CN108264499A - A kind of preparation method of benzodiazepine * derivatives - Google Patents
A kind of preparation method of benzodiazepine * derivatives Download PDFInfo
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- CN108264499A CN108264499A CN201810003775.2A CN201810003775A CN108264499A CN 108264499 A CN108264499 A CN 108264499A CN 201810003775 A CN201810003775 A CN 201810003775A CN 108264499 A CN108264499 A CN 108264499A
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- 0 C1**COC1 Chemical compound C1**COC1 0.000 description 9
- NTDNEOWLKYXXQX-UHFFFAOYSA-N C1NCC[U]C1 Chemical compound C1NCC[U]C1 NTDNEOWLKYXXQX-UHFFFAOYSA-N 0.000 description 1
- KVTBAGHTJLKAON-UHFFFAOYSA-N CN1CC[U]CC1 Chemical compound CN1CC[U]CC1 KVTBAGHTJLKAON-UHFFFAOYSA-N 0.000 description 1
- HINRIEKCOPUIHF-UHFFFAOYSA-N O[P-](N1CCNCC1)[NH+]1CCOCC1 Chemical compound O[P-](N1CCNCC1)[NH+]1CCOCC1 HINRIEKCOPUIHF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention relates to a kind of benzodiazepinesThe preparation method of derivative.In particular it relates to one kind as shown in starting material formula (V) compound shown in preparation of compounds of formula (III), prepare compound shown in formula (II) after the reaction was continued, finally obtain benzodiazepine shown in formula (I)Derivative, its officinal salt preparation method and preparation process in intermediate and preparation method thereof.This method shortens reaction step, improves reaction yield, simple easily manipulation, conducive to industrial expanding production, and specific preparation method is as follows.
Description
Technical field
The present invention relates to a kind of benzodiazepinesThe preparation method of derivative.
Background technology
Entitled (S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazoles of chemistry of formula (Ia) compound
And [1,2-a] [1,4] diaza- 4- bases) methyl propionate,
Report contains carboxylate and benzodiazepine * in patent WO0069836A1The compound of structure is short-acting nervous centralis
System (CNS, Central Nervous System) inhibitor, have include tranquilizing soporific, antianxiety, it is of flaccid muscles and it is anti-shy
The effect of fainting.The intravenously administrable that they can be used in clinical treatment：Operation consent calmness, antianxiety and something lost in during such as performing the operation
Forget purposes；Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure；Application other anesthetic and analgesic it
It is preceding and/or simultaneously, as the induction for general anesthesia and the component of maintenance；ICU calmness etc..WO0069836A1 and
WO2013029431A1 discloses a kind of benzodiazepineThe preparation method of derivative and its tosilate, specific method is such as
Under：
This method reactant needs used in compound shown in formula (4) are coupled under heated reflux condition
Reaction, ring-closure reaction under alkaline condition, and addition acid is needed to slough protecting group Fmoc, yield 55%；In formula (6)
Inert gas shielding reaction system is not carried out during shown compound, highly basic class deprotonation agent used is sodium hydride, and yield is only
It is 37%；In compound shown in formula (Ia), the feed way of DMSO used, oxalyl chloride and dichloromethane are directly mixed
It closes, this method is unfavorable for industrial expanding production.
WO2011032692A1 discloses another benzodiazepineThe preparation method of derivative, specific method are as follows：
Initial reactant of this method in compound shown in formula (D) betBoc-Glu (OMe)-OH, is being coupled
Compound shown in formula (B) is obtained by the reaction under agent DCC effects, adds hydrochloric acid and takes off Boc protecting groups and obtain compound shown in formula (C),
Add in sodium bicarbonate cyclization and obtain compound shown in formula (D), under the effect of deprotonation reagent with dimorpholine base time phosphono
Compound shown in formula (E) is obtained by the reaction in chlorine, and compound shown in formula (F) is obtained by the reaction with the R- isopropanolamines of single configuration, and 1,
1,1- triacetoxyl group -1,1- dihydro -1,2- benzenesulfonyl -3 (1H) ketone (Dai Si-Martin's oxidant, Dess-Martin
Periodinane compound shown in formula (G)) is obtained by the reaction, cyclization obtains compound shown in formula (Ia) after adding in hydrochloric acid；Its
In, the reaction of compound shown in formula (F) isopropanolamine used is single R configurations, yield 56%, chemical combination shown in formula (Ia)
The chemical purity of object reaction is 93.91%, and the purity with single configuration R- isopropanolamines reaction products therefrom is relatively low, therefore, has
Necessity improves existing preparation method.
