-Dihydrobenzofuranes-5-yl) methoxyl group-tert-butyl diphenyl silane 22d (3.69g; 7.89mmol) be dissolved in the 30mL THF, the dropping n-Butyl Lithium (3.85mL, 7.89mmol); Stirring reaction 45 minutes; (1.07mL, tetrahydrofuran solution 9.46mmol) continued stirring reaction 1.5 hours to Dropwise 5 mL 3-chlorinated benzene formaldehyde.Add the 40mL saturated ammonium chloride solution,, merge organic phase with ethyl acetate extraction (30mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product [5-[(tert-butyl diphenyl is silica-based) oxygen Ji Jia]-2,3-Dihydrobenzofuranes-7-yl]-(3-chloro-phenyl-) methyl alcohol 22e (2.00g with silica gel column chromatography; White solid), productive rate: 48.2%.
1H?NMR(400MHz，CDCl 3)：δ7.47-7.27(m，10H)，7.14(s，1H)，6.95(s，1H)，5.93(s，1H)，4.69(s，2H)，4.66(t，J＝8.8Hz，2H)，3.24(t，J＝8.8Hz，2H)，1.09(s，9H)
The 5th step
2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ETHYLE ACETATE
Under the ice bath, (377mg 15.7mmol) is suspended in the 10mL THF with sodium hydride; Drip 6.5mL [5-[(tert-butyl diphenyl is silica-based) oxygen Ji Jia]-2,3-Dihydrobenzofuranes-7-yl]-(3-chloro-phenyl-) methyl alcohol 22e (1.52g, tetrahydrofuran solution 2.89mmol); Stirring reaction 1 hour drips 6.5mL METHYL BROMOACETATE (0.96mL, tetrahydrofuran solution 8.66mmol); Refluxing and stirring reaction 3 hours, be chilled to 0 ℃ add sodium hydride (207mg, 8.67mmol); (0.96mL, 8.66mmol), 50 ℃ were reacted 12 hours down dripping bromine ETHYLE ACETATE.Be chilled to 0 ℃, drip the 20mL saturated ammonium chloride solution, with ethyl acetate extraction (20mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains bullion title product 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2 with silica gel column chromatography; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ETHYLE ACETATE 22f (2g, colorless oil), product is not purified directly to carry out next step reaction.
1H?NMR(400MHz，CDCl 3)：δ7.72-7.68(m，4H)，7.42-7.14(m，10H)，6.90(s，2H)，5.81(s，1H)，4.61(t，J＝2.4Hz，2H)，4.29-4.11(m，6H)，3.23(t，J＝8.8Hz，2H)，1.31(m，3H)，1.09(s，9H)
The 6th step
2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] methanesulfonic ethyl ester
Under the ice bath; With bullion 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] (12.00g 18.25mmol) is dissolved in the 180mL methyl alcohol ETHYLE ACETATE 22f, adds Peng Qinghuana (6.99g in batches; 126mmol), the stirring at room reaction is 3 hours.The reaction solution concentrating under reduced pressure adds 100mL water, with ethyl acetate extraction (100mL * 3), merges organic phase, uses anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates, and it is for use to obtain product.
Under the ice bath, above-mentioned resistates is dissolved in the 150mL methylene dichloride, add successively triethylamine (7.6mL, 69.75mmol) and methane sulfonyl chloride (27mL, 182.5mmol), stirring reaction 2 hours.Add 100mL water,, merge organic phase with dichloromethane extraction (100mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; Obtain bullion title product 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] methanesulfonic ethyl ester 22g (10g, yellow oil), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：669[M+18]
The 7th step
[7-[2-azidoethyl-(3-chlorophenyl) methyl]-2,3-Dihydrobenzofuranes-5-yl] methoxyl group-tert-butyl diphenyl
Silane
With bullion 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] methanesulfonic ethyl ester 22g (628mg; 0.97mmol) be dissolved in 20mL N, in the dinethylformamide, add sodiumazide (189mg; 2.9mmol), 50 ℃ were reacted 12 hours down.Add 20mL water,, merge organic phase with ethyl acetate extraction (20mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product [7-[2-azidoethyl-(3-chlorophenyl) methyl]-2,3-Dihydrobenzofuranes-5-yl] methoxyl group-tert-butyl diphenyl silane 22h (551mg with silica gel column chromatography; Colorless oil), productive rate: 95.5%.
The 8th step
2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethamine
With [7-[2-azidoethyl-(3-chlorophenyl) methyl]-2; 3-Dihydrobenzofuranes-5-yl] methoxyl group-tert-butyl diphenyl silane 22h (551mg; 0.92mmol) be dissolved in 21mL THF and water (V/V=20: in the mixed solvent 1); The adding triphenylphosphine (968mg, 3.69mmol), stirring reaction 12 hours.Add 20mL water,, merge organic phase with ethyl acetate extraction (20mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; Obtain bullion title product 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethamine 22j (500mg, colorless oil), product is not purified directly to carry out next step reaction.
The 9th step
N-[2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] Urethylane
Under the ice bath, with bullion 2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethamine 22j (527mg; 0.92mmol) be dissolved in the 20mL methylene dichloride, (1.28mL is 9.2mmol) with 4-Dimethylamino pyridine (56mg to add triethylamine successively; 0.46mmol), stirring reaction 10 minutes drips methyl-chloroformate (0.36mL; 4.61mmol), continued stirring reaction 2 hours.Add 20mL water,, merge organic phase with ethyl acetate extraction (20mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product N-[2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] Urethylane 22k (409mg with silica gel column chromatography; Colorless oil), productive rate: 70.5%.
The tenth step
N-[2-[(3-chlorophenyl)-[5-(hydroxymethyl)-2,3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] Urethylane
With N-[2-[[5-[(tert-butyl diphenyl is silica-based) oxygen ylmethyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] Urethylane 22k (409mg; 0.65mmol) be dissolved in the 10mL THF; The adding tetrabutyl ammonium fluoride (308mg, 0.98mmol), stirring reaction 12 hours.Add 10mL water,, merge organic phase with ethyl acetate extraction (10mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain bullion title product N-[2-[(3-chlorophenyl)-[5-(hydroxymethyl)-2,3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] Urethylane 22m (254mg with silica gel column chromatography; Colorless oil), product is not purified directly carries out next step reaction.
The 11 step
N-[2-[(3-chlorophenyl)-[5-carboxaldehyde radicals-2,3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] Urethylane
Under the dry ice bath, (0.16mL 2.28mmol) is dissolved in the 10mL methylene dichloride with methyl-sulphoxide; Under the argon atmospher, slowly drip oxalyl chloride (0.12mL, 1.25mmol); Stirring reaction 1 hour, slowly Dropwise 5 mL bullion N-[2-[(3-chlorophenyl)-[5-(hydroxymethyl)-2,3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] Urethylane 22m (223mg; 0.57mmol) dichloromethane solution, continued stirring reaction 1 hour, add triethylamine (0.79mL; 5.7mmol), to react 0.5 hour, stirring reaction is 0.5 hour under the room temperature.Add 15mL water,, merge organic phase with dichloromethane extraction (10mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; Obtain bullion title product N-[2-[(3-chlorophenyl)-[5-carboxaldehyde radicals-2; 3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] Urethylane 22n (276mg, colorless oil), product is not purified directly to carry out next step reaction.
The 12 step
7-[(3-chlorophenyl)-[2-(methoxyl group formic acid is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-5-formic acid
With bullion N-[2-[(3-chlorophenyl)-[5-carboxaldehyde radicals-2; 3-Dihydrobenzofuranes-7-yl] methoxyl group] ethyl] (276mg 0.71mmol) is dissolved in the 10mL acetonitrile Urethylane 22n, adds 5mL SODIUM PHOSPHATE, MONOBASIC (863mg successively; 5.53mmol) solution; 5mL Youxiaolin (286mg, 3.16mmol) solution and 0.1mL ydrogen peroxide 50, stirring reaction 12 hours.Add 10mL water,, merge organic phase with ethyl acetate extraction (10mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; Obtain bullion title product 7-[(3-chlorophenyl)-[2-(methoxyl group formic acid is amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-5-formic acid 22p (220mg, colorless oil), product is not purified directly to carry out next step reaction.
The 13 step
N-[2-[[5-[[(1S)-and 1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] methyl-formiate
Under the ice bath, with bullion 7-[(3-chlorophenyl)-[2-(methoxyl group formic acid is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-5-formic acid 22p (100mg; 0.25mmol) be dissolved in 10mL N, in the dinethylformamide, add N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 1g (67mg successively; 0.25mmol), the 1-hydroxy benzo triazole (67mg, 0.49mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (95mg; 0.49mmol); (0.17mL, 0.94mmol), stirring at room was reacted 12 hours to drip diisopropylethylamine.Add 20mL water,, merge organic phase with dichloromethane extraction (10mL * 3); Use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product N-[2-[[5-[[(1S)-1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-2,3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl with silica gel column chromatography] methyl-formiate 22q (100mg; Colorless oil), productive rate: 61.6%.
MS?m/z(ESI)：658[M+1]
The 14 step
N-[2-[(3-chlorophenyl)-[5-[[(1S)-and (cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-7-yl]-methoxyl group] ethyl] methyl-formiate
Under the ice bath with N-[2-[[5-[[(1S)-1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-2; 3-Dihydrobenzofuranes-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] methyl-formiate 22q (120mg; 0.18mmol) be dissolved in the 4mL methylene dichloride; Drip 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Ice bath drips saturated sodium bicarbonate solution down, and regulating pH is 8, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product N-[2-[(3-chlorophenyl)-[5-[[(1S)-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-7-yl]-methoxyl group] ethyl with silica gel column chromatography] methyl-formiate 22 (15mg; White solid), productive rate: 14.7%.
MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.91-7.16(m，6H)，5.50(m，1H)，4.60(m，2H)，3.63(s，3H)，3.58-3.35(m，4H)，3.04-3.01(m，1H)，2.65(s，3H)，1.78-0.83(m，15H)
Embodiment 23
N-[2-[(3-chlorophenyl)-[5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-7-yl]-methoxyl group] ethyl] methyl-formiate
The first step
5-allyloxy benzene-1,3-dioctyl phthalate dimethyl ester
With 5-phenol-1,3-dioctyl phthalate dimethyl ester 1h (8.40g 40mmol) is dissolved in the 80mL acetone, add successively allyl bromide 98 (7.5mL, 88mmol) and salt of wormwood (12.40g, 92mmol), 70 ℃ of following stirring reactions 3 hours, 50 ℃ are continued reaction 12 hours down.Reacting liquid filtering, filtrate decompression concentrate, and obtain bullion title product 5-allyloxy benzene-1,3-dioctyl phthalate dimethyl ester 23b (10g, white solid), and product is not purified directly to carry out next step reaction.
Second step
4-allyl group-5-hydroxyl-benzene-1,3-dioctyl phthalate dimethyl ester
With bullion 5-allyloxy benzene-1, and 3-dioctyl phthalate dimethyl ester 23b (10g 40mmol) is dissolved in 50mL N, in the N-Diethyl Aniline, and 220 ℃ of following stirring reactions 5 hours.Add 40mL saturated sodium bicarbonate solution and 160mL water under the room temperature, with petroleum ether (150mL * 3), it is 4～5 that water uses 6M hydrochloric acid to regulate pH; Have solid to separate out, filter, filter cake in vacuum is dry; Obtain bullion title product 4-allyl group-5-hydroxyl-benzene-1; 3-dioctyl phthalate dimethyl ester 23c (7.00g, yellow oil), product is not purified directly to carry out next step reaction.
1H?NMR(400MHz，CDCl 3)：δ8.12(d，1H)，7.67(d，1H，J＝4Hz)，6.03(m，1H)，5.14-5.09(m，2H)，3.93(s，3H)，3.92(s，3H)，3.83(d，J＝8.0Hz，2H)
The 3rd step
5-hydroxyl-4-(3-hydroxypropyl) benzene-1,3-dioctyl phthalate dimethyl ester
Under the ice bath, with bullion 4-allyl group-5-hydroxyl-benzene-1,3-dioctyl phthalate dimethyl ester 23c (3.50g; 14mmol) be dissolved in the 60mL THF; Dropping borine tetrahydrofuran solution (28mL, 28mmol), stirring reaction 5 hours; Add 60mL saturated sodium bicarbonate solution and 7mL ydrogen peroxide 50 successively, continued stirring reaction 12 hours.Add the 60mL saturated ammonium chloride solution, concentrating under reduced pressure, water merge organic phase with ethyl acetate extraction (100mL * 3); Water (50mL) and saturated nacl aqueous solution washing (50mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 5-hydroxyl-4-(3-hydroxypropyl) benzene-1 with silica gel column chromatography; 3-dioctyl phthalate dimethyl ester 23d (3.20g, white solid), productive rate: 85.1%.
The 4th step
3,4-dihydro-2H-chromene-5,7-dioctyl phthalate dimethyl ester
With 5-hydroxyl-4-(3-hydroxypropyl) benzene-1, (1.30g 4.85mmol) is dissolved in the 25mL dioxane 3-dioctyl phthalate dimethyl ester 23d; Add diethylazodicarboxylate (1.27g successively; 7.28mmol) and triphenylphosphine (1.90g, 7.28mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 40mL ETHYLE ACETATE, and organic phase is water (30mL) and saturated nacl aqueous solution washing (30mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product 3,4-dihydro-2H-chromene-5 with silica gel column chromatography; 7-dioctyl phthalate dimethyl ester 23e (0.98g, white solid), productive rate: 81.7%.
The 5th step
7-methoxycarbonyl-3,4-dihydro-2H-chromene-5-formic acid and 5-methoxycarbonyl-3,4-dihydro-2H-chromene-7-formic acid
With 3,4-dihydro-2H-chromene-5,7-dioctyl phthalate dimethyl ester 23e (1.30g 5.2mmol) is dissolved in the 2.5mL methyl alcohol, add sodium hydroxide (0.21g, 5.2mmol), 75 ℃ of following stirring reactions 8 hours.The reaction solution concentrating under reduced pressure adds 20mL water and 30mL methylene dichloride, and dripping 1M hydrochloric acid adjusting pH is 3～4, separatory; Water merges organic phase with dichloromethane extraction (20mL * 3), uses anhydrous sodium sulfate drying, filters; Filtrate decompression concentrates, and obtains bullion title product 7-methoxycarbonyl-3,4-dihydro-2H-chromene-5-formic acid 23f and 5-methoxycarbonyl-3; 4-dihydro-2H-chromene-7-formic acid 23g (1.15g, yellow oil), product is not purified directly to carry out next step reaction.
The 6th step
5-hydroxymethyl-3,4-dihydro-2H-chromene-7-methyl-formiate and 7-hydroxymethyl-3,4-dihydro-2H-chromene-5-methyl-formiate
Under the ice bath; With bullion 7-methoxycarbonyl-3,4-dihydro-2H-chromene-5-formic acid 23f and 5-methoxycarbonyl-3,4-dihydro-2H-chromene-7-formic acid 23g (1.15g; 4.88mmol) be dissolved in the 75mL THF; Drip borine (7.3mL, tetrahydrofuran solution 7.3mmol), the 50 ℃ of following stirring reactions 12 hours of 1M.Add 2mL methyl alcohol, stirred 10 minutes, concentrating under reduced pressure adds 30mL ETHYLE ACETATE; Organic phase is used 30% solution of potassium carbonate (20mL) successively, 1M hydrochloric acid (20mL) and saturated sodium bicarbonate solution washing (20mL), and anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-hydroxymethyl-3 with silica gel column chromatography, 4-dihydro-2H-chromene-7-methyl-formiate 23h (195mg; White solid), productive rate: 18.1% and 7-hydroxymethyl-3; 4-dihydro-2H-chromene-5-methyl-formiate 23i (500mg, white solid), productive rate: 46.3%.