Invention content
The technical problem to be solved in the present invention is to provide the method for compound shown in a kind of formula (Ia), by changing
Beginning raw material improves intermediate yield, optimizes the approach such as reaction condition, such as reaction temperature, change post-processing approach to improve product
Purity and yield；Simply easily purchase, the simple controllable, reaction of reaction condition of the reactants such as this method is simple and easy to control, starting material
Post-processing approach is simple, and reaction yield significantly improves, conducive to industrial expanding production.
Technical scheme is as follows：
Present invention offer is a kind of to prepare formula (III) compound represented, its pharmaceutically acceptable salt or its alloisomerism
The method of body, which is characterized in that described method includes following steps：
First step reaction in the presence of a coupling agent as shown in formula (V) compound and (2- amino -5- bromophenyls) (pyridine -
2- yls) formula (IV) compound represented is obtained by the reaction in ketone,
The chemical combination shown in formula (III) is obtained by the reaction for the reaction of formula (IV) compound represented under alkaline conditions for second step reaction
Object,
Wherein,
R is hydrogen or amino protecting group；
The preferred alkoxy carbonyl group class amino protecting group of the amino protecting group, acyl group class amino protecting group, sulphonyl base class amino
Protecting group or alkyls amino protecting group,
The alkoxy carbonyl group class amino protecting group is selected from benzyloxycarbonyl group (Cbz), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyloxycarbonyl
(Alloc), trimethylsilyl ethoxycarbonyl (Teoc), methoxycarbonyl group or carbethoxyl group；
The acyl group class amino protecting group is selected from phthalyl (Pht), trifluoroacetyl group (Tfa), pivaloyl group, benzene
Formoxyl, formoxyl or acetyl group；
The sulphonyl base class amino protecting group is selected from p-toluenesulfonyl (Tos or Ts), ortho-nitrophenyl sulfonyl (o-Ns)
Or p-nitrophenyl sulfonyl (p-Ns)；
The alkyls amino protecting group is selected from trityl (Trt), 2,4- dimethoxy-benzyls (Dmb), to methoxyl group
Benzyl (PMB) or benzyl (Bn).
In a preferred scheme of the invention, R is selected from alkoxy carbonyl group class amino protecting group, the alkoxy carbonyl group class amino
The preferred benzyloxycarbonyl group of protecting group (Cbz), tablet held before the breast by officials methoxycarbonyl group (Fmoc) or allyloxycarbonyl (Alloc), more preferable tablet held before the breast by officials methoxycarbonyl group
(Fmoc)。
Preferably, the method is
It is furthermore preferred that the method is
In said program, the coupling agent of the first step reaction is selected from dicyclohexylcarbodiimide (DCC), (7- is aoxidized 2-
Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), O- benzotriazole-tetramethylurea hexafluorophosphoric acid
Ester (HBTU), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), propylphosphonic anhydride (T3P), six
Fluorophosphoric acid benzotriazole -1- bases-oxygroup tripyrrole alkyl phosphorus (PyBop), N, N'- carbonyl dimidazoles (CDI), N, N- diisopropyls
Carbodiimide (DIC) or isobutyl chloride formates, preferably dicyclohexylcarbodiimide (DCC).
In said program, second step reaction be added in organic solvent or mixed organic solvents under conditions of alkali into
Row cyclization and deprotection reaction,
The organic solvent is selected from halogenated hydrocarbon solvent, ether solvent, amide solvent, nitrile solvents or alcohols solvent,
The preferred dichloromethane of halogenated hydrocarbon solvent or chloroform, the preferred tetrahydrofuran of ether solvent or ether, amide solvent preferred N, N-
Dimethylformamide, the preferred acetonitrile of nitrile solvents, the preferred methanol of alcohols solvent or ethyl alcohol, ORGANIC SOLVENT MIXTURES be selected from alcohols,
The mixed solvent of the mixed solvent or halogenated hydrocarbon and nitrile composition of ethers and nitrile solvents composition, the preferred dichloromethane of organic solvent
Alkane, the preferred methanol/Isosorbide-5-Nitrae-dioxane/acetonitrile of mixed organic solvents or dichloromethane/acetonitrile, alkali are selected from morpholine, N- methyl
Morpholine, diisopropylethylamine, triethylamine, n,N-Dimethylaniline, pyridine or alkali metal hydrogencarbonate, preferably morpholine or three
Ethamine, the preferred sodium bicarbonate of alkali metal hydrogencarbonate.