1H?NMR(400MHz，CDCl 3)：δ7.52(s，1H)，7.03(s，1H)，4.68(d，J＝5.6Hz，2H)，4.22(t，J＝4.8Hz，2H)，3.92(s，3H)，3.13(t，J＝6.8Hz，2H)，2.03(m，2H)
The 7th step
7-carboxaldehyde radicals-3,4-dihydro-2H-chromene-5-methyl-formiate
With 7-hydroxymethyl-3, (500mg 2.25mmol) is dissolved in the 15mL methylene dichloride 4-dihydro-2H-chromene-5-methyl-formiate 23i; Add sodium acetate (460mg successively; 6.75mmol) and pyridinium chloro-chromate (1.45g, 6.75mmol), stirring reaction 12 hours.Reaction solution is used filtered through silica gel, and filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 7-carboxaldehyde radicals-3 with silica gel column chromatography, 4-dihydro-2H-chromene-5-methyl-formiate 23j (420mg, white solid), productive rate: 84.8%.
The 8th step
7-[(3-chloro-phenyl-)-hydroxyl-methyl]-3,4-dihydro-2H-chromene-5-methyl-formiate
Under the ice bath, with 7-carboxaldehyde radicals-3,4-dihydro-2H-chromene-5-methyl-formiate 23j (430mg 1.95mmol) is dissolved in the 6mL THF, and the 3-chlorophenyl magnesium bromide of dropping 1.0M (3mL, 3mmol), stirring at room reaction 0.5 hour.Add the 20mL saturated sodium bicarbonate solution,, merge organic phase with ethyl acetate extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 7-[(3-chloro-phenyl-)-hydroxyl-methyl]-3 with silica gel column chromatography; 4-dihydro-2H-chromene-5-methyl-formiate 23k (570mg, faint yellow oily thing), productive rate: 88.1%.
The 9th step
7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-5-methyl-formiate
With 7-[(3-chloro-phenyl-)-hydroxyl-methyl]-3; 4-dihydro-2H-chromene-5-methyl-formiate 23k (570mg; 1.77mmol) be dissolved in the 30mL toluene, add successively N-(2-hydroxyethyl) Urethylane 1t (212mg, 1.77mmol) and tosic acid (338mg; 1.77mmol), refluxing and stirring reaction 1.5 hours.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3; 4-dihydro-2H-chromene-5-methyl-formiate 23m (300mg, colorless oil), productive rate: 40.4%.
The tenth step
7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-5-formic acid
With 7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3; (300mg 0.69mmol) is dissolved in the 1mL methyl alcohol 4-dihydro-2H-chromene-5-methyl-formiate 23m, adds Pottasium Hydroxide (81mg; 1.41mmol), 50 ℃ of following stirring reactions 12 hours.Add 10mL water, dripping 1M hydrochloric acid adjusting pH is 3～4, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains title product 7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-5-formic acid 23n (185mg; Faint yellow solid), productive rate: 64.0%.
The 11 step
N-[2-[[5-[[(1S)-and 1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-3,4-dihydro-2H-chromene-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] methyl-formiate
Under the ice bath, with 7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-5-formic acid 23n (85mg; 0.2mmol) be dissolved in 4mL N, in the dinethylformamide, add N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 1g (70mg successively; 0.26mmol), the 1-hydroxy benzo triazole (54mg, 0.4mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (76mg; 0.4mmol); (0.14mL, 0.8mmol), stirring at room was reacted 18 hours to drip diisopropylethylamine.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, organic phase water (20mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product N-[2-[[5-[[(1S)-1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-3; 4-dihydro-2H-chromene-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] methyl-formiate 23p (82mg, yellow oil), productive rate: 60.3%.
MS?m/z(ESI)：674[M+1]
The 12 step
N-[2-[(3-chlorophenyl)-[5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-7-yl]-methoxyl group] ethyl] methyl-formiate
Under the ice bath; With N-[2-[[5-[[(1S)-1-[(tert-butoxycarbonyl methylamino) methyl]-2-cyclohexyl-ethyl] formamyl]-3; 4-dihydro-2H-chromene-7-yl]-(3-chlorophenyl) methoxyl group] ethyl] methyl-formiate 23p (80mg; 0.12mmol) be dissolved in the 4mL methylene dichloride, drip 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1.2 hours.Drip saturated sodium bicarbonate solution, regulating pH is 8, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates; With developping agent system B purifying gained resistates, obtain title product N-[2-[(3-chlorophenyl)-[5-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-7-yl]-methoxyl group] ethyl with tlc] methyl-formiate 23 (25mg; White solid), productive rate: 36.8%.
MS?m/z(ESI)：572[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.67-7.13(m，6H)，6.72(m，1H)，5.76(br.s，1H)，5.29and?5.23(s，1H)，4.57(br.s，1H)，4.17(m，2H)，3.66?and?3.63(s，3H)，3.50-2.80(m，7H)，2.75-2.67(m，3H)，2.06-0.88(m，15H)
Embodiment 24
N-[2-[(3-chlorophenyl)-[4-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-6-yl] methoxyl group] ethyl] methyl-formiate
Figure BSA00000486338900831
The first step
2-hydroxyl-2,3-Dihydrobenzofuranes-4,6-dioctyl phthalate dimethyl ester
Under the dry ice bath, with 4-allyl group-5-hydroxyl-benzene-1,3-dioctyl phthalate dimethyl ester 23c (3.50g; 14mmol) be dissolved in the 60mL ETHYLE ACETATE, fed ozone 5 hours, bubbling air 2 hours; (3.70g, 14mmol), stirring at room was reacted 12 hours to add Tritolyl Phosphate.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 2-hydroxyl-2 with silica gel column chromatography, 3-Dihydrobenzofuranes-4,6-dioctyl phthalate dimethyl ester 24a (1.70g, light yellow solid), productive rate: 48.6%.
1H?NMR(400MHz，CDCl 3)：δ8.27(s，1H)，7.65(s，1H)，6.20(m，1H)，3.94(s，6H)，3.68(dd，J＝8.0Hz，20.0Hz，1H)，3.51(dd，J＝4.0Hz，16.0Hz，1H)
Second step
2,3-Dihydrobenzofuranes-4,6-dioctyl phthalate dimethyl ester
With 2-hydroxyl-2,3-Dihydrobenzofuranes-4,6-dioctyl phthalate dimethyl ester 24a (1.70g 6.7mmol) is dissolved in the 10mL formic acid, 100 ℃ of following stirring reactions 5 hours, and 50 ℃ were continued stirring reaction 12 hours down.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains bullion title product cumarone-4 with silica gel column chromatography, 6-dioctyl phthalate dimethyl ester 24b (1.50g, white solid), and product is not purified directly to carry out next step reaction.
The 3rd step
With bullion cumarone-4, (1.56g 6.6mmol) is dissolved in the 80mL ETHYLE ACETATE 6-dioctyl phthalate dimethyl ester 24b, adds palladium/carbon (400mg, 10%), hydrogen exchange three times, 50 ℃ of following stirring reactions 12 hours.Reacting liquid filtering, filter cake are used the 50mL methanol wash, and filtrate decompression concentrates, and obtains title product 2,3-Dihydrobenzofuranes-4,6-dioctyl phthalate dimethyl ester 24c (1.50g, white solid), productive rate: 93.7%.
1H?NMR(400MHz，CDCl 3)：δ8.25(d，J＝1.2Hz，1H)，7.61(d，J＝1.6Hz，1H)，4.71(t，J＝8.8Hz，2H)，3.97?and?3.96(2s，6H)，3.64(t，J＝8.8Hz，2H)
The 4th step
6-methoxycarbonyl-2,3-Dihydrobenzofuranes-4-formic acid and 4-methoxycarbonyl-2,3-Dihydrobenzofuranes-6-formic acid
With 2,3-Dihydrobenzofuranes-4, (1.50g 6.3mmol) is dissolved in the 3.2mL methyl alcohol 6-dioctyl phthalate dimethyl ester 24c, and (0.25g, 6.3mmol), refluxing and stirring was reacted 8 hours to add sodium hydroxide.The reaction solution concentrating under reduced pressure adds 20mL water, and dripping 1M hydrochloric acid adjusting pH is 3～4, and water is with dichloromethane extraction (20mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains bullion title product 6-methoxycarbonyl-2,3-Dihydrobenzofuranes-4-formic acid 24d and 4-methoxycarbonyl-2; 3-Dihydrobenzofuranes-6-formic acid 24e (1.32g, yellow oil), product is not purified directly to carry out next step reaction.
The 5th step
4-(methylol)-2,3-Dihydrobenzofuranes-6-methyl-formiate and 6-(methylol)-2,3-Dihydrobenzofuranes-4-methyl-formiate
Under the ice bath; With bullion 6-methoxycarbonyl-2,3-Dihydrobenzofuranes-4-formic acid 24d and 4-methoxycarbonyl-2,3-Dihydrobenzofuranes-6-formic acid 24e (1.50g; 5.85mmol) be dissolved in the 9mL THF; Drip the borine tetrahydrofuran solution (8.8mL, 8.8mmol), 50 ℃ of following stirring reactions 24 hours.Add 2mL methyl alcohol, stirred 10 minutes, concentrating under reduced pressure adds 30mL ETHYLE ACETATE; Organic phase is used 30% solution of potassium carbonate (20mL) successively, 1M hydrochloric acid (20mL) and saturated sodium bicarbonate solution (20mL) and saturated nacl aqueous solution washing (20mL), and anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 4-(methylol)-2 with silica gel column chromatography, 3-Dihydrobenzofuranes-6-methyl-formiate 24f (295mg; White solid), productive rate: 24.4%, and 6-(methylol)-2; 3-Dihydrobenzofuranes-4-methyl-formiate 24g (310mg, white solid), productive rate: 25.6%.
1H?NMR(400MHz，CDCl 3)：δ7.49(s，1H)，6.98(s，1H)，4.67(d，J＝4.4Hz，2H)，4.62(t，J＝8.8Hz，2H)，3.90s，3H)，3.52(t，J＝8.8Hz，2H)，1.60(br.s，1H)
The 6th step
6-carboxaldehyde radicals-2,3-Dihydrobenzofuranes-4-methyl-formiate
With 6-(methylol)-2,3-Dihydrobenzofuranes-4-methyl-formiate 24g (310mg 1.49mmol) is dissolved in the 15mL methylene dichloride, add successively sodium acetate (367mg, 4.47mmol) and pyridinium chloro-chromate (960mg, 4.47mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 6-carboxaldehyde radicals-2 with silica gel column chromatography, 3-Dihydrobenzofuranes-4-methyl-formiate 24h (245mg, white solid), productive rate: 79.8%.
The 7th step
6-[(3-chloro-phenyl-)-hydroxyl-methyl]-2,3-Dihydrobenzofuranes-4-methyl-formiate
Under the ice bath, with 6-carboxaldehyde radicals-2,3-Dihydrobenzofuranes-4-methyl-formiate 24h (245mg 1.19mmol) is dissolved in the 4mL THF, and the 3-chlorophenyl magnesium bromide of dropping 1.0M (1.8mL, 1.8mmol), stirring reaction 0.5 hour.Add 20mL water,, merge organic phase with ethyl acetate extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 6-[(3-chloro-phenyl-)-hydroxyl-methyl]-2 with silica gel column chromatography; 3-Dihydrobenzofuranes-4-methyl-formiate 24i (350mg, faint yellow oily thing), productive rate: 92.6%.
The 8th step
6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-methyl-formiate
With 6-[(3-chloro-phenyl-)-hydroxyl-methyl]-2; 3-Dihydrobenzofuranes-4-methyl-formiate 24i (350mg; 1.1mmol) be dissolved in the 30mL toluene, add successively N-(2-hydroxyethyl) Urethylane 1t (131mg, 1.1mmol) and tosic acid (209mg; 1.1mmol), refluxing and stirring reaction 1.5 hours.The reaction solution concentrating under reduced pressure; With eluent system A purifying gained resistates, obtain title product 6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-methyl-formiate 24j (220mg with silica gel column chromatography; Colorless oil), productive rate: 47.7%.
MS?m/z(ESI)：2385-85
1H?NMR(400MHz，CDCl 3)：δ7.37(d，J＝4.0Hz，1H)，7.31(m，2H)，7.18(m，1H)，7.12(m，1H)，6.76(s，1H)，6.29(s，1H)，4.64(t，J＝8.0Hz，2H)，4.38(t，J＝8.0Hz，8.0Hz，2H)，3.89(s，3H)，3.55(t，J＝8.0Hz，2H)，3.93(t，J＝6.0Hz，2H)
The 9th step
6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-formic acid
With 6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2; (220mg 0.53mmol) is dissolved in the 1mL methyl alcohol 3-Dihydrobenzofuranes-4-methyl-formiate 24j, adds Pottasium Hydroxide (59mg; 1.05mmol), 50 ℃ of following stirring reactions 12 hours.Add 10mL water, dripping 1M hydrochloric acid adjusting pH is 3～4, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains title product 6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-formic acid 24k (195mg; Faint yellow solid), productive rate: 92.0%.
The tenth step
N-[(2S)-2-[[6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
Under the ice bath, with 6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-4-formic acid 24k (81mg; 0.2mmol) be dissolved in 4mL N, in the dinethylformamide, add N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 1g (70mg successively; 0.26mmol), the 1-hydroxy benzo triazole (54mg, 0.4mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (76mg; 0.4mmol); (0.14mL, 0.8mmol), stirring at room was reacted 18 hours to drip diisopropylethylamine.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, organic phase water (20mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product N-[(2S)-2-[[6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-4-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 24m (67mg, colorless oil), productive rate: 51.1%.
MS?m/z(ESI)：658[M+1]
The 11 step
N-[2-[(3-chlorophenyl)-[4-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-6-yl] methoxyl group] ethyl] methyl-formiate
Under the ice bath; With N-[(2S)-2-[[6-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-4-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 24m (67mg; 0.10mmol) be dissolved in the 6mL methylene dichloride, drip 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1.2 hours.Drip saturated sodium bicarbonate solution, regulating pH is 8, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[(3-chlorophenyl)-[4-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2 with tlc; 3-Dihydrobenzofuranes-6-yl] methoxyl group] ethyl] methyl-formiate 24 (50mg, white solid), productive rate: 88.0%.
MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.76-6.66(m，7H)，5.82?and?5.75(2s，1H)，5.30?and5.25(2s，1H)，4.54(m，3H)，3.71-3.01(m，12H)，2.65(s，3H)，1.75-0.84(m，13H)
Embodiment 25
N-[2-[(3-chlorophenyl)-[7-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-5-yl]-methoxyl group] ethyl] methyl-formiate
The first step
5-carboxaldehyde radicals-3,4-dihydro-2H-chromene-7-methyl-formiate
Under the dry ice bath, (194mg 2.63mmol) is dissolved in the 5mL methylene dichloride, under the argon atmospher with methyl-sulphoxide; The dropping oxalyl chloride (334mg, 2.63mmol), stirring reaction 40 minutes; Dropwise 5 mL 5-hydroxymethyl-3,4-dihydro-2H-chromene-7-methyl-formiate 23h (195mg, dichloromethane solution 0.88mmol); Continued stirring reaction 1 hour, and added the 1.5mL triethylamine, stirring at room reaction 0.5 hour.Reacting liquid filtering, filter cake are used the 50mL washed with dichloromethane, and filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product 5-carboxaldehyde radicals-3 with silica gel column chromatography, 4-dihydro-2H-chromene-7-methyl-formiate 25a (125mg; White solid), productive rate: 64.8%.
1H?NMR(400MHz，CDCl 3)：δ10.15(s，1H)，8.01(s，1H)，7.69(s，1H)，4.23(t，J＝8.0Hz，2H)，3.94(s，3H)，3.24(t，J＝8.0Hz，2H)，2.05(m，2H)
Second step
5-[(3-chloro-phenyl-)-hydroxyl-methyl]-3,4-dihydro-2H-chromene-7-methyl-formiate
Under the ice bath, with 5-carboxaldehyde radicals-3,4-dihydro-2H-chromene-7-methyl-formiate 25a (125mg 0.57mmol) is dissolved in the 2mL THF, and the 3-chlorophenyl magnesium bromide of dropping 1.0M (1mL, 1mmol), stirring reaction 0.5 hour.Add the 20mL saturated sodium bicarbonate solution,, merge organic phase with ethyl acetate extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 5-[(3-chloro-phenyl-)-hydroxyl-methyl]-3 with silica gel column chromatography; 4-dihydro-2H-chromene-7-methyl-formiate 25b (150mg, faint yellow oily thing), productive rate: 79.4%.
The 3rd step
5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-7-methyl-formiate
With 5-[(3-chloro-phenyl-)-hydroxyl-methyl]-3; 4-dihydro-2H-chromene-7-methyl-formiate 25b (150mg; 0.45mmol) be dissolved in the 30mL toluene, add successively N-(2-hydroxyethyl) Urethylane 1t (108mg, 0.9mmol) and tosic acid (85mg; 0.45mmol), water trap back flow reaction 1.5 hours.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3; 4-dihydro-2H-chromene-7-methyl-formiate 25c (100mg, colorless oil), productive rate: 51.3%.
The 4th step
5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-7-formic acid
With 5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3; (100mg 0.23mmol) is dissolved in the 1mL methyl alcohol 4-dihydro-2H-chromene-7-methyl-formiate 25c, adds Pottasium Hydroxide (26mg; 0.46mmol), 50 ℃ of following stirring reactions 12 hours.Add 10mL water, dripping 1M hydrochloric acid adjusting pH is 3～4, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains bullion title product 5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-7-formic acid 25d (98mg; White solid), product is not purified directly carries out next step reaction.
The 5th step
N-[(2S)-2-[[5-[(3-chlorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-7-carbonyl]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
Under the ice bath, with 5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-3,4-dihydro-2H-chromene-7-formic acid 25d (98mg; 0.23mmol) be dissolved in 4mL N, in the dinethylformamide, add N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 1g (82mg successively; 0.3mmol), the 1-hydroxy benzo triazole (62mg, 0.46mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (88mg; 0.46mmol); (0.2mL, 0.8mmol), stirring at room was reacted 18 hours to drip diisopropylethylamine.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, organic phase water (20mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product N-[(2S)-2-[[5-[(3-chlorophenyl)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-3; 4-dihydro-2H-chromene-7-carbonyl]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 25e (100mg, white solid), productive rate: 64.9%.
MS?m/z(ESI)：672[M+1]
The 6th step
N-[2-[(3-chlorophenyl)-[7-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-5-yl]-methoxyl group] ethyl] methyl-formiate
Under the ice bath; With N-[(2S)-2-[[5-[(3-chlorophenyl)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-3; 4-dihydro-2H-chromene-7-carbonyl]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 25e (100mg; 0.15mmol) be dissolved in the 6mL methylene dichloride, drip 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1.2 hours.Drip saturated sodium bicarbonate solution, regulating pH is 8, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates; With developping agent system B purifying gained resistates, obtain title product N-[2-[(3-chlorophenyl)-[7-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-3,4-dihydro-2H-chromene-5-yl]-methoxyl group] ethyl with tlc] methyl-formiate 25 (38mg; White solid), productive rate: 44.7%.
MS?m/z(ESI)：572[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.90-7.70(m，2H)，7.40-7.19(m，7H)，5.80(2br.s，1H)，5.37(m，1H)，4.62(m，1H)，4.09(m，2H)，3.66-3.03(m，9H)，2.70(s，3H)，2.55-2.49(m，2H)，1.98-0.86(m，15H)
Embodiment 26
N-[2-[(3-chlorophenyl)-[6-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate
Figure BSA00000486338900891
The first step
4-formyl radical-2,3-Dihydrobenzofuranes-6-methyl-formiate
With 4-(methylol)-2,3-Dihydrobenzofuranes-6-methyl-formiate 24f (295mg 1.42mmol) is dissolved in the 20mL methylene dichloride, add successively sodium acetate (270mg, 4.25mmol) and pyridinium chloro-chromate (914mg, 4.25mmol), stirring reaction 12 hours.Reacting liquid filtering, filter cake are used the 30mL washed with dichloromethane, and filtrate decompression concentrates; With eluent system A purifying gained resistates, obtain title product 4-formyl radical-2 with silica gel column chromatography, 3-Dihydrobenzofuranes-6-methyl-formiate 26a (240mg; White solid), productive rate: 82.2%.
Second step
4-[(3-chloro-phenyl-)-hydroxyl-methyl]-2,3-Dihydrobenzofuranes-6-methyl-formiate
Under the ice bath, with 4-formyl radical-2,3-Dihydrobenzofuranes-6-methyl-formiate 26a (240mg 1.16mmol) is dissolved in the 4mL THF, and the 3-chlorophenyl magnesium bromide of dropping 1.0M (1.8mL, 1.8mmol), stirring reaction 0.5 hour.Add the 20mL saturated sodium bicarbonate solution, water merges organic phase with ethyl acetate extraction (20mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 4-[(3-chloro-phenyl-)-hydroxyl-methyl]-2 with silica gel column chromatography; 3-Dihydrobenzofuranes-6-methyl-formiate 26b (315mg, colorless oil), productive rate: 85.4%.
The 3rd step
4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-methyl-formiate
With 4-[(3-chloro-phenyl-)-hydroxyl-methyl]-2; 3-Dihydrobenzofuranes-6-methyl-formiate 26b (315mg; 0.99mmol) be dissolved in the 30mL toluene, add successively N-(2-hydroxyethyl) Urethylane 1t (238mg, 2mmol) and tosic acid (190mg; 0.99mmol), back flow reaction 1.2 hours.The reaction solution concentrating under reduced pressure; With eluent system A purifying gained resistates, obtain title product 4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-methyl-formiate 26c (280mg with silica gel column chromatography; Colorless oil), productive rate: 67.5%.
The 4th step
4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid
With 4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2; (280mg 0.66mmol) is dissolved in the 1mL methyl alcohol 3-Dihydrobenzofuranes-6-methyl-formiate 26c, adds Pottasium Hydroxide (74mg; 1.32mmol), 50 ℃ of following stirring reactions 12 hours.Add 10mL water, dripping 1M hydrochloric acid adjusting pH is 3～4, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and obtains title product 4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid 26d (250mg; Faint yellow solid), productive rate: 92.6%.
The 5th step
N-[(2S)-2-[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
Under the ice bath, with 4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid 26d (70mg; 0.17mmol) be dissolved in 4mL N, in the dinethylformamide, add N-[(2S)-2-amino-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 1g (61mg successively; 0.22mmol), the 1-hydroxy benzo triazole (66mg, 0.34mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (47mg; 0.34mmol); (0.14mL, 0.86mmol), stirring at room was reacted 18 hours to drip diisopropylethylamine.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, and organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with tlc with developping agent system B purifying gained resistates; Obtain title product N-[(2S)-2-[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-6-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 26e (71mg, white solid), productive rate: 62.8%.
MS?m/z(ESI)：658[M+1]
The 6th step
N-[2-[(3-chlorophenyl)-[6-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate
Under the ice bath; With N-[(2S)-2-[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-6-carbonyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 26e (71mg; 0.11mmol) be dissolved in the 6mL methylene dichloride, drip 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1.2 hours.Drip saturated sodium bicarbonate solution, regulating pH is 8, with dichloromethane extraction (10mL * 3); Merge organic phase, use anhydrous sodium sulfate drying, filter; Filtrate decompression concentrates, and with developping agent system B purifying gained resistates, obtains title product N-[2-[(3-chlorophenyl)-[6-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2 with tlc; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate 26 (42mg, white solid), productive rate: 70.0%.
MS?m/z(ESI)：558[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.90-7.65(m，2H)，7.43-7.22(m，5H)，5.86?and?5.74(2s，1H)，5.30(m，1H)，4.59-4.51(m，3H)，3.66-2.94(m，11H)，2.71(s，3H)，1.77-0.86(m，13H)
Embodiment 27
N-[2-[(3-chloro-phenyl-)-[5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] chroman-7-yl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900911
The first step
N-[(1S)-1-[[[7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] chroman-5-carbonyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
With 7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-3, and 4-dihydro-2H-chromene-5-formic acid 23n (30mg, 0.07mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (29mg; 0.11mmol) be dissolved in 3mL N, in the dinethylformamide, add I-hydroxybenzotriazole (19mg; 0.14mmol); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (27mg, 0.14mmol) and N, N-diisopropylethylamine (45mg; 0.35mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; Add the 25mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] chroman-5-carbonyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 27a (36mg with tlc; White oily matter), productive rate: 75.5%.
Second step
N-[2-[(3-chloro-phenyl-)-[5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] chroman-7-yl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[7-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] chroman-5-carbonyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 27a (36mg; 0.053mmol) be dissolved in the 8mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] chroman-7-yl] methoxyl group] ethyl] Urethylane 27 (13mg, white solid), productive rate: 42.0%.
MS?m/z(ESI)：574[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.11(m，1H)，7.42-6.65(m，6H)，5.60(m，1H)，5.22(m，1H)，4.11-2.70(m，21H)，1.92-1.22(m，9H)
Embodiment 28,29
N-[2-[(R)-(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane
N-[2-[(S)-(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane
With N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane 2 (300mg; 0.55mmol) carry out chiral separation; Adopt the HPLC method; With chiral column chiral isomer is separated (separation condition: chiral column ChiralcelODH with preparation equipment; Moving phase: normal hexane: Virahol: diethylolamine=60: 40: 0.1, flow velocity: 1.0mL/ minute), collect its respective components; Rotary evaporation removes and desolvates; Obtain title product N-[2-[(R)-(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane 28 (and 129.3mg, 0.24mmol) and N-[2-[(S)-(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methoxyl group-phenyl] methoxyl group] ethyl] Urethylane 29 (108.2mg, 0.20mmol).
28MS?m/z(ESI)：546[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.38-7.21(m，6H)，6.98(s，1H)，6.58(d，J＝7.2Hz，1H)，5.34(s，1H)，5.23(s，1H)，4.39(s，1H)，3.86(s，3H)，3.69(s，3H)，3.57(m，2H)，3.47(m，2H)，2.78(m，2H)，2.49(s，3H)，1.85-0.91(m，13H)
29MS?m/z(ESI)：546[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.39-7.21(m，6H)，6.98(s，1H)，6.58(d，J＝7.0Hz，1H)，5.34(s，1H)，5.23(br.s，1H)，4.39(br.s，1H)，3.86(s，3H)，3.69(s，3H)，3.57(m，2H)，3.47(m，2H)，2.80-2.73(m，2H)，2.49(s，3H)，1.88-0.92(m，13H)
Embodiment 30,31
N-[2-[(R)-(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
N-[2-[(S)-(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900931
With N-[2-[(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 4 (149mg; 0.25mmol) carry out chiral separation; Adopt the HPLC method; With chiral column chiral isomer is separated (separation condition: chiral column Chiralcel ODH with preparation equipment; Moving phase: normal hexane: Virahol: diethylolamine=60: 40: 0.1; Flow velocity: 1.0mL/ minute); Collect its respective components, rotary evaporation removes and to desolvate, and obtains title product N-[2-[(R)-(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 30 (64.6mg; 0.11mmol) and N-[2-[(S)-(3-chloro-phenyl-)-[3-(3-methoxy propoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 31 (57.8mg, 0.10mmol).
30:MS m/z (ESI): 606 [M+1], RT 12.47 minutes, ee value 100%.
31:MS m/z (ESI): 606 [M+1], RT 12.42 minutes, ee value 99.63%.
Embodiment 32,33
N-[2-[(S)-(3-chlorophenyl)-[6-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate
N-[2-[(R)-(3-chlorophenyl)-[6-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate
Figure BSA00000486338900932
With N-[2-[(3-chlorophenyl)-[6-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate 26 (150.4mg; 0.27mmol) carry out chiral separation (separation condition: chiral column Chiralpak IC; Moving phase: vinyl cyanide: Virahol: diethylolamine=95: 5: 0.1, flow velocity: 1.0mL/ minute), collect its respective components; Rotary evaporation removes and desolvates; Obtain title product N-[2-[(S)-(3-chlorophenyl)-[6-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate 32 (60.8mg, 0.11mmol) and N-[2-[(R)-(3-chlorophenyl)-[6-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] formamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] methyl-formiate 33 (54.8mg, 0.10mmol).32:MS m/z (ESI): 558 [M+1], RT 12.25 minutes, ee value 99.57%.33:MS m/z (ESI): 558 [M+1], RT 12.24 minutes, ee value 99.11%.
Embodiment 34
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-(2,2, the 2-trifluoro ethoxy) phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900941
The first step
2,2,2 tfifluoroethyl alcohol
2,2,2-trifluoroethyl methanesulfonates
Under 5 ℃, with 2,2,2 tfifluoroethyl alcohol 34a (5g 50mmol) is dissolved in the 30mL methylene dichloride, add successively triethylamine (10.10g, 100mmol) and methylsulfonyl chloride (8.60g, 75mmol), stirring at room reaction 12 hours.Reaction solution is poured in 5% the sodium hydrogen carbonate solution, stirred 15 minutes, and separatory, organic phase is used anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates, and obtains title product 2,2,2-trifluoroethyl methanesulfonates 34b (8.0g, brown oil), productive rate: 90.0%.
Second step
5-(2,2, the 2-trifluoro ethoxy) benzene-1,3-dicarboxylicacid methyl esters
With 5-phenol-1, (3g is 14.3mmol) with 2,2 for 3-dicarboxylicacid methyl esters 1h; (3.31g 18.6mmol) is dissolved in 40mL N, in the dinethylformamide to 2-trifluoroethyl methanesulfonates 34b; Add cesium carbonate (6.06g, 18.6mmol), 80 ℃ of following stirring reactions 12 hours.Reaction solution is poured in the 250mL mixture of ice and water, with ethyl acetate extraction (100mL * 3), merges organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 5-(2,2, the 2-trifluoro ethoxy) benzene-1; 3-dicarboxylicacid methyl esters 34c (2.92g, white solid), productive rate: 70.0%.
The 3rd step
3-(methoxycarbonyl)-5-(2,2, the 2-trifluoro ethoxy) phenylformic acid
With 5-(2,2, the 2-trifluoro ethoxy) benzene-1,3-dicarboxylicacid methyl esters 34c (3g 10.3mmol) is dissolved in the 50mL methyl alcohol, and adding 1M sodium hydroxide solution (10mL, 10mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 50mL water, with ethyl acetate extraction (100mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains title product 3-(methoxycarbonyl)-5-(2,2; The 2-trifluoro ethoxy) phenylformic acid 34d (2.29g, white solid), productive rate: 80.0%.
The 4th step
3-(methylol)-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe
With 3-(methoxycarbonyl)-5-(2,2, the 2-trifluoro ethoxy) phenylformic acid 34d (2.30g 8.27mmol) is dissolved in the 15mL THF, add the 1M borine tetrahydrofuran solution (12.4mL, 12.4mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure adds 50mL ETHYLE ACETATE; Use 30% solution of potassium carbonate (20mL), hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and the saturated nacl aqueous solution washing (20mL) of 1M successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and obtains bullion title product 3-(methylol)-5-(2,2; The 2-trifluoro ethoxy) oil of Niobe 34e (2.20g, faint yellow oily thing), product is not purified directly to carry out next step reaction.
The 5th step
3-formyl radical-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe
With bullion 3-(methylol)-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe 34e (2.20g 8.33mmol) is dissolved in the 30mL methylene dichloride, add pyridinium chloro-chromate (3.60g, 16.7mmol) and sodium acetate (2.05g, 25mmol), stirring reaction 12 hours.Add 3.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyl radical-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe 34f (1.54g, white solid), productive rate: 70.0% with silica gel column chromatography.
The 6th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe
Under the ice bath, with 3-formyl radical-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe 34f (1g 3.82mmol) is dissolved in the 10mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (3.82mL, 3.82mmol), stirring reaction 1 hour.Add the shrend reaction of going out, with ethyl acetate extraction (25mL * 3), the merging organic phase, water (15mL) and saturated nacl aqueous solution wash (20mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With developping agent system A purifying gained resistates, obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2,2 with tlc; The 2-trifluoro ethoxy) oil of Niobe 34g (1.19g, colorless oil), productive rate: 84.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(2; 2,2-trifluoro ethoxy) oil of Niobe 34g (500mg, 1.34mmol) and N-(2-hydroxyethyl) Urethylane 1t (316mg; 2.67mmol) be dissolved in the 25mL toluene; (267mg 1.41mmol), stirs and divides water reaction 1 hour to add tosic acid.Add 100mL ETHYLE ACETATE, with saturated sodium bicarbonate solution washing (20mL * 2), anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe 34h (285mg; Colorless oil), productive rate: 45.0%.
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) oil of Niobe 34h (280mg; 0.6mmol) be dissolved in the 1mL methyl alcohol; Add sodium hydroxide (47mg, 1.18mmol), 50 ℃ of following stirring reactions 12 hours.Add the hydrochloric acid cancellation reaction of 1M, concentrating under reduced pressure is with dichloromethane extraction (20mL * 3); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2 with silica gel column chromatography; The 2-trifluoro ethoxy) phenylformic acid 34i (220mg, white solid), product is not purified directly to carry out next step reaction.
The 9th step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) benzoyl-] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
With bullion 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2,2, the 2-trifluoro ethoxy) phenylformic acid 34i (90mg; 0.2mmol) and N-[(1S)-1-(amino methyl)-2-[(3R)-and tetrahydropyran-3-base] ethyl]-(68mg 0.25mmol) is dissolved in 3mL N, in the dinethylformamide to N-methyl-carboxylic acid tertiary butyl ester 3a; The adding I-hydroxybenzotriazole (54mg, 0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (77mg; 0.4mmol) and N; The N-diisopropylethylamine (99mg, 0.76mmol), stirring reaction 12 hours.Go into the 25mL methylene dichloride in the reaction solution, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, with tlc with developping agent system A purifying gained resistates, obtain bullion title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2; 2; The 2-trifluoro ethoxy) benzoyl-] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 34j (140mg, faint yellow oily thing), product is not purified directly to carry out next step reaction.
The tenth step
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-(2,2, the 2-trifluoro ethoxy) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With bullion N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2; 2, the 2-trifluoro ethoxy) benzoyl-] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-(90mg 0.12mmol) is dissolved in the 8mL methylene dichloride N-methyl-t-butyl carbamate 34j; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-(2 with tlc; 2; The 2-trifluoro ethoxy) phenyl] methoxyl group] ethyl] Urethylane 34 (12mg, white solid), productive rate: 14.0%.
MS?m/z(ESI)：616[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.46-7.03(m，8H)，5.33(s，1H)，5.19(s，1H)，4.39(q，J＝8.0Hz，2H)，3.86(m，2H)，3.66(s，3H)，3.56-3.38(m，7H)，3.08(m，2H)，2.74(s，1H)，2.43(s，3H)，1.90-1.21(m，7H)
Embodiment 35
N-[2-[(S)-(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900971
N-[2-[(S)-(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
With N-[2-[(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxy ethyl] Urethylane 9 (126mg; 0.22mmol) carry out chiral separation; Adopt the HPLC method; With preparation equipment and chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IC, moving phase: vinyl cyanide: Virahol: diethylolamine=95: 5: 0.1, flow velocity: 1.0mL/ divides total); Collect its respective components; Rotary evaporation removes and to desolvate, and obtains title product N-[2-[(S)-(3-chloro-phenyl-)-[3-oxyethyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] and Urethylane 35 (31mg, 0.055mmol).
Embodiment 36
N-[2-[(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900981
The first step
N-[(1S)-1-[[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carbonyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, with 4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid 26d (200mg; 0.51mmol) be dissolved in 3mL N, in the dinethylformamide, add N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (151mg successively; 0.56mmol), the 1-hydroxy benzo triazole (322mg, 2.5mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (191mg; 1mmol); (135mg, 1mmol), stirring at room was reacted 18 hours to drip diisopropylethylamine.Add the 20mL methylene dichloride in the reaction solution; Organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively, and anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; With developping agent system A purifying gained resistates, obtain title product N-[(1S)-1-[[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carbonyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 36a (292mg with tlc; Colorless oil), productive rate: 88.8%.
Second step
N-[2-[(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[4-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-6-carbonyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 36a (290mg; 0.45mmol) be dissolved in the 10mL methylene dichloride, add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; With developping agent system A purifying gained resistates, obtain title product N-[2-[(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl with tlc] Urethylane 36 (110mg; White solid), productive rate: 45.0%.
MS?m/z(ESI)：560[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.86-7.07(m，7H)，5.71(s，1H)，5.29(s，1H)，4.56(m，2H)，3.91-3.31(m，13H)，3.15-2.94(m，4H)，2.71(m，3H)，2.15-1.24(m，7H)
Embodiment 37
N-[2-[(3-chloro-phenyl-)-[3-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338900991
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxyl group-benzoyl-] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, [(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(300mg 0.76mmol) is dissolved in 10mL N to 5-methoxyl group-phenylformic acid 2g with 3-; In the dinethylformamide, add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (270mg, 0.99mmol); 1-hydroxy benzo triazole (207mg; 1.53mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (293mg, 1.5mmol), dropping diisopropylethylamine (375mg; 2.9mmol), stirring at room reaction 18 hours.The reaction solution concentrating under reduced pressure; Add the 20mL methylene dichloride, organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methoxyl group-benzoyl-] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 37a (340mg with tlc; Colorless oil), productive rate: 69.0%.MS?m/z(ESI)：648[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methoxyl group-benzoyl-] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 37a (340mg; 0.53mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-methoxyl group-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 37 (150mg, colorless oil), productive rate: 52.3%.
MS?m/z(ESI)：548[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.42-7.15(m，7H)，6.97(s，1H)，5.41(s，1H)，5.34(s，1H)，3.89(m，2H)，3.68(s，3H)，3.56-3.38(m，10H)，3.10(m，1H)，2.76(m，1H)，2.45(s，3H)，1.93-1.23(m，7H)
Embodiment 38
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbonyl is amino) phenyl] methoxyl group] ethyl] Urethylane
The first step
3-(methylol)-5-nitro-oil of Niobe
Under the ice bath, with 3-methoxycarbonyl-5-nitro-phenylformic acid 38a (10g 44.4mmol) is dissolved in the 120mL THF, add the 1M borine tetrahydrofuran solution (89mL, 89mmol), stirring reaction 12 hours.Add methyl alcohol cancellation reaction,, merge organic phase with ethyl acetate extraction (100mL * 3); Water (50mL) and saturated nacl aqueous solution washing (50mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain bullion title product 3-(methylol)-5-nitro-oil of Niobe 38b (yellow solid), product is not purified directly to carry out next step reaction.
Second step
3-formyl radical-5-nitro-oil of Niobe
With 3-(methylol)-5-nitro-oil of Niobe 38b (9.38g 44.4mmol) is dissolved in the 50mL methylene dichloride, add pyridinium chloro-chromate (19.10g, 88.8mmol) and sodium acetate (10.92g, 133.2mmol), stirring reaction 12 hours.Add 6.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyl radical-5-nitro-oil of Niobe 38c (4g, white solid), productive rate: 43.1% with silica gel column chromatography.
The 3rd step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-nitro-oil of Niobe
Under the ice bath, with 3-formyl radical-5-nitro-oil of Niobe 38c (4g 19.14mmol) is dissolved in the 40mL THF, drip 1.5M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (19.14mL, 28.71mmol), stirring reaction 1 hour.Add saturated ammonium chloride solution cancellation reaction,, merge organic phase with ethyl acetate extraction (50mL * 3); Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-nitro-oil of Niobe 38d (3.80g with silica gel column chromatography; Yellow oil), productive rate: 62.0%.
The 4th step
3-[(3-chloro-phenyl-)-(2,2,2-trichlorine acetimidoyl) oxygen-methyl]-5-nitro-oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-nitro-oil of Niobe 38d (3g 11.84mmol) is dissolved in the 40mL toluene, add Trichloroacetonitrile (8.55g, 59.2mmol) and diazabicylo (182.7mg, 1.2mmol), stirring reaction 3 hours.The reaction solution concentrating under reduced pressure with ethyl acetate extraction (50mL * 3), merges organic phase, successively water (15mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 3-[(3-chloro-phenyl-)-(2,2 with silica gel column chromatography; 2-trichlorine acetimidoyl) oxygen-methyl]-5-nitro-oil of Niobe 38e (3g, yellow oil), productive rate: 54.3%.
The 5th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-nitro-oil of Niobe
With 3-[(3-chloro-phenyl-)-(2; 2,2-trichlorine acetimidoyl) oxygen-methyl]-5-nitro-oil of Niobe 38e (3g, 6.44mmol) and N-(2-hydroxyethyl) Urethylane 1t (760mg; 6.44mmol) be dissolved in the 50mL methylene dichloride; The adding trifluoromethyl sulfonic acid trimethylsilyl ester (1.43g, 6.44mmol), stirring reaction 1 hour.With saturated sodium bicarbonate solution cancellation reaction,, merge organic phase with dichloromethane extraction (100mL * 3); Water (20mL) and saturated nacl aqueous solution washing (10mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-nitro-oil of Niobe 38f (1g with silica gel column chromatography; Colorless oil), productive rate: 37.0%.
The 6th step
3-amino-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-nitro-oil of Niobe 38f (1g 2.38mmol) is dissolved in the 50mL methyl alcohol, add Raney Ni (250mg, 0.60mmol), hydrogen exchange three times, stirring reaction 4 hours.Reacting liquid filtering, filtrate decompression concentrates, and obtains title product 3-amino-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 38g (800mg, colorless oil), productive rate: 80.0%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) oil of Niobe
Under the ice bath; With 3-amino-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 38g (300mg; 0.77mmol) and triethylamine (154.53mg 1.53mmol) is dissolved in the 50mL methylene dichloride, drips the ring third formyl chloride (80.5mg; 0.77mmol), stirring at room reaction 12 hours.Water cancellation reaction with dichloromethane extraction (50mL * 3), merges organic phase; Water (20mL) and saturated nacl aqueous solution washing (10mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) oil of Niobe 38h (280mg with silica gel column chromatography; Faint yellow oily thing), productive rate: 79.3%.MS?m/z(ESI)：483[M+23]
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) phenylformic acid
Under the ice bath; With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) oil of Niobe 38h (280mg; 0.61mmol) be dissolved in the 15mL THF; Add 15mL sodium hydroxide (24.34mg, methanol solution 0.61mmol), stirring at room reaction 12 hours.It is 2～3 that reaction solution uses the salt acid for adjusting pH value of 1M; With ethyl acetate extraction (20mL * 3), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) phenylformic acid 38i (240mg, faint yellow solid), productive rate: 88.4%.
MS?m/z(ESI)：446[M+1]
The 9th step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) phenylformic acid 38i (240mg, 0.54mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(190.4mg 0.7mmol) is dissolved in 10mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (146mg, 1.08mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (207mg; 1.08mmol) and N; The N-diisopropylethylamine (265mg, 2.05mmol), stirring reaction 12 hours.Add 50mL water; With dichloromethane extraction (30mL * 3), water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl amino) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 38j (230mg with silica gel column chromatography; Faint yellow oily thing), productive rate: 61.2%.
MS?m/z(ESI)：699[M+1]
The tenth step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbonyl is amino) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(cyclopropyl carbonyl is amino) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 38j (230mg; 0.33mmol) be dissolved in the 8mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, regulating pH is 7～8, with dichloromethane extraction (10mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbonyl amino) phenyl] methoxyl group] ethyl with tlc] Urethylane 38 (140mg; Colorless oil), productive rate: 71.1%.
MS?m/z(ESI)：599[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.76-7.01(m，9H)，6.10(m，1H)，5.23(m，1H)，4.65(m，1H)，3.69-2.81(m，13H)，1.67-0.78(m，13H)
Embodiment 39
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbamyl) phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901031
The first step
Between benzene tricarbonic acid's methyl esters
Under the ice bath, with 1,3,5-Benzenetricarboxylic acid 39a (15g 0.07mol) is dissolved in the 200mL methylene dichloride, add methylsulfonyl chloride (15.5mL, 0.21mol), 60 ℃ of following stirring reactions 3 hours.The reaction solution concentrating under reduced pressure adds less water cancellation reaction, separatory, and water is with dichloromethane extraction (200mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain benzene tricarbonic acid's methyl esters 39b (17g, white solid) between title product, 94.0%.
1H?NMR(400MHz，CDCl 3)：δ8.87(s，3H)，3.99(S，9H).
Second step
3,5-two (methoxycarbonyl) phenylformic acid
Will between benzene tricarbonic acid's methyl esters 39b (3g 11.9mmol) is dissolved in the 30mL acetone, adds 20mL sodium hydroxide (476mg, methanol solution 11.9mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 50mL water, and with dichloromethane extraction (100mL * 3), it is 2～3 that water uses the salt acid for adjusting pH value of 1M; Separate out white solid, filter, solid vacuum-drying obtains title product 3; 5-two (methoxycarbonyl) phenylformic acid 39c (2.3g, white solid), productive rate: 82.0%.