Formula (II) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared the present invention also provides a kind of
The method of body, which is characterized in that described method includes following steps：
The first step reaction be in the presence of two (trimethyl silicon substrate) lithium amides (LiHMDS) as shown in formula (III) compound with
Compound shown in formula (II ˊ) is obtained by the reaction in dimorpholine base time phosphonic chloride,
Compound shown in formula (II) is obtained by the reaction with isopropanolamine for compound shown in formula (II ˊ) in second step reaction.
It is further included in method and step and adds in the step of acid is post-processed, the acid preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzene
Sulfonic acid or p-methyl benzenesulfonic acid, more preferable hydrochloric acid；Water phase uses saturation NaHCO after being extracted with organic solvent3Aqueous solution, saturation NH4Cl water
For solution with after purifying water washing, organic phase is dry, filters, product is obtained after concentration.
It is further included in above method step and prepares formula (I) compound represented, its pharmaceutically acceptable salt or its solid
The step of isomers：
Wherein, compound shown in formula (II) first passes through oxidation reaction, then is obtained shown in formula (I) in acid condition cyclization
Compound, the acid preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, more preferable p-methyl benzenesulfonic acid.
Preferably, the method is
In said program, compound shown in the formula (IIIa) is dissolved in organic solvent, and low temperature adds in two (trimethyl silicanes
Base) lithium amide (LiHMDS), stirs, adds in dimorpholine base time phosphonic chloride, low temperature is stirred to react, and adds in isopropanolamine, and reaction is tied
Shu Hou adds in diluted hydrochloric acid aqueous solution into reaction solution, and water phase is extracted with organic solvent, and after organic phase drying, filtering is concentrated to give
Product；The organic solvent is selected from ether organic solvent, the preferred tetrahydrofuran of ether solvent.
In said program, dimethyl sulfoxide (DMSO) is added in, oxalyl chloride is added under low temperature, is stirred, is added shown in the formula (II)
The dichloromethane solution of compound, stirring add in triethylamine, wash, dry, filter, and concentration, gained residue is dissolved in organic
In solvent, carry out cyclization in acid condition, concentrate, wash, it is dry, filter, concentration, column chromatography purify shown in formula (I)
Compound；The organic solvent is selected from alcohols or esters solvent, the preferred methanol of alcohols solvent, esters solvent ethyl acetate；
The acid preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, more preferable p-methyl benzenesulfonic acid.
Formula (I) compound represented, its pharmaceutically acceptable salt or its solid are prepared the present invention further provides a kind of
The method of isomers, which is characterized in that described method includes following steps：
Compound is reacted with (2- amino -5- bromophenyls) (pyridine -2- bases) ketone as shown in formula (V) in the presence of a coupling agent
Compound shown in formula (IV) is obtained, compound shown in formula (III), institute is obtained by the reaction in formula (IV) compound represented under alkaline conditions
The preferred morpholine of alkali is stated, compound shown in formula (III) is in the presence of two (trimethyl silicon substrate) lithium amide (LiHMDS) alkali with two
Compound shown in formula (II ˊ) is obtained by the reaction in quinoline base time phosphonic chloride, and formula is obtained by the reaction with tert-butyl alcohol amine in compound shown in formula (II ˊ)
(II) compound shown in, compound shown in formula (II) first passes through oxidation reaction, then obtains formula (I) institute in acid condition cyclization
Show compound, the preferred p-methyl benzenesulfonic acid of acid.
Preferably, the method is
It is furthermore preferred that the method is
The present invention also provides the method for the pharmaceutically acceptable salt of compound shown in a kind of formula (Ia), including above-mentioned
Step in scheme and the step that its pharmaceutically acceptable salt is prepared is reacted with acid by compound shown in formula (Ia)
Suddenly, the acid is selected from organic acid or inorganic acid, preferably organic acid；The organic acid is selected from acetic acid, trifluoroacetic acid, oxalic acid, winestone
Acid, maleic acid, fumaric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, ethanesulfonic acid or methanesulfonic acid, preferably p-methyl benzenesulfonic acid；The inorganic acid choosing
From hydrochloric acid, sulfuric acid or phosphoric acid.
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, science used herein and skill
Art noun has the normally understood meaning of those skilled in the art institute.However, it for a better understanding of the present invention, is provided below
The definition and explanation of part relational language.In addition, as the definition and explanation of term provided herein and people in the art
When the normally understood meaning of member institute is inconsistent, with the definition of term provided herein and it is construed to accurate.
" amino protecting group " of the present invention is to refer to protection amino, avoid the group to react, common ammonia
Base protecting group includes but not limited to：(amino and carbonochloridic acid ester, diazo ester or all kinds of carbonic esters etc. react system to formate ester
It is standby), imines (primary amine and aromatic aldehyde, aromatic ketone or aliphatic ketone etc. react preparation), alkoxy carbonyl group class (benzyloxycarbonyl group (Cbz), uncle
Butoxy carbonyl (Boc), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), methoxy
Carbonyl or carbethoxyl group), (amino and acyl chlorides or acid anhydrides etc. react preparation to acyl group class, such as phthalyl (Pht), trifluoro second
Acyl group (Tfa), pivaloyl group, benzoyl, formoxyl or acetyl group), sulphonyl base class (aromatic amide class such as tolysulfonyl
Base (Tos or Ts), ortho-nitrophenyl sulfonyl (o-Ns) or p-nitrophenyl sulfonyl (p-Ns)) or alkyls (trityl
(Trt), 2,4- dimethoxy-benzyls (Dmb), to methoxy-benzyl (PMB) or benzyl (Bn)) etc., wherein " alkoxy carbonyl group class, acyl
Base class, sulphonyl base class " refer respectively to R-O-C (O)-, R-C (O)-, R-S (O)2, wherein R can be hydrogen atom, alkyl or aryl
Wait groups.
" aryl " of the present invention refer to that 6 to 14 yuan of full carbon with conjugated pi electron system are monocyclic or fused polycycle (also
It is the ring of shared adjacent carbon atoms pair) group, preferably 6 to 8 yuan of aryl, more preferable phenyl, anthryl or phenanthryl.
" halogenated " of the present invention refers to be replaced by " halogen atom ", and " halogen atom " refers to that fluorine atom, chlorine atom, bromine are former
Son, iodine atom etc..
" alkyl " of the present invention refers to the alkyl containing 1-20 carbon atom of linear chain or branch chain, including such as " C1-6Alkane
Base ", " C1-4Alkyl " etc., specific example includes but not limited to：It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, secondary
Butyl, tertiary butyl, n-pentyl, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, n-hexyl, isohesyl, 3- methylpents
Base, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- bis-
Methyl butyl, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- ethyl-butyls, 1,2- dimethyl propyls etc..
" amide-type organic solvent " of the present invention refers to hydroxyl in carboxylic acid molecules in carboxyl by amino or hydrocarbon amino
(- NHR or-NR2) replace the liquid compound formed；Also the hydrogen in ammonia or amine molecule on nitrogen-atoms is considered as by acyl group to be replaced
The liquid compound formed；Specific example includes but not limited to：N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
" ether solvent " of the present invention refers to containing the chain compound that ehter bond-O- and carbon atom number are 1 to 10
Or cyclic compound, specific example include but not limited to：Propylene glycol monomethyl ether, tetrahydrofuran or 1,4- dioxane.
" esters solvent " of the present invention refers to the rudimentary organic acid and carbon atom quantity that carbon atom quantity is 1 to 4
For the conjugate of the lower alcohol of 1 to 6, specific example includes but not limited to：Ethyl acetate, isopropyl acetate or butyl acetate.
" alcohols solvent " of the present invention refers to one or more hydrogen on one or more " hydroxyl " substitutions " alkyl "
Group derived from atom, " alkyl " as defined hereinabove, specific example includes but not limited to：Methanol, ethyl alcohol, second two
Alcohol, normal propyl alcohol or 2- propyl alcohol.
" halogenated hydrocarbon solvent " of the present invention refers to one on one or more " halogen atom " substitutions " alkyl "
Or group derived from multiple hydrogen atoms, as defined hereinabove, specific example is included but not for " halogen atom " and " alkyl "
It is limited to：Chloromethanes, dichloromethane, chloroform or carbon tetrachloride.
" nitrile solvents " of the present invention refer to one or more hydrogen on one or more " cyano " substitutions " alkyl "
Group derived from atom, " alkyl " as defined hereinabove, specific example includes but not limited to：Acetonitrile or propionitrile.
" mixed solvent " of the present invention refers to that one or more different types of organic solvents mix according to a certain percentage
Close the solvent that the solvent formed or organic solvent mix according to a certain percentage with water.
Advantageous effect of the invention
With the prior art (WO0069836A1, publication date 2000-11-23；WO2011032692A1, publication date 2011-03-
24) it compares, the technical solution that the present invention prepares compound shown in formula (I) has the following advantages：
The present invention is different from the starting material of the prior art, prepares coupled reaction step letter during formula (III) compound
Single, ring-closure reaction and deprotection reaction condition can carry out under the same conditions, and obtained formula (III) compound purity is high；It prepares
The post-processing step of intermediate is avoided in formula (II) chemical procedure, under the premise of ensureing purity, yield improves；Present invention contracting
Short reaction step avoids multistep post-processing approach, and operating method is more simpler, easy to operate with art methods.