MS?m/z(ESI)：237[M+1]
The 3rd step
5-(methylol) phenyl-1,3-dicarboxylicacid methyl esters
With 3,5-two (methoxycarbonyl) phenylformic acid 39c (11.30g 47mmol) is dissolved in the 50mL THF, add the 1M borine tetrahydrofuran solution (71mL, 71mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 5-(methylol) phenyl-1,3-dicarboxylicacid methyl esters 39d (6g, white solid), productive rate: 55.5% with silica gel column chromatography.
The 4th step
5-formyl radical phenyl-1,3-dicarboxylicacid methyl esters
With 5-(methylol) phenyl-1,3-dicarboxylicacid methyl esters 39d (5.89g 26mmol) is dissolved in the 50mL methylene dichloride, add pyridinium chloro-chromate (11.30g, 53mmol) and sodium acetate (6.47g, 79mmol), stirring reaction 12 hours.Add 6.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-formyl radical phenyl-1,3-dicarboxylicacid methyl esters 39e (4.04g, white solid), productive rate: 70.0% with silica gel column chromatography.
The 5th step
5-[(3-chloro-phenyl-)-hydroxyl-methyl] phenyl-1,3-dicarboxylicacid methyl esters
Under the ice bath, with 5-formyl radical phenyl-1,3-dicarboxylicacid methyl esters 39e (4.06g 70mmol) is dissolved in the 50mL THF, and the tetrahydrofuran solution of dropping 1M 3-chloro-phenyl-magnesium bromide (140mL, 140mmol), stirring reaction 1 hour.Add saturated ammonium chloride solution cancellation reaction,, merge organic phase with ethyl acetate extraction (50mL * 3); Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-[(3-chloro-phenyl-)-hydroxyl-methyl] phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 39f (4.62g, faint yellow oily thing), productive rate: 77.0%.
The 6th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxycarbonyl-phenylformic acid
With 5-[(3-chloro-phenyl-)-hydroxyl-methyl] phenyl-1,3-dicarboxylicacid methyl esters 39f (2.92g, 8.76mmol) be dissolved in 40mL first alcohol and water (V/V=3: in the mixed solvent 1), add lithium hydroxide solution (368mL, 8.76mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds less water cancellation reaction, separatory, and regulating the pH value is 4; With ethyl acetate extraction (150mL * 3), merge organic phase, successively water (30mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxycarbonyl-phenylformic acid 39g (2.78g, colorless oil), 99.9%.
The 7th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(methylol) oil of Niobe
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methoxycarbonyl-phenylformic acid 39g (3g 9.4mmol) is dissolved in the 50mL THF, add the 1M borine tetrahydrofuran solution (14mL, 14.1mmol), 50 ℃ of following stirring reactions 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure is with ethyl acetate extraction (150mL * 3); Merge organic phase, water (30mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains bullion title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(methylol) oil of Niobe 39h (2.86g; Colorless oil), product is not purified directly carries out next step reaction.
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(methylol) oil of Niobe
With bullion 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-(methylol) oil of Niobe 39h (2.77g; 9.1mmol) and N-(2-hydroxyethyl) Urethylane 1t (2.15g 18.1mmol) is dissolved in the 50mL toluene, adds tosic acid (1.72g; 9.1mmol), refluxing and stirring reaction 3 hours.The reaction solution concentrating under reduced pressure with ethyl acetate extraction (30mL * 3), merges organic phase; Water (20mL) and saturated nacl aqueous solution washing (10mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(methylol) oil of Niobe 39i (890mg with silica gel column chromatography; Colorless oil), productive rate: 24.0%.
The 9th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-formyl radical-oil of Niobe
[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(890mg 2.19mmol) is dissolved in the 30mL methylene dichloride 5-(methylol) oil of Niobe 39i, adds (1 with 3-; 1; 1-triacetyl oxygen base)-1,1-dihydro-1,2-benzenesulfonyl-3 (1H)-ketone (1.11g; 2.62mmol), stirring reaction 3 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure is with ethyl acetate extraction (80mL * 3); Merge organic phase, water (30mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-formyl radical-oil of Niobe 39j (500mg, colorless oil), productive rate: 56.0%.
The tenth step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxycarbonyl-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-formyl radical-oil of Niobe 39j (500mg; 1.23mmol) be dissolved in the 20mL acetonitrile; Add 10mL SODIUM PHOSPHATE, MONOBASIC (1.5mg, 9.6mmol) solution, 10mL Youxiaolin (494mg successively; 5.49mmol) solution and 0.6mL ydrogen peroxide 50, stirring reaction 12 hours.Add 10mL water,, merge organic phase with ethyl acetate extraction (20mL * 3); Water (10mL) and saturated nacl aqueous solution washing (10mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methoxycarbonyl-phenylformic acid 39k (520mg, white solid) bullion, product is not purified directly to carry out next step reaction.
The 11 step
3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methoxycarbonyl-phenylformic acid 39k (518mg, 1.23mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(365mg 1.35mmol) is dissolved in 4mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (332mg, 2.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (472mg; 2.46mmol) and N; The N-diisopropylethylamine (1mL, 4.92mmol), stirring reaction 12 hours.Add 50mL water; With dichloromethane extraction (30mL * 3), water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl with silica gel column chromatography]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] oil of Niobe 39m (585mg; White oily matter), productive rate: 66.0%.
The 12 step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(cyclopropyl carbamyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 39m (195mg; 0.29mmol) be dissolved in the 10mL methyl alcohol; Add cyclopropylamine (165mg; 2.9mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure; With tlc with developping agent system B purifying gained resistates; Obtain title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(cyclopropyl carbamyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 39n (25mg; Yellow), productive rate: 12.0%.MS?m/z(ESI)：699[M+1]
The 13 step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbamyl) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(cyclopropyl carbamyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 39n (30mg; 0.14mmol) be dissolved in the 2mL methylene dichloride; Add 3mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, regulating pH is 7～8, with dichloromethane extraction (10mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(cyclopropyl carbamyl) phenyl] methoxyl group] ethyl with tlc] Urethylane 39 (5mg; White solid), productive rate: 25.0%.
MS?m/z(ESI)：599[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.57-7.86(m，5H)，7.31-7.18(m，4H)，5.64-5.54(m，1H)，5.34(m，1H)，4.64(m，1H)，3.71-2.69(m，5H)，1.72-0.76(m，13H)
Embodiment 40
N-[2-[(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901081
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy)
Benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, [(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(150mg 0.34mmol) is dissolved in 10mL N to 5-(2-methoxy ethoxy) phenylformic acid 19g with 3-; In the dinethylformamide, add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (103mg, 0.38mmol); 1-hydroxy benzo triazole (55mg; 0.41mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (78mg, 0.41mmol), dropping diisopropylethylamine (132mg; 1.02mmol), stirring at room reaction 18 hours.The reaction solution concentrating under reduced pressure; Add the 20mL methylene dichloride, organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 40a (120mg with tlc; Colorless oil), productive rate: 51.1%.
MS?m/z(ESI)：692[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-methoxy ethoxy) benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 40a (100mg; 0.15mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 40 (61mg, white solid), productive rate: 71.7%.
MS?m/z(ESI)：592[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.47-6.93(m，8H)，5.67(s，1H)，5.29?and?5.25(2s，1H)，4.14(m，2H)，3.98-3.11(m，19H)，2.71(m，3H)，2.01-1.26(m，7H)
Embodiment 41
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-hydroxyethylamino formyl) phenyl] methoxyl group] ethylidene dicarbamate
Figure BSA00000486338901091
The first step
3-[[(1S)-and 1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] phenylformic acid
With 3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 39m (585mg; 0.87mmol) be dissolved in 12mL first alcohol and water (V/V=3: in the mixed solvent 1); Add lithium hydroxide solution (73mg; 1.74mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, using the lemon acid for adjusting pH value is 6～7, adds 10mL water; With ethyl acetate extraction (10mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl with silica gel column chromatography]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl] phenylformic acid 41a (110mg; Colourless viscous liquid), 20.0%.
Second step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-hydroxyethylamino formyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-carbamyl tert-butyl ester
With 3-[[(1S)-1-[(tertbutyloxycarbonyl (methyl) amino) methyl]-2-cyclohexyl-ethyl] carbamyl]-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] phenylformic acid 41a (110mg; 0.17mmol) be dissolved in the 10mL methyl alcohol, the adding thanomin (20mg, 0.33mmol); 1-hydroxy benzo triazole (45mg; 0.33mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (64mg, 0.33mmol), dropping diisopropylethylamine (0.12mL; 0.67mmol), stirring reaction 12 hours.The cancellation of reaction solution water; With ethyl acetate extraction (10mL * 3); Merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, reaction solution concentrating under reduced pressure; With tlc with developping agent system B purifying gained resistates; Obtain title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-hydroxyethylamino formyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-carbamyl tert-butyl ester 41b (65mg, white solid), productive rate: 56.0%.
MS?m/z(ESI)：704[M+1]
The 3rd step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-hydroxyethylamino formyl) phenyl] methoxyl group] ethylidene dicarbamate
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-hydroxyethylamino formyl) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-carbamyl tert-butyl ester 41b (65mg; 0.09mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-hydroxyethylamino formyl) phenyl] methoxyl group] ethylidene dicarbamate 41 (35mg, white solid), productive rate: 63.0%.
MS?m/z(ESI)：603[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.92-6.90(m，9H)，5.80(s，1H)，5.38(m，1H)，4.69(s，1H)，3.93-2.73(m，15H)，2.02-0.87(m，13H)
Embodiment 42
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901101
Figure BSA00000486338901111
The first step
5-chloro sulfonyl-phenyl-1,3-dicarboxylicacid methyl esters
Under the ice bath, with 3,5-two (methoxycarbonyl) phenylbenzimidazole sulfonic acid sodium 42a (5g 16.89mmol) is dissolved in 10mLN, in the dinethylformamide, adds the 5mL acetonitrile, drip POCl3 (5mL, 55mmol), 70 ℃ of following stirring reactions 4 hours.Reaction solution adds in the 200mL frozen water, stirs 1 hour, filters, and obtains white solid, and vacuum-drying obtains title product 5-chloro sulfonyl-phenyl-1,3-dicarboxylicacid methyl esters 42b (4.70g, pink solid), productive rate: 95.0%.
Second step
5-sulfonyloxy methyl phenyl-1,3-dicarboxylicacid methyl esters
With sodium sulfate (2.80g, 22.50mmol) and sodium hydrogencarbonate (2g 24.1mmol) is dissolved in the 45mL water, drips 18mL 5-chloro sulfonyl-phenyl-1,3-dicarboxylicacid methyl esters 42b (4.70g, tetrahydrofuran solution 16.07mmol), 50 ℃ of following stirring reactions 24 hours.Reacting liquid filtering adds less water, and filtrating merges organic phase with ethyl acetate extraction (150mL * 3); Water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 5-sulfonyloxy methyl phenyl-1 with silica gel column chromatography; 3-dicarboxylicacid methyl esters 42c (3.70g, yellow solid), productive rate: 84.0%.
The 3rd step
3-methoxycarbonyl-5-methyl sulphonyl-phenylformic acid
With 5-sulfonyloxy methyl phenyl-1, (3.70g 13.6mmol) is dissolved in the 30mL acetone 3-dicarboxylicacid methyl esters 42c, adds 10mL sodium hydroxide (544mg, methanol solution 13.6mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 50mL water, and with washed with dichloromethane (20mL * 3), it is 3～4 that water uses the salt acid for adjusting pH value of 1M; With ethyl acetate extraction (100mL * 3), merge organic phase, successively water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-methoxycarbonyl-5-methyl sulphonyl-phenylformic acid 42d (3.20g, white solid), productive rate: 91.4%.
The 4th step
3-(methylol)-5-methyl sulphonyl-oil of Niobe
Under the ice bath, with 3-methoxycarbonyl-5-methyl sulphonyl-phenylformic acid 42d (3.20g 12.4mmol) is dissolved in the 38mL THF, add the 1M borine tetrahydrofuran solution (19mL, 19mmol), stirring reaction 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure with ethyl acetate extraction (50mL * 3), merges organic phase; Use 30% solution of potassium carbonate (50mL) successively, the hydrochloric acid of 1M (50mL), saturated sodium bicarbonate solution (50mL) and saturated nacl aqueous solution washing (50mL * 2); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-(methylol)-5-methyl sulphonyl-oil of Niobe 42e (2.85g, white solid), productive rate: 95.5%.
The 5th step
3-formyl radical-5-methyl sulphonyl-oil of Niobe
With 3-(methylol)-5-methyl sulphonyl-oil of Niobe 42e (2.85g 11.68mmol) is dissolved in the 25mL methylene dichloride, add pyridinium chloro-chromate (6.30g, 29.2mmol) and sodium acetate (2.40g, 29.2mmol), stirring reaction 12 hours.Add 6.0g silica gel, filter, filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 3-formyl radical-5-methyl sulphonyl-oil of Niobe 42f (2g, white solid), productive rate: 70.6% with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)：δ10.16(s，1H)，8.84(s，1H)，8.80(s，1H)，8.64(s，1H)，4.03(s，3H)，3.14(s，3H)
The 6th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methyl sulphonyl-oil of Niobe
Under the ice bath, with 3-formyl radical-5-methyl sulphonyl-oil of Niobe 42f (1g 4.1mmol) is dissolved in the 8.5mL THF, drip 1M 3-chloro-phenyl-magnesium bromide tetrahydrofuran solution (8.5mL, 8.5mmol), stirring reaction 1 hour.Add saturated ammonium chloride solution cancellation reaction,, merge organic phase with ethyl acetate extraction (80mL * 3); Water (15mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methyl sulphonyl-oil of Niobe 42g (1.30g with silica gel column chromatography; White solid), productive rate: 89.0%.
The 7th step
3-[(3-chloro-phenyl-)-(2,2,2-trichlorine acetimidoyl) oxygen-methyl]-5-methyl sulphonyl-oil of Niobe
Under the ice bath, (1.30g 3.67mmol) is dissolved in the 12mL toluene with 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-methyl sulphonyl-oil of Niobe 42g; Add Trichloroacetonitrile (2.65g; 18.35mmol) and diazabicylo (56mg, 0.37mmol), stirring at room reaction 3 hours.Reaction solution is with 300-400 order filtered through silica gel; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains bullion title product 3-[(3-chloro-phenyl-)-(2 with silica gel column chromatography; 2; 2-trichlorine acetimidoyl) oxygen-methyl]-5-methyl sulphonyl-oil of Niobe 42h (1.90g, yellow oil), product is not purified directly to carry out next step reaction.
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-oil of Niobe
With bullion 3-[(3-chloro-phenyl-)-(2; 2,2-trichlorine acetimidoyl) oxygen-methyl]-5-methyl sulphonyl-oil of Niobe 42h (1.90g, 3.67mmol) and N-(2-hydroxyethyl) Urethylane 1t (672mg; 5.64mmol) be dissolved in the 15mL methylene dichloride; The adding trifluoromethyl sulfonic acid trimethylsilyl ester (896mg, 4.04mmol), stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction, with dichloromethane extraction (50mL * 3), water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-oil of Niobe 42i (1g; Colorless oil), productive rate: 59.0%.