Specific embodiment
It is used to further describe the present invention, but these embodiments are not intended to limit the scope of the invention with reference to embodiments.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition or according to raw material or
Condition proposed by commodity manufacturer.The reagent in specific source is not specified, the conventional reagent for market purchase.
Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-6
(ppm) unit provides.The measure of NMR is to use Bruker AVANCE-500 nuclear magnetic resonance spectrometers, and measure solvent is deuterated methanol
(CD3OD), inside it is designated as tetramethylsilane (TMS).
The measure of MS is with FINNIGAN LCQ (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan LCQ
DECA XP MAX)。
The measure of HPLC uses Agilent 1200DAD high pressure liquid chromatographs (Agilent Plus C18150 × 4.6mm
Chromatographic column).
Embodiment 1, (S) -3- (the bromo- 2- oxos -5- of 7- (pyridine -2- bases) -2,3- dihydro -1H- benzos [e] [1,4] phenodiazines
It is miscellaneous- 3- bases) methyl propionate preparation
The first step
(2- amino -5- bromophenyls) (pyridine -2- bases) ketone
Tetrahydrofuran (44mL) is added in into reaction bulb, nitrogen is protected, -40 DEG C of addition n-BuLis (51mL), in control
Temperature is no more than -20 DEG C, reduces temperature to -40 DEG C, 2- bromopyridines (15.8g) are slowly added dropwise, and drips and finishes insulation reaction 1 hour, control
- 40 DEG C of temperature is hereinafter, the dropwise addition bromo- benzoic acid of 2- amino -5- (6.7g) is dissolved in the solution of (44mL) tetrahydrofuran, drop Bi Ziran liters
Temperature to 0 DEG C or so react 3 hours.10 DEG C of temperature in control hereinafter, saturated ammonium chloride solution (11mL) is slowly added dropwise, react by termination,
Water (50mL) is added, stratification divides and takes organic layer, and aqueous layer with ethyl acetate (50mL) extraction merges organic layer, uses saturation
Sodium-chloride water solution (40mL × 2) washs, anhydrous sodium sulfate drying, filtering, and grease, column chromatography purification are obtained after reduced pressure
(eluant, eluent PE:EA=3:1-1:1, volume ratio), positive component is collected, is concentrated to give solid product (4.37g, yield 50.7%).
Second step
(S) -4- ((((9H- fluorenes -9- bases) methoxyl group) carbonyl) amino) -5- ((4- bromo-2-pyridyls aminosulfonylphenyl) amino) -
5- oxos penta
Sour methyl esters
(2- amino -5- bromophenyls) (pyridine -2- bases) ketone (4g), Fmoc-L- glutamic acid methyl esters are added in reaction bulb
(6.2g) is dissolved in dichloromethane (50mL), is cooled to -10 DEG C, and the dichloromethane of 1,3- dicyclohexylcarbodiimides (3.0g) is added dropwise
Alkane (8mL) solution, -10 DEG C to -5 DEG C of temperature control keep the temperature -5 DEG C to 0 DEG C and react 48 hours, and filtering, filtrate decompression is concentrated into oily
Object obtains product crude product, direct plunges into next step.
Third walks
(S) -3- (the bromo- 2- oxos -5- of 7- (pyridine -2- bases) -2,3- dihydro -1H- benzos [e] [1,4] diazas-3-
Base) methyl propionate
20% morpholine/dichloromethane (35mL) stirring and dissolving is added in into grease, is reacted at room temperature about 20 hours, reaction
After wash four times, by morpholine cleaning, drying concentrate after column chromatography (eluant, eluent：CH2Cl2→CH2Cl2:CH3OH=100:1
~50:1, volume ratio), obtain crude product (3.7g, yield 63.7%, HPLC>96%), addition isopropanol (15mL) is heated to molten
Clearly, stirring and crystallizing at room temperature, is obtained by filtration target product (2.8g, yield 48.2%, HPLC:99.84%).