The 9th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-oil of Niobe 42i (1g; 2.2mmol) be dissolved in 40mL first alcohol and water (V/V=3: in the mixed solvent 1); The adding lithium hydroxide solution (277mg, 6.6mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds ETHYLE ACETATE (100mL) and water (50mL), with 1M salt acid for adjusting pH value less than 3, separatory; With ethyl acetate extraction (30mL * 3), merge organic phase, successively water (30mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-phenylformic acid 42j (810mg, white solid), 83.6%.
The tenth step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, [(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(150mg 0.34mmol) is dissolved in 10mL N to 5-methyl sulphonyl-phenylformic acid 42j with 3-; In the dinethylformamide, add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (102mg, 0.37mmol); 1-hydroxy benzo triazole (91.8mg; 0.68mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (130mg, 0.68mmol), dropping diisopropylethylamine (132mg; 1.02mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure; Add the 20mL methylene dichloride, organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 42k (127mg with tlc; Colorless oil), productive rate: 53.8%.
MS?m/z(ESI)：696[M+1]
The 11 step
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 42k (127mg; 0.18mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane 42 (90.9mg, white solid), productive rate: 83.0%.
MS?m/z(ESI)：596[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.70-7.15(m，8H)，5.55(s，1H)，5.45(s，1H)，3.95-3.15(m，14H)，3.10(s，3H)，2.75(s，3H)，2.00(m，4H)，1.31(m，3H)
Embodiment 43
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901141
The first step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methyl sulphonyl-phenylformic acid 42j (150mg, 0.34mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(101mg 0.37mmol) is dissolved in 6mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (91.8mg, 0.68mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (130mg; 0.68mmol) and N; The N-diisopropylethylamine (131.6mg, 1.02mmol), stirring reaction 12 hours.Add the 50mL methylene dichloride; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 43a (131mg, colourless dope), productive rate: 55.7%.
MS?m/z(ESI)：694[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-methyl sulphonyl-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 43a (131mg; 0.19mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-methyl sulphonyl-phenyl] methoxyl group] ethyl] Urethylane 43 (91mg, white solid), productive rate: 90.5%.
MS?m/z(ESI)：594[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.61-7.10(m，8H)，5.69?and?5.60(2s，1H)，5.46(s，1H)，4.68(m，1H)，3.69-3.20(m，8H)，3.11(br.s，4H)，2.75(s，3H)，1.95-0.87(m，13H)
Embodiment 44
N-[2-[(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
The first step
4-[(3-fluorophenyl)-hydroxyl-methyl]-2,3-Dihydrobenzofuranes-6-carboxylate methyl ester
Under the ice bath, with 4-formyl radical-2,3-Dihydrobenzofuranes-6-methyl-formiate 26a (2g 9.6mmol) is dissolved in the 20mL THF, and the tetrahydrofuran solution of the 3-chlorophenyl magnesium bromide of dropping 1.0M (20mL, 20mmol), stirring reaction 0.5 hour.Add the 20mL saturated sodium bicarbonate solution, water merges organic phase with ethyl acetate extraction (80mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 4-[(3-fluorophenyl)-hydroxyl-methyl]-2 with silica gel column chromatography; 3-Dihydrobenzofuranes-6-carboxylate methyl ester 44a (2.40g, faint yellow oily thing), productive rate: 83.0%.
Second step
4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carboxylate methyl ester
With 4-[(3-fluorophenyl)-hydroxyl-methyl]-2; 3-Dihydrobenzofuranes-6-carboxylate methyl ester 44a (2.40g; 7.9mmol) be dissolved in the 50mL toluene, (1.90g is 15.8mmol) with tosic acid monohydrate (1.50g to add N-(2-hydroxyethyl) Urethylane 1t successively; 7.9mmol), 130 ℃ of following stirring reactions 1.5 hours.The reaction solution concentrating under reduced pressure; With eluent system B purifying gained resistates, obtain title product 4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carboxylate methyl ester 44b (2.60g with silica gel column chromatography; Faint yellow oily thing), productive rate: 81.5%.
The 3rd step
4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid
With 4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-6-carboxylate methyl ester 44b (2.60g; 6.45mmol) be dissolved in 33mL acetone and methyl alcohol (V/V=10: in the mixed solvent 1); Adding sodium hydroxide (258mg, 6.45mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 10mL water, drips 1M hydrochloric acid and regulates pH less than 3; With ethyl acetate extraction (80mL * 3), merge organic phase, use anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2; 3-Dihydrobenzofuranes-6-formic acid 44c (2.30g, white solid), productive rate: 91.6%.
The 4th step
N-[2-[[6-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl]-(3-fluorophenyl) methoxyl group] ethyl] Urethylane
N-[(2S)-3-cyclohexyl-2-[[4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-carbonyl] amino] propyl group]-N-methyl-t-butyl carbamate
Under the ice bath, with 4-[(3-fluorophenyl)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-2,3-Dihydrobenzofuranes-6-formic acid 44c (150mg; 0.39mmol) be dissolved in 4mL N, in the dinethylformamide, add N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (115mg successively; 0.42mmol), the 1-hydroxy benzo triazole (104mg, 0.77mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (147mg; 0.77mmol); (150mg, 1.16mmol), stirring at room was reacted 12 hours to drip diisopropylethylamine.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, and organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[[6-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl]-(3-fluorophenyl) methoxyl group] ethyl] Urethylane 44d (131mg, colourless wax), productive rate: 52.8%.MS?m/z(ESI)：644[M+1]
The 5th step
N-[2-[(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[2-[[6-[[(2S)-2-(tertbutyloxycarbonyl (methyl) amino)-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl]-(3-fluorophenyl) methoxyl group] ethyl] Urethylane 44d (131mg; 0.20mmol) be dissolved in the 10mL methylene dichloride, add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; With developping agent system A purifying gained resistates, obtain title product N-[2-[(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl with tlc] Urethylane 44 (102mg; White solid), productive rate: 91.0%.
MS?m/z(ESI)：544[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.60-6.96(m，7H)，5.85(s，1H)，5.36(s，1H)，4.61-4.53(m，2H)，4.04-3.03(m，13H)，2.76(s，3H)，2.06-1.29(m，13H)
Embodiment 45
N-[2-[(3-chloro-phenyl-)-[3-cyanic acid-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901171
The first step
3-carbamyl-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe is with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-methoxycarbonyl-phenylformic acid 39k (2.46g; 5.83mmol) be dissolved in the 50mL THF; Add 1-hydroxy benzo triazole (866mg successively; 6.41mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.34g, 7mmol), dropping ammonia (3.89mL; 58.3mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure, with ethyl acetate extraction (50mL * 3), organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 3-carbamyl-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl] oil of Niobe 45a (710mg, white powder), productive rate: 28.9%.
Second step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-oil of Niobe
Under the ice bath; (510mg 1.21mmol) is dissolved in the 20mL methylene dichloride triethylamine (368mg to oil of Niobe 45a with 3-carbamyl-5-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]; 3.64mmol); Drip 10mL trifluoroacetic anhydride (304mg, dichloromethane solution 1.45mmol), stirring at room reaction 1 hour.Add less water in the reaction solution,, merge organic phase with dichloromethane extraction (50mL * 3); With the salt acid elution (20mL * 2) with 1M, saturated sodium bicarbonate solution (20mL) and saturated nacl aqueous solution wash (20mL), anhydrous sodium sulfate drying successively; Filter, filtrate decompression concentrates, and obtains bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-oil of Niobe 45b (480mg; The white oily liquids), productive rate: 98.4%.
The 3rd step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-oil of Niobe 45b (668mg; 1.66mmol) be dissolved in 40mL first alcohol and water (V/V=3: in the mixed solvent 1); The adding lithium hydroxide solution (209mg, 5mmol), stirring reaction 3 hours.The reaction solution concentrating under reduced pressure adds ETHYLE ACETATE (100mL) and water (50mL), with 1M salt acid for adjusting pH value less than 3, separatory; With ethyl acetate extraction (30mL * 3), merge organic phase, successively water (30mL) and saturated nacl aqueous solution washing (20mL); Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-phenylformic acid 45c (482mg, colourless viscous liquid), 74.8%.
The 4th step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-cyanic acid-phenylformic acid 45c (100mg; 0.25mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(67.3mg 0.25mmol) is dissolved in 6mL N, in the dinethylformamide to N-methyl-carboxylamine tertiary butyl ester 1g; Add I-hydroxybenzotriazole (67.3mg; 0.5mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (95.4mg, 0.5mmol) and 10mLN; The N-diisopropylethylamine, stirring reaction 12 hours.Add the 50mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyanic acid-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 45d (125mg with tlc; White solid), productive rate: 76.0%.
MS?m/z(ESI)：641[M+1]
The 5th step
N-[2-[(3-chloro-phenyl-)-[3-cyanic acid-5-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-cyanic acid-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 45d (125mg; 0.20mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-cyanic acid-5-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 45 (24mg, white solid), productive rate: 22.7%.
MS?m/z(ESI)：541[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.57-7.09(m，8H)，5.76(m，1H)，5.40(m，1H)，4.65(m，1H)，3.94-3.08(m，9H)，2.71(s，3H)，1.88-0.85(m，13H)
Embodiment 46
N-[2-[(3-chloro-phenyl-)-[3-[(2R)-2,3-dihydroxyl propoxy-]-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901191
Figure BSA00000486338901201
The first step
3-hydroxy-5-methyl base carbonyl-phenylformic acid
With 5-phenol-1,3-dicarboxylicacid methyl esters 1h (10.50g, 50mmol) be dissolved in 120mL first alcohol and water (V/V=3: in the mixed solvent 1), add lithium hydroxide solution (4.70g, 112mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, filters less than 3 with 1M salt acid for adjusting pH value, obtains white solid, and vacuum-drying obtains title product 3-hydroxy-5-methyl base carbonyl-phenylformic acid 46a (7g, white solid), 71.4%.
Second step
3-benzoyloxy-5-methyl carbonyl-phenylformic acid
With 3-hydroxy-5-methyl base carbonyl-phenylformic acid 46a (3g 15.3mmol) is dissolved in the 100mL water, add salt of wormwood (5.28g, 38.2mmol), drip Benzoyl chloride 99min. (2.37g, 16.8mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with 1M salt acid for adjusting pH value less than 3, with ethyl acetate extraction (200mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-benzoyloxy-5-methyl carbonyl-phenylformic acid 46b (17g, white solid), product is not purified directly to carry out next step reaction.
The 3rd step
3-benzoyloxy-5-(methylol) oil of Niobe
Under the ice bath, (16g 50mmol) is dissolved in the 200mL THF, and (75mL, 75mmol), 50 ℃ were stirred stirring reaction 3 hours down to the borine of dropping 1.0M with bullion 3-benzoyloxy-5-methyl carbonyl-phenylformic acid 46b.Add methyl alcohol cancellation reaction, concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 3-benzoyloxy-5-(methylol) oil of Niobe 46c (9g, white solid), productive rate: 60.0% with silica gel column chromatography.
The 4th step
3-benzoyloxy-5-formyl radical-oil of Niobe
Under the ice bath, (9g 30mmol) is dissolved in the 250mL methylene dichloride, and (20.30g, 94mmol) (7.74g, 94mmol), stirring at room was reacted 2 hours with sodium acetate to add pyridinium chloro-chromate with 3-benzoyloxy-5-(methylol) oil of Niobe 46c.Add 6.0g silica gel, filter, filtrate decompression concentrates; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-benzoyloxy-5-formyl radical-oil of Niobe 46d (9g, gray solid), product is not purified directly to carry out next step reaction.
The 5th step
3-benzoyloxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe
Under the ice bath, with bullion 3-benzoyloxy-5-formyl radical-oil of Niobe 46d (8.90g 30mmol) is dissolved in the 60mL THF, drip 1.0M 3-chlorophenyl magnesium bromide (60mL, 60mmol), stirring reaction 0.5 hour.Add the 150mL saturated ammonium chloride solution, water merges organic phase with ethyl acetate extraction (100mL * 3); With saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; Obtain bullion title product 3-benzoyloxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe 46e (12.50g, white solid), product is not purified directly to carry out next step reaction.
The 6th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-hydroxy-benzoic acid methyl esters
With bullion 3-benzoyloxy-5-[(3-chloro-phenyl-)-hydroxyl-methyl] oil of Niobe 46e (12.50g; 30mmol) be dissolved in 160mL first alcohol and water (V/V=3: in the mixed solvent 1); The adding lithium hydroxide solution (1.19g, 28mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure less than 3, adds 100mL water with 1M salt acid for adjusting pH value; With ethyl acetate extraction (150mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-hydroxy-benzoic acid methyl esters 46f (7g, white waxy solid), 76.3%.
The 7th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-hydroxy-benzoic acid methyl esters
With 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-hydroxy-benzoic acid methyl esters 46f (7g; 24mmol) and N-(2-hydroxyethyl) Urethylane 1t (5.66g 47.9mmol) is dissolved in the 150mL toluene, adds tosic acid (4.55g; 24mmol), 130 ℃ were descended the dehydration stirring reaction 1.5 hours.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-hydroxy-benzoic acid methyl esters 46g (3.50g, yellow waxy solid), productive rate: 37.0%.
The 8th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] oil of Niobe
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-hydroxy-benzoic acid methyl esters 46g (500mg, 1.27mmol), [(4S)-2; 2-dimethyl--1,3-dioxolane-4-yl] and methyl alcohol (202mg, 1.53mmol) and triphenylphosphine (500mg; 1.9mmol) be dissolved in the 3mL THF; The dropping diethyl azodiformate (332mg, 1.9mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain bullion title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] oil of Niobe 46h (945mg; White waxy solid), product is not purified directly carries out next step reaction.
The 9th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(2; 2-dimethyl--1; 3-dioxolane-4-yl) methoxyl group] (645mg 1.27mmol) is dissolved in 12mL first alcohol and water (V/V=3: in the mixed solvent 1), add lithium hydroxide solution (134mg to oil of Niobe 46h; 3.18mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, using the lemon acid for adjusting pH value is 6～7, adds 10mL water, with ethyl acetate extraction (10mL * 3); Merge organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1; 3-dioxolane-4-yl) methoxyl group] phenylformic acid 46i (376mg, colourless viscous liquid), 60.0%.
The tenth step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(2; 2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, with 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1; 3-dioxolane-4-yl) methoxyl group] (313mg 0.64mmol) is dissolved in 4mL N, in the dinethylformamide to phenylformic acid 46i; Add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (175mg, 0.64mmol), 1-hydroxy benzo triazole (104mg; 0.77mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (147mg, 0.77mmol), dropping diisopropylethylamine (413mg; 3.2mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure adds the 20mL methylene dichloride, and organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(2,2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 46j (199mg; White solid), productive rate: 75.0%.
MS?m/z(ESI)：748[M+1]
The 11 step
N-[2-[(3-chloro-phenyl-)-[3-[(2R)-2,3-dihydroxyl propoxy-]-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(2; 2-dimethyl--1,3-dioxolane-4-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-(199mg 0.27mmol) is dissolved in the 10mL methylene dichloride N-methyl-t-butyl carbamate 46j; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying filters; Filtrate decompression concentrates; With developping agent system A purifying gained resistates, obtain title product N-[2-[(3-chloro-phenyl-)-[3-[(2R)-2,3-dihydroxyl propoxy-]-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl with tlc] Urethylane 46 (149mg; White solid), productive rate: 92.0%.