Embodiment 2, (S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazos [1,2-a] [1,4]
Diaza- 4- bases) methyl propionate preparation
The first step
3- (the bromo- 2- of (3S) -7- ((2- hydroxypropyls) amino) -5- (pyridine -2- bases) -3H- benzos [e] [1,4] diazas- 3- bases) methyl propionate
Under argon gas protection, phosphorus oxychloride (1.2kg) is added in toluene (6.4kg) in reaction bulb, stirring and dissolving, cooling
To 5 DEG C, by morpholine (2.68kg) in being instilled in 2h wherein, temperature control is no more than 20 DEG C.Drop finishes, and reacts at room temperature 3h.It filters insoluble
Object washs (1kg × 3), merging filtrate three times with toluene, is concentrated under reduced pressure into grease, adds in toluene about (1.92kg), is heated to
It is uniformly dissolved, is added with stirring petroleum ether (860g) (if any insoluble matter, need to filter while hot), adds petroleum ether (3.48kg),
It is cooled to room temperature, filters, filter cake is dried under reduced pressure to obtain dimorpholine base time phosphonic chloride solid with petroleum ether (1.2kg × 2)
(1.3kg), kept dry is spare.
(S) -3- (the bromo- 2- oxos -5- of 7- (pyridine -2- bases) -2,3- dihydro -1H- benzos [e] [1,4] are added in reaction bulb
Diaza- 3- bases) methyl propionate (800g), tetrahydrofuran (6.8kg), the lower stirring and dissolving of argon gas protection.Reaction solution is cooled down
To -30 DEG C, the THF solution (2.5kg) of bis- (trimethyl silicon substrate) lithium amides (LiHMDS) of 1M of (2.4L) is instilled, about 1h is dripped off,
Exothermic heat of reaction controls temperature to be no more than -20 DEG C during dropwise addition, drop, which finishes, to be continued to stir 1h in -20 DEG C.Then in 30min in batches
Dimorpholine base time phosphonic chloride (1.2kg) is added in, finishes and stirs 4h in -10 DEG C~0 DEG C.
Isopropanolamine (524g) is added drop-wise in above-mentioned reaction solution, temperature control is no more than 0 DEG C, drips and finishes 0 DEG C of reaction 15h of temperature control,
Isopropanolamine (149.4g) is added, continues to be stirred to react 5h, stops reaction.
The fast drop 1N HCl/waters solution (5L) into reaction solution, temperature control are no more than 30 DEG C, are stirred to react 0.5h, liquid separation,
Concentration of organic layers.Water layer is extracted through dichloromethane (5.4kg × 2), gained organic phase and saturated sodium bicarbonate aqueous solution (6kg) one
It rises and adds in into concentrated residues object, fully liquid separation after dissolving.Organic phase is respectively with saturated aqueous ammonium chloride (4.8kg) and purifying
Water (3.6kg) washs, and anhydrous sodium sulfate drying, filtering is concentrated to dryness, gained grease column chromatography purifying (eluent petroleum ether:
Ethyl acetate=1:1 → ethyl acetate), collect positive component, be concentrated under reduced pressure in 45 DEG C product (730g, yield 80.0%,
HPLC:98.5%).
Second step
(S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazo [1,2-a] [1,4] diazas
- 4- bases) methyl propionate
Dimethyl sulfoxide (DMSO) (493g), dichloromethane (12.5kg), stirring cooling, in -60 DEG C~-70 DEG C are added in reaction bulb
Lower dropwise addition oxalyl chloride (413g), finishes insulation reaction 1h, adds in 3- (the bromo- 2- of (3S) -7- ((2- hydroxypropyls) amino) -5- (pyrroles
Pyridine -2- bases) -3H- benzos [e] [1,4] diaza- 3- bases) methyl propionate (725g) and the mixing of dichloromethane (1.9kg) it is molten
After insulated and stirred reacts 3h, triethylamine (924g) is added dropwise in liquid, and drop Bi Ziran, which is warmed to room temperature, is stirred to react 3h.After reaction, instead
System is answered to be washed successively with saturated sodium bicarbonate aqueous solution (8.6kg), water (7kg) and saturated sodium-chloride water solution (8.6kg), is had
Machine is mutually dried over anhydrous sodium sulfate, filtering, is concentrated under reduced pressure in 40 DEG C and is done to obtain product.
Above-mentioned products therefrom is dissolved in methanol (4.49kg), p-methyl benzenesulfonic acid (120g) is added in, is stirred to react in 25 DEG C
Reaction solution is concentrated under reduced pressure into dry by 16h.Residue with Ethyl acetate (10kg) dilutes, and uses saturated sodium bicarbonate aqueous solution successively
(8.6kg), water (7kg) and saturated sodium-chloride water solution (8.6kg) washing, organic phase are dried over anhydrous sodium sulfate, and are filtered, 40 DEG C
It is concentrated under reduced pressure into dry.Gained grease column chromatography purifies (eluant ethyl acetate:Petroleum ether=1:1 → ethyl acetate), it collects
Positive component, 40 DEG C are concentrated under reduced pressure to obtain target product (526g, yield 75.9%, HPLC:99.4%).