MS?m/z(ESI)：608[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.72-7.22(m，7H)，6.98(s，1H)，6.51(s，1H)，5.30(s，1H)，4.03(m，3H)，3.89-3.02(m，16H)，2.54(m，3H)，1.96-1.23(m，7H)
Embodiment 47
N-[2-[(3-chloro-phenyl-)-[3-(methylol)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901231
The first step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(methylol) benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, [(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(155mg 0.39mmol) is dissolved in 4mL N to 5-(methylol) oil of Niobe 39i with 3-; In the dinethylformamide, add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (107mg, 0.39mmol); 1-hydroxy benzo triazole (106mg; 0.77mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (151mg, 0.78mmol), dropping diisopropylethylamine (413mg; 3.2mmol), stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure; Add the 20mL methylene dichloride, organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(methylol) benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 47a (128mg with tlc; White solid), productive rate: 50.0%.MS?m/z(ESI)：648[M+1]
Second step
N-[2-[(3-chloro-phenyl-)-[3-(methylol)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group]
Carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(methylol) benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 47a (128mg; 0.19mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-(methylol)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 47 (40mg, white solid), productive rate: 37.0%.
MS?m/z(ESI)：548[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.63-7.24(m，8H)，5.62(s，1H)，5.34(s，1H)，4.03(m，3H)，4.59(m，2H)，3.85-3.40(m，13H)，3.07(m，1H)，2.65(s，3H)，2.00-1.22(m，7H)
Embodiment 48,49
N-[2-[(S)-(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
N-[2-[(R)-(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901241
With N-[2-[(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 36 (609mg; 1.09mmol) carry out chiral separation; Adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IC, moving phase: vinyl cyanide: Virahol: diethylolamine=95: 5: 0.1 with preparation equipment; Flow velocity: 1.0mL/ minute); Collect its respective components, rotary evaporation removes and to desolvate, obtain title product N-[2-[(S)-(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 48 (240mg; 0.36mmol) and N-[2-[(R)-(3-chloro-phenyl-)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 49 (250mg, 0.38mmol).
48:MS m/z (ESI): 560 [M+1], RT 10.82 minutes, ee value＞98%.
49:MS m/z (ESI): 560 [M+1], RT 10.77 minutes, ee value＞98%.
Embodiment 50
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-dimethylamino ethoxy) phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901251
The first step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) oil of Niobe
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-hydroxy-benzoic acid methyl esters 46g (200mg; 0.5mmol), dimethylethanolamine (54mg, 0.6mmol) and triphenylphosphine (200mg; 0.76mmol) be dissolved in the 1mL THF; The dropping diethyl azodiformate (133mg, 0.76mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; With tlc with developping agent system A purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) oil of Niobe 50a (132mg; Colourless viscous liquid), productive rate: 56.0%.
Second step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) oil of Niobe 50a (132mg; 0.28mmol) be dissolved in 8mL first alcohol and water (V/V=3: in the mixed solvent 1); Add lithium hydroxide solution (30mg; 0.71mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, using 1M salt acid for adjusting pH value is 4, adds 10mL water; With ethyl acetate extraction (10mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) phenylformic acid 50b (98mg, colourless viscous liquid), 76.6%.
The 3rd step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) phenylformic acid 50b (97mg, 0.2mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(58mg 0.2mmol) is dissolved in 6mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (35mg, 0.26mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (50mg; 0.26mmol) and N; The N-diisopropylethylamine (140mg, 1mmol), stirring reaction 12 hours.Add the 50mL methylene dichloride; Water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 50c (97mg, white solid), productive rate: 64.0%.
MS?m/z(ESI)：703[M+1]
The 4th step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-dimethylamino ethoxy) phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-(2-dimethylamino ethoxy) benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 50c (97mg; 0.14mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-(2-dimethylamino ethoxy) phenyl] methoxyl group] ethyl] Urethylane 50 (35mg, faint yellow solid), productive rate: 42.2%.
MS?m/z(ESI)：603[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.58-7.47(m，2H)，7.34-7.26(m，5H)，7.03(s，1H)，5.39(s，1H)，5.28(m，1H)，4.52(m，1H)，4.12(m，2H)，3.68-2.80(m，11H)，2.60(m，3H)，2.41(s，6H)，1.78-0.91(m，13H)
Embodiment 51
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901271
The first step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] oil of Niobe
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-hydroxy-benzoic acid methyl esters 46g (200mg; 0.5mmol), (3-methyl oxa-fourth ring-3-yl) methyl alcohol (62mg, 0.61mmol) and triphenylphosphine (200mg; 0.76mmol) be dissolved in the 1mL THF; The dropping diethyl azodiformate (133mg, 0.76mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure; With tlc with developping agent system A purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] oil of Niobe 51a (214mg; White solid), productive rate: 88.0%.
Second step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] oil of Niobe 51a (217mg; 0.45mmol) be dissolved in 8mL first alcohol and water (V/V=3: in the mixed solvent 1); Add lithium hydroxide solution (48mg; 1.14mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, using 1M salt acid for adjusting pH value is 4, adds 10mL water; With ethyl acetate extraction (10mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] phenylformic acid 51b (180mg, white solid), 85.7%.
The 3rd step
N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-and tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate
Under the ice bath, [(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-(180mg 0.39mmol) is dissolved in 4mL N to phenylformic acid 51b to 5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] with 3-; In the dinethylformamide, add successively N-[(1S)-1-(amino methyl)-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-carboxylic acid tertiary butyl ester 3a (117mg, 0.43mmol); 1-hydroxy benzo triazole (63mg; 0.47mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (89mg, 0.47mmol), dropping diisopropylethylamine (250mg; 2mmol), the stirring at room reaction is 12 hours.Add the 20mL methylene dichloride in the reaction solution; Organic phase is water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 51c (222mg, white solid), productive rate: 79.6%.
MS?m/z(ESI)：718[M+1]
The 4th step
N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(1S)-1-[[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] benzoyl] amino] methyl]-2-[(3R)-tetrahydropyran-3-base] ethyl]-N-methyl-t-butyl carbamate 51c (220mg; 0.31mmol) be dissolved in the 10mL methylene dichloride; Add 6mL trifluoroacetic acid and methylene dichloride (V/V=2: mixing solutions 1), stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-5-[(3-methyl oxa-cyclobutyl-3-yl) methoxyl group] phenyl] methoxyl group] ethyl] Urethylane 51 (124mg, faint yellow solid), productive rate: 65.6%.
MS?m/z(ESI)：618[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.78-7.70(m，8H)，5.30-5.25(m，2H)，4.62(m，2H)，4.45(m，2H)，4.04-3.02(m，16H)，2.62-2.55(m，3H)，2.01-1.25(m，10H)
Embodiment 52
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-morpholine-phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901281
Figure BSA00000486338901291
The first step
5-oil of mirbane-1,3-dicarboxylicacid methyl esters
Under the ice bath, (5g 22.21mmol) is dissolved in the 15mL methyl alcohol, and (2.43mL, 33.31mmol), stirring at room was reacted 12 hours to add thionyl chloride with 3-methoxycarbonyl-5-nitro-phenylformic acid 38a.The reaction solution concentrating under reduced pressure, with ethyl acetate extraction (100mL * 3), water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 5-oil of mirbane-1; 3-dicarboxylicacid methyl esters 52a (4.78g, white solid), productive rate: 90.0%.
Second step
5-amino-benzene-1,3-dicarboxylicacid methyl esters
With 5-oil of mirbane-1,3-dicarboxylicacid methyl esters 52a (3g 12.6mmol) is dissolved in the 15mL methyl alcohol, and the adding Raney Ni (300mg, 1.26mmol), hydrogen exchange three times, stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentrates, and obtains title product 5-amino-benzene-1,3-dicarboxylicacid methyl esters 52b (2.20g, pale solid), productive rate: 84.6%.
The 3rd step
5-morpholinyl phenyl-1,3-dicarboxylicacid methyl esters
With 5-amino-benzene-1, and 3-dicarboxylicacid methyl esters 52b (2g, 9.6mmol) with 2,2-two bromodiethyl ether (1.5mL; 11.5mmol) be dissolved in 20mL N, in the dinethylformamide, add N; The N-diisopropylethylamine (3.3mL, 19.1mmol), 180 ℃ of following microwave reactions 0.5 hour.The reaction solution concentrating under reduced pressure, with ethyl acetate extraction (50mL * 3), water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With eluent system B purifying gained resistates, obtain title product 5-morpholinyl phenyl-1 with silica gel column chromatography, 3-dicarboxylicacid methyl esters 52c (800mg; White solid), productive rate: 30.0%.
MS?m/z(ESI)：280[M+1]
The 4th step
3-methyl carbonyl-5-morpholine-phenylformic acid
With 5-morpholinyl phenyl-1,3-dicarboxylicacid methyl esters 52c (630mg 2.26mmol) is dissolved in the 5mL methyl alcohol, and adding sodium hydroxide (90mg, 2.26mmol) with 10mL acetone, stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds 20mL water, drip 1M hydrochloric acid to reaction solution pH be 3～4; With ethyl acetate extraction (20mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-methyl carbonyl-5-morpholine-phenylformic acid 52d (560mg; Faint yellow solid), productive rate: 93.7%.
MS?m/z(ESI)：266[M+1]
The 5th step
3-(methylol)-5-morpholine-oil of Niobe
Under the ice bath, with 3-methyl carbonyl-5-morpholine-phenylformic acid 52d (560mg 2.1mmol) is dissolved in the 5mL THF, add the 1M borine tetrahydrofuran solution (3.2mL, 3.2mmol), stirring reaction 12 hours.Add methyl alcohol cancellation reaction, concentrating under reduced pressure is with ethyl acetate extraction (20mL * 3); Merge organic phase, usefulness successively, saturated sodium bicarbonate solution (10mL) washs (10mL) with saturated nacl aqueous solution; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; Obtain title product 3-(methylol)-5-morpholine-oil of Niobe 52e (420mg, colourless transparent liquid), productive rate: 79.2%.
MS?m/z(ESI)：252[M+1]
The 6th step
3-formyl radical-5-morpholine-oil of Niobe
With 3-(methylol)-5-morpholine-oil of Niobe 52e (400mg 1.6mmol) is dissolved in the 10mL methylene dichloride, add pyridinium chloro-chromate (685mg, 3.2mmol) and sodium acetate (392mg, 4.8mmol), stirring reaction 12 hours.Add 2.0g silica gel, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-formyl radical-5-morpholine-oil of Niobe 52f (260mg, yellow solid), productive rate: 65.3% with silica gel column chromatography.
MS?m/z(ESI)：251[M+1]
The 7th step
3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-morpholine-oil of Niobe
Under the ice bath, with 3-formyl radical-5-morpholine-oil of Niobe 52f (850mg 3.4mmol) is dissolved in the 10mL THF, drip 1.0M 3-chlorophenyl magnesium bromide (6.8mL, 6.8mmol), stirring reaction 0.5 hour.Add the 50mL saturated ammonium chloride solution, water merges organic phase with ethyl acetate extraction (50mL * 3); With saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying filters; Filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-morpholine-oil of Niobe 52g (1.10g with silica gel column chromatography; Faint yellow solid), productive rate: 89.4%.
The 8th step
3-[(3-chloro-phenyl-)-(2,2,2-trichlorine acetimidoyl) oxygen-methyl]-5-morpholine-oil of Niobe
Under the ice bath, (830mg 2.3mmol) is dissolved in the 10mL toluene with 3-[(3-chloro-phenyl-)-hydroxyl-methyl]-5-morpholine-oil of Niobe 52g; Add Trichloroacetonitrile (1.70g; 11.5mmol) and diazabicylo (35mg, 0.23mmol), stirring at room reaction 1 hour.Reaction solution is with 300-400 order filtered through silica gel, and filtrate decompression concentrates, and obtains bullion title product 3-[(3-chloro-phenyl-)-(2; 2; 2-trichlorine acetimidoyl) oxygen-methyl]-5-morpholine-oil of Niobe 52h (1.19g, faint yellow oily thing), product is not purified directly to carry out next step reaction.
The 9th step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-morpholine-oil of Niobe
With bullion 3-[(3-chloro-phenyl-)-(2; 2,2-trichlorine acetimidoyl) oxygen-methyl]-5-morpholine-oil of Niobe 52h (1.16g, 2.3mmol) and N-(2-hydroxyethyl) Urethylane 1t (567mg; 4.8mmol) be dissolved in the 10mL methylene dichloride; The adding trifluoromethyl sulfonic acid trimethylsilyl ester (555mg, 2.5mmol), stirring reaction 1 hour.Add saturated sodium bicarbonate solution cancellation reaction, with dichloromethane extraction (50mL * 3), water (20mL) and saturated nacl aqueous solution washing (20mL) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography with eluent system B purifying gained resistates; Obtain title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-morpholine-oil of Niobe 52i (1.10g, white solid), productive rate: 61.0%.MS?m/z(ESI)：463[M+1]
The tenth step
3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-morpholine-phenylformic acid
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-morpholine-oil of Niobe 52i (295mg 0.65mmol) is dissolved in the 5mL methyl alcohol, add sodium hydroxide (52mg, 1.3mmol), 50 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure adds 20mL water, drip 1M hydrochloric acid to reaction solution pH be 1～2; With ethyl acetate extraction (20mL * 3), merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression concentrates, and obtains title product 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-morpholine-phenylformic acid 52j (245mg; Yellow oil), productive rate: 85.7%.
MS?m/z(ESI)：447[M-1]
The 11 step
N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl is amino) oxyethyl group] methyl]-5-morpholine-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate
With 3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-morpholine-phenylformic acid 52j (245mg, 0.55mmol) and N-[(2S)-2-amino-3-cyclohexyl-propyl group]-(177mg 0.66mmol) is dissolved in 6mL N to N-methyl-carboxylamine tertiary butyl ester 1g; In the dinethylformamide; The adding I-hydroxybenzotriazole (148mg, 1.1mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (210mg; 1.1mmol) and N; The N-diisopropylethylamine (269mg, 2.1mmol), stirring reaction 12 hours.Add the 50mL methylene dichloride, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively, anhydrous sodium sulfate drying; Filter; Filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-morpholine-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 52k (334mg with tlc; White solid), productive rate: 87.2%.
MS?m/z(ESI)：701[M+1]
The 12 step
N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-and 1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-morpholine-phenyl] methoxyl group] ethyl] Urethylane
Under the ice bath; With N-[(2S)-2-[[3-[(3-chloro-phenyl-)-[2-(methoxycarbonyl amino) oxyethyl group] methyl]-5-morpholine-benzoyl] amino]-3-cyclohexyl-propyl group]-N-methyl-t-butyl carbamate 52k (300mg; 0.43mmol) be dissolved in the 8mL methylene dichloride; Add the 2mL trifluoroacetic acid, stirring reaction 1 hour.Add saturated sodium carbonate solution cancellation reaction, water merges organic phase with dichloromethane extraction (10mL * 3); Water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively; Anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; With tlc with developping agent system A purifying gained resistates; Obtain title product N-[2-[(3-chloro-phenyl-)-[3-[[(1S)-1-(cyclohexyl methyl)-2-methylamino-ethyl] carbamyl]-5-morpholine-phenyl] methoxyl group] ethyl] Urethylane 52 (245mg, white solid), productive rate: 95.3%.