Embodiment 3, (S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazos [1,2-a] [1,4]
Diaza- 4- bases) methyl propionate toluene fulfonate preparation
(1) preparation of crude product
(S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazos [1,2- are added in reaction bulb
A] [1,4] diaza- 4- bases) methyl propionate (519g), ethyl acetate (3.76kg), stirring and dissolving, in 30min be added dropwise pair
Methanol (416g) solution of toluenesulfonic acid (213.8g), drop, which finishes, is stirred at room temperature 50min, filters, obtains filter cake, be dried under reduced pressure to obtain class
White powdery solids (537g, yield 74.3%, HPLC:99.81%).
(2) purifying of product
Into reaction bulb, put into (S) -3- (the bromo- 1- methyl -6- of 8- (pyridine -2- bases) -4H- benzos [f] imidazo [1,
2-a] [1,4] diaza- 4- bases) methyl propionate toluene fulfonate crude product (532g), it is added with stirring 80~90 DEG C of purifying
Water (6.38kg) stirs 5min, filters while hot, filtrate water-bath stirring and crystallizing 20h, filters, and is dried under reduced pressure, obtains white solid at 40 DEG C
Body (356g, yield 66.9%, HPLC:99.89%).
MS m/z(ESI):439.09[M–C7H8SO3+1]
1H-NMR(500MHz,CD3OD)δ8.56-8.57(d,1H),8.14-8.16(d,1H),8.03-8.05(m,1H),
7.99-8.01(dd,1H),7.80-7.82(d,1H),7.67-7.70(m,3H),7.57-7.59(m,1H),7.45(d,1H),
7.20-7.22(d,2H),4.45-4.48(m,1H),3.69(s,3H),2.77-2.86(m,2H),2.67-2.74(m,1H),
2.57-2.64(m,1H),2.49-2.49(s,3H),2.35(s,3H)。
Claims (15)
1. a kind of method for preparing formula (III) compound represented, its pharmaceutically acceptable salt or its stereoisomer, special
Sign is that described method includes following steps：
First step reaction is compound and (2- amino -5- bromophenyls) (pyridine -2- bases) as shown in formula (V) in the presence of a coupling agent
Formula (IV) compound represented is obtained by the reaction in ketone,
Formula (III) compound represented is obtained by the reaction for the reaction of formula (IV) compound represented in second step reaction under alkaline conditions,
Wherein,
R is hydrogen or amino protecting group.
2. formula (III) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as described in claim 1
The method of body, wherein,
R is selected from alkoxy carbonyl group class amino protecting group, the preferred benzyloxycarbonyl group of the alkoxy carbonyl group class amino protecting group, tablet held before the breast by officials methoxycarbonyl group
Or allyloxycarbonyl, more preferable tablet held before the breast by officials methoxycarbonyl group.
3. formula (III) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 2
The method of body, which is characterized in that the method is
4. formula (III) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 3
The method of body, which is characterized in that the method is
5. preparation formula (III) compound represented, its pharmaceutically acceptable salt as described in any one of claim 1-4 or
The method of its stereoisomer, which is characterized in that the coupling agent of the first step reaction is selected from dicyclohexylcarbodiimide, 2-
(7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, O- benzotriazole-tetramethylurea hexafluorophosphoric acid
Ester, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, propylphosphonic anhydride, hexafluorophosphoric acid benzotriazole -1- bases -
Oxygroup tripyrrole alkyl phosphorus, N, N'- carbonyl dimidazoles, N, N- diisopropylcarbodiimide or isobutyl chloride formates, preferably two
Carbodicyclo hexylimide.
6. preparation formula (III) compound represented, its pharmaceutically acceptable salt as described in any one of claim 1-4 or
The method of its stereoisomer, which is characterized in that the second step reaction is added in organic solvent or mixed organic solvents
Cyclization and deprotection reaction are carried out under conditions of alkali,
The preferred dichloromethane of organic solvent, the preferred methanol/Isosorbide-5-Nitrae-dioxane/acetonitrile of mixed organic solvents or dichloromethane
Alkane/acetonitrile, the preferred morpholine of alkali or triethylamine.
7. a kind of method for preparing formula (II) compound represented, its pharmaceutically acceptable salt or its stereoisomer, special
Sign is that described method includes following steps：
The first step reaction be in the presence of two (trimethyl silicon substrate) lithium amides (LiHMDS) as shown in formula (III) compound and two
Compound shown in formula (II ˊ) is obtained by the reaction in quinoline base time phosphonic chloride,
Compound shown in formula (II) is obtained by the reaction with isopropanolamine for compound shown in formula (II ˊ) in second step reaction.
8. formula (II) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 7
The method of body, which is characterized in that the method, which further includes, adds in acid the step of being post-processed, the acid preferably hydrochloric acid, acetic acid,
Ethanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, more preferable hydrochloric acid.
9. formula (II) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 8
The method of body, which is characterized in that the method further include prepare formula (I) compound represented, its pharmaceutically acceptable salt or
The step of its stereoisomer：
Wherein, compound shown in formula (II) first passes through oxidation reaction, then obtains chemical combination shown in formula (I) in acid condition cyclization
Object, the acid preferably hydrochloric acid, acetic acid, ethanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, more preferable p-methyl benzenesulfonic acid.
10. formula (II) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 7
The method of body, which is characterized in that the method is
11. formula (II) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 9
The method of body, which is characterized in that the method is
12. a kind of method for preparing formula (I) compound represented, its pharmaceutically acceptable salt or its stereoisomer, special
Sign is that described method includes following steps：
Compound is obtained by the reaction with (2- amino -5- bromophenyls) (pyridine -2- bases) ketone as shown in formula (V) in the presence of a coupling agent
Compound shown in formula (III), formula is obtained by the reaction in compound shown in formula (IV), formula (IV) compound represented under alkaline conditions
(III) compound shown in is reacted in the presence of two (trimethyl silicon substrate) lithium amide (LiHMDS) alkali with dimorpholine base time phosphonic chloride
To compound shown in formula (II ˊ), compound shown in formula (II), formula is obtained by the reaction with isopropanolamine in compound shown in formula (II ˊ)
(II) compound shown in first passes through oxidation reaction, then obtains compound shown in formula (I) in acid condition cyclization.
13. formula (I) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 12
The method of body, which is characterized in that the method is
14. formula (I) compound represented, its pharmaceutically acceptable salt or its alloisomerism are prepared as claimed in claim 13
The method of body, which is characterized in that the method is
15. a kind of method of the pharmaceutically acceptable salt of compound shown in formula (Ia), including claim 12 to 14 times
Step described in one and the step that its pharmaceutically acceptable salt is prepared is reacted with acid by compound shown in formula (Ia)
Suddenly, the acid is selected from organic acid or inorganic acid, preferably organic acid；The organic acid is selected from acetic acid, trifluoroacetic acid, oxalic acid, winestone
Acid, maleic acid, fumaric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, ethanesulfonic acid or methanesulfonic acid, preferably p-methyl benzenesulfonic acid；The inorganic acid choosing
From hydrochloric acid, sulfuric acid or phosphoric acid.
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| WO2019020790A1 (en) * | 2017-07-28 | 2019-01-31 | Moehs Iberica S.L. | Method for preparing 3-[(3s)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1h-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester, and compounds useful in that method |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| CN112321594A (en) * | 2020-12-07 | 2021-02-05 | 扬子江药业集团有限公司 | Preparation method of benzodiazepine medicine |
| CN112661759A (en) * | 2019-10-16 | 2021-04-16 | 浙江京新药业股份有限公司 | Benzodiazepine compound and preparation method thereof |
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| CN114014839A (en) * | 2021-12-16 | 2022-02-08 | 上海再启生物技术有限公司 | Method for preparing key intermediate of remimazolam |
| CN114644612A (en) * | 2020-12-17 | 2022-06-21 | 成都苑东生物制药股份有限公司 | Preparation method of benzodiazepine neuroleptic intermediate compound |
| CN115385891A (en) * | 2022-09-06 | 2022-11-25 | 上海药坦药物研究开发有限公司 | Preparation method of remazolam intermediate |
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| WO2019020790A1 (en) * | 2017-07-28 | 2019-01-31 | Moehs Iberica S.L. | Method for preparing 3-[(3s)-7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1h-[1,4]-benzodiazepin-3-yl] propionic acid methyl ester, and compounds useful in that method |
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| CN112661759A (en) * | 2019-10-16 | 2021-04-16 | 浙江京新药业股份有限公司 | Benzodiazepine compound and preparation method thereof |
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| CN112321594B (en) * | 2020-12-07 | 2022-05-20 | 扬子江药业集团有限公司 | Preparation method of benzodiazepine medicine |
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| CN114014839A (en) * | 2021-12-16 | 2022-02-08 | 上海再启生物技术有限公司 | Method for preparing key intermediate of remimazolam |
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