MS?m/z(ESI)：601[M+1]
1H?NMR(400MHz，CDCl 3)：δ8.06-7.15(m，7H)，6.92(s，1H)，5.76?and?5.63(2s，1H)，5.34(s，1H)，4.65(m，1H)，3.84-3.03(m，17H)，2.70(s，3H)，1.81-0.86(m，13H)
Embodiment 53,54
N-[2-[(S)-(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
N-[2-[(R)-(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901321
With N-[2-[(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 44 (620mg; 1.14mmol) carry out chiral separation; Adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IC, moving phase: vinyl cyanide: Virahol: diethylolamine=95: 5: 0.1 with preparation equipment; Flow velocity: 1.0mL/ minute); Collect its respective components, rotary evaporation removes and to desolvate, obtain title product N-[2-[(S)-(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] propyl group] carbamyl]-2; 3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 53 (190mg; 0.35mmol) and N-[2-[(R)-(3-fluorophenyl)-[6-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] propyl group] carbamyl]-2,3-Dihydrobenzofuranes-4-yl] methoxyl group] ethyl] Urethylane 54 (200mg, 0.37mmol).
53:MS m/z (ESI): 544 [M+1], RT 9.77 minutes, ee value 96.33%.
54:MS m/z (ESI): 544 [M+1], RT 9.81 minutes, ee value 99.74%.
Embodiment 55,56
N-[2-[(R)-(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
N-[2-[(S)-(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane
Figure BSA00000486338901331
With N-[2-[(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 40 (616mg; 1.04mmol) carry out chiral separation; Adopt the HPLC method; With chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IC with preparation equipment; Moving phase: vinyl cyanide: Virahol: diethylolamine=95: 5: 0.1; Flow velocity: 1.0mL/ minute); Collect its respective components, rotary evaporation removes and to desolvate, and obtains title product N-[2-[(R)-(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 55 (207mg; 0.35mmol) and N-[2-[(S)-(3-chloro-phenyl-)-[3-(2-methoxy ethoxy)-5-[[(2S)-2-methylamino-3-[(3R)-and tetrahydropyran-3-base] phenyl] carbamyl] phenyl] methoxyl group] ethyl] Urethylane 56 (222.9mg, 0.38mmol).
55:MS m/z (ESI): 592 [M+1], RT 9.24 minutes, ee value 99.68%.
56:MS m/z (ESI): 592 [M+1], RT 10.05 minutes, ee value 99.32%.
Test case:
Biological assessment
Test case 1, compound suppress the RA test
Following method is to be used for measuring the inhibition ability of invention compound to the feritin protease activity.The half-inhibition concentration IC of each compound 50(suppressing enzymic activity to 50% o'clock compound concentrations of surveying) is to be used for measuring with the substrate of the enzyme Mixed Stationary amount of fixed amount and the testing compound of different concns.
The compounds of this invention suppresses active mensuration to feritin
Material:
1. black 96 orifice plates (Greiner bio-one #655087)
2.10X damping fluid
The 1X damping fluid
50mM?Tris-HCl
100mM?NaCl
pH?8.0
(Cayman?#10006870)
3.Renin enzyme (sigma-aldrich #R2779)
4.Renin substrate (Cayman #100068720)
5.ddH 2O
(6.DMSO traditional Chinese medicines #30072418)
Method:
Undertaken by following working order:
1. with 50% DMSO (DMSO: ddH 2O, 1: 1) compound is diluted in advance the final concentration that needs.
2. use dd H 2O is diluted to the 1X damping fluid with the 10X damping fluid.37 ℃ of preheating 1X damping fluids.
3.Blank (blank group)-Jia 10 μ L substrates, 80 μ L 1X damping fluids, 5 μ L 50%DMSO are established the contrast of multiple hole to every hole.
4.Negative control (100% active control group)-Jia 10 μ L substrates, 75 μ L 1X damping fluids, 5 μ L50%DMSO establish the contrast of multiple hole to every hole.
(5.Sample test-compound group)-Jia 10 μ L substrates, 75 μ L 1X damping fluids, the contrast of multiple hole is established in 5 μ L compounds (being dissolved in 50%DMSO) to every hole.
6. dilute the Renin enzyme to 8.33ng/ μ L with the 1X damping fluid.
7. add 5 μ L Renin to Negative control reacting holes and Sample reacting hole and start reaction.Micro oscillator shake 10 second mixing, shrouding film shrouding was hatched 90 minutes for 37 ℃.
8. remove the shrouding film, under excitation wavelength 335～345nm and emission wavelength 485～510nm condition, read fluorescent value.
Inhibiting rate calculates:
IR(％)＝100-100*(S-B)/(N-B)
S=adds the fluorescent value of the reacting hole of test compounds
The fluorescent value of N=negative control reacting hole
The fluorescent value of B=blank well
IC 50Value can be calculated through the IR value of test compounds under concentration gradient and get.
The activity of The compounds of this invention
The biochemical activity of The compounds of this invention is measured through above test, the IC that records 50Value sees the following form.
The embodiment compound IC 50Value (nM)
3 2
4 6
5 4
6 8
7 8
9 1
10 6
11 2
14 7
15 1
16 1
18 1
20 1
21 1
23 6
25 7
27 4
28 1
30 1
32 2
34 1
37 1
38 4
39 9
40 10
42 8
43 1
44 11
45 8
46 6
47 2
48 3
51 20
52 24
53 1
55 3
Conclusion: compound of the present invention all has inhibition significantly active to feritin proteolytic enzyme.
Pharmacokinetics is estimated
The pharmacokinetics test of test case 2, The compounds of this invention
1, summary
With the rat is animal subject, uses the LC/MS/MS method and has measured rat oral gavage and give the drug level in the different moment blood plasma behind embodiment 4,23,30,48,53 and 55 compounds.Study oral The compounds of this invention in the pharmacokinetics in rats behavior, estimate its characteristics of pharmacokinetics.
2, testing program
2.1 test drug
Embodiment 4,23,30,48,53 and 55 compounds.
2.2 experimental animal
24 of healthy adult SD rats, male and female half and half, 4 every group, available from west, Shanghai pul-Bi Kai laboratory animal ltd, animal production licence number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparation
Take by weighing a certain amount of medicine, add 0.5% sodium cellulose glycolate and be mixed with the 3.0mg/mL suspension liquid.
2.4 administration
24 of SD rats, male and female half and half, 4 every group, difference gastric infusion behind the overnight fasting, dosage is 30.0mg/kg.
3, operation
20 of SD rats, male and female half and half, gastric infusion after one night of fasting, dosage is 30.0mg/kg, embodiment 2,4,23 and 26 compounds are before administration and after the administration 0.5; 1.0,2.0,3.0,4.0,6.0; 8.0,12.0,24.0,36.0,48.0; 72.0 hour by eye socket blood sampling 0.2mL, place the heparinization test tube, 4 ℃, 10000 rev/mins centrifugal 10 minutes separated plasmas, in-20 ℃ of preservations, feed in 2 hours after the administration.
Measure the testing compound in the rat plasma behind the medicine gastric infusion of different concns: draw each rat plasma 50 μ L constantly behind the medicine; Add inner mark solution 50 μ L; Methyl alcohol 100 μ L; Vortex mixed 3 minutes, centrifugal 10 minutes (13500 rev/mins), plasma sample are got supernatant 10 μ L and are carried out the LC/MS/MS analysis.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of The compounds of this invention is following:
Figure BSA00000486338901361
Figure BSA00000486338901371
Conclusion: behind the The compounds of this invention oral administration in the rat body Plasma Concentration and exposure level all higher, long half time has good pharmacokinetics characteristic.

Claims (19)

1. compound shown in the general formula (I) and enantiomorph thereof, diastereomer or its pharmaceutically useful salt:
Wherein:
R 1Be alkyl;
Each R 2Be selected from independently of one another Wasserstoffatoms, halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,, wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl be optional independently of one another further one or morely to be selected from, halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9Substituting group replace;
R 3, R 4And R 5In one be selected from cyanic acid, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11The NR of ,-SO) 10R 11Or-S (O) mR 9, wherein said alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, cyanic acid, hydroxyl, nitro, alkyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 9,-OC (O) R 9,-C (O) R 9,-NHC (O) R 9,-NR 10R 11,-OC (O) NR 10R 11,-NHC (O) NR 10R 11Or-S (O) mR 9Substituting group replace, two other is selected from Wasserstoffatoms;
Perhaps, R 3And R 4Or R 4And R 5Form a heterocyclic radical with the atom that is connected, wherein said heterocyclic radical contains one and is selected from N, O or S (O) mHeteroatoms, and said heterocyclic radical is optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 6Be Wasserstoffatoms, R 7For-(CH 2) p-R 12, perhaps R 6For-(CH 2) p-R 12, R 7Be Wasserstoffatoms;
R 8Be selected from Wasserstoffatoms or alkyl;
R 9Be selected from Wasserstoffatoms, alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl are optional independently of one another further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 10Or R 11Independently be selected from separately Wasserstoffatoms, alkyl, naphthenic base, heterocyclic radical, aryl, heteroaryl or-S (O) mR 9, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl are optional independently of one another further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
Perhaps, R 10And R 11Nitrogen-atoms with being connected forms heterocyclic radical, and wherein said heterocyclic radical contains one or more N of being selected from, O or S (O) mHeteroatoms, and said heterocyclic radical is optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
R 12Be selected from naphthenic base, heterocyclic radical, aryl or heteroaryl, wherein said naphthenic base, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylicesters;
M is 0,1 or 2;
N is 1,2,3,4 or 5; And
P is 0,1,2 or 3.
2. compound shown in the general formula according to claim 1 (I) and enantiomorph thereof, diastereomer or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) and enantiomorph, diastereomer or its pharmaceutically useful salt:
Figure FSA00000486338800021
R wherein 1～R 8, n definition such as claim 1 described in.
3. compound shown in the general formula according to claim 1 (I) and enantiomorph thereof, diastereomer or its pharmaceutically useful salt, comprising general formula (III) with the compound (IV) and enantiomorph, diastereomer or its pharmaceutically useful salt:
R wherein 1～R 5, R 8, R 12, n and p definition such as claim 1 described in.
4. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～3, wherein: R 4Be selected from cyanic acid, alkyl, alkoxyl group, heterocyclic radical, naphthenic base or aryl.
5. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～3, wherein: p is 1.
6. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～3, wherein: R 3And R 4Or R 4And R 5Form 5～6 yuan of heterocyclic radicals with the atom that is connected, wherein said heterocyclic radical contains an O atom.
7. compound shown in the general formula according to claim 6 (I) and enantiomorph thereof, diastereomer or its pharmaceutically useful salt, comprising logical formula V with (VI) shown in compound and enantiomorph, diastereomer or its pharmaceutically useful salt:
Figure FSA00000486338800031
Wherein X is-CH 2-, Y is the O atom, or X is the O atom, Y is-CH 2-;
Q is 1 or 2;
R 1, R 2, R 6～R 8, n definition such as claim 1 described in.
8. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～7, wherein n is 1, R 2Be halogen.
9. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～8, wherein p is 1, R 12Be selected from naphthenic base or heterocyclic radical, be preferably cyclohexyl or THP trtrahydropyranyl.
10. according to compound and enantiomorph, diastereomer or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～9, wherein this compound is:
Figure FSA00000486338800032
Figure FSA00000486338800051
11. a method for preparing the compound shown in the general formula according to claim 1 (I) and enantiomorph, diastereomer or its pharmaceutically useful salt, this method comprises:
Figure FSA00000486338800061
General formula (IA) compound optionally hydrolyse is become carboxylic acid and the reaction of general formula (IB) compound, and the protection base PG of optional further deaminize obtains general formula (I) compound;
Wherein: n, R 1～R 8Definition such as claim 1 described in;
G is selected from hydroxyl, alkoxy or halogen;
PG is amino protection base, is preferably tert-butoxycarbonyl.
12. compound shown in the general formula (IA) and enantiomorph thereof, diastereomer or its pharmaceutically useful salt, wherein:
Figure FSA00000486338800062
Wherein: n, R 1～R 5Definition such as claim 1 described in;
G is selected from hydroxyl, alkoxy or halogen.
13. a method for preparing the compound shown in the general formula according to claim 12 (IA) and enantiomorph, diastereomer or its pharmaceutically useful salt, this method comprises:
Figure FSA00000486338800063
The grignard reagent reaction of phenyl aldehyde compounds a and substituted benzene obtains benzhydrol compounds b;
Figure FSA00000486338800064
Compound b and compound c are carried out condensation reaction and are obtained general formula (IA) compound;
Wherein: n, R 1～R 5Definition such as claim 1 described in;
G is selected from hydroxyl, alkoxy or halogen.
14. a method for preparing the compound shown in the general formula according to claim 12 (IA) and enantiomorph, diastereomer or its pharmaceutically useful salt, this method comprises:
Figure FSA00000486338800071
Bromobenzene compounds e and substituted benzoyl aldehyde reaction obtain benzhydrol compounds f;
Figure FSA00000486338800072
Benzhydrol compounds f changes into compound g;
Figure FSA00000486338800073
Compound g obtains compound h with the methylsulfonyl chloride reaction after being reduced into alcohol again;
Figure FSA00000486338800074
Compound h carries out azido reaction and obtains compound i;
The compound i reduction obtains ethylamine compounds j;
Figure FSA00000486338800076
Compound j changes into compound k;
Compound k sloughs hydroxyl protecting group M and obtains general formula (IA) compound;
Wherein: n, R 1～R 5Definition such as claim 1 described in;
G is selected from hydroxyl, alkoxy or halogen;
M is a hydroxyl protecting group, is preferably methyl or tertiary butyl hexichol is silica-based.
15. a pharmaceutical composition, its contain the treatment effective dose like each described compound of claim 1～10 and enantiomorph, diastereomer or its pharmaceutically useful salt, and pharmaceutically useful carrier or vehicle.
16. like each described compound of claim 1～10 and enantiomorph, diastereomer or its pharmaceutically useful salt, the purposes of pharmaceutical composition as claimed in claim 15 in the medicine of preparation treatment and RA diseases associated.
17. purposes according to claim 16; Wherein said and RA diseases associated is selected from: the restenosis of the complication that myocardosis, instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, mellitus cause after hypertension, atherosclerosis, instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, the infraction, coronary artery disease, postangioplasty, the rising of eye-chamber pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dementia, anxiety state or cognitive disorders, the complication that wherein said mellitus cause comprises ephrosis, vascular disease and neuropathy.
18. like each described compound of claim 1～10 and enantiomorph, diastereomer or its pharmaceutically useful salt, the purposes of pharmaceutical composition as claimed in claim 15 in the preparation renin inhibitor.
19. a method that suppresses feritin, this method comprise patient's effective dose of treating like each described compound of claim 1～10 and enantiomorph, diastereomer or its pharmaceutically useful salt, pharmaceutical composition as claimed in claim 15.
CN2011101121688A 2010-08-10 2011-04-25 Diphenyl methanol derivative, preparation method thereof and application of diphenyl methanol derivative in medicine Pending CN102372653A (en)

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