CN104892555B - The preparation method of your intermediate of treprostinil - Google Patents
The preparation method of your intermediate of treprostinil Download PDFInfo
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- CN104892555B CN104892555B CN201510093682.XA CN201510093682A CN104892555B CN 104892555 B CN104892555 B CN 104892555B CN 201510093682 A CN201510093682 A CN 201510093682A CN 104892555 B CN104892555 B CN 104892555B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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Abstract
The present invention relates to the preparation methods of your intermediate (I) of treprostinil comprising: formula (II) compound reacts to obtain formula (IV) compound in the presence of condensing agent with formula (III) compound or its acid salt；Formula (IV) compound reacts to obtain formula (I) compound with formula (V) compound.The present invention, which is reacted using weber amide with alkynes anion, directly obtains ketone compound (I), it avoids using environmental pollution caused by heavy metal (PCC oxidant), the low-temp reaction method using butyl lithium is also avoided simultaneously, reaction condition of the present invention is mild, high income, good product purity, prospects for commercial application are wide.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of preparation method of your intermediate of treprostinil.
Background technique
Pulmonary hypertension (PAH) is the raised disease of pressure anomaly in a kind of pulmonary artery as caused by known or unknown cause
Or pathologic, physiologic syndrome, with the vasopasm of lung parteriole, endometrial hyperplasia, middle layer plumpness, outer membrane hyperplasia, primary thrombus shape
Change etc. at, different degrees of inflammation and plexi and be characterized, clinical manifestation is that pulmonary arterial pressure progressive increases and eventually leads to the right side
Heart failure.Pulmonary hypertension is a kind of cardiovascular disease that prognosis is very poor, and disease incidence is low, in Europe and the U.S. every million people every year
In have that 1~2 human hair is sick, be rare disease, WHO defines the diagnostic criteria of PAH are as follows: mean pulmonary arterial pressure is greater than under quiescent condition
25mmHg (1mmHg=0.133kPa) is greater than 30mmHg under motion state, and the country there is no exact epidemiologic data.
In terms of existing therapeutic agent, external there are many specific antihypertensive drugs object listings, including the smooth class medicine of life
Object (ambrisentan, Bosentan), 5 type phosphodiesterase inhibitors (silaenafil, Tadalafil), prostacyclin class drug (she
Lip river forefront element, treprostinil that, Epoprostenol).The country is seldom for the specific treatment drug of pulmonary hypertension, only Yi Luo
Forefront element (commodity life: Wan Tawei), Bosentan (trade name: Quan Keli), ambrisentan piece (all Rakes) are approved to list, and control at present
Treat drug there are half-life short, must can using administration pump Intravenous Infusion by the permanent catheter being placed in big vein
Infusion interruption and bloodstream infection etc. can be will lead to.Therefore, existing sitaxsentan sodium object is difficult to meet clinical demand, urgently
Need to introduce new active drug.
Your injection of treprostinil is one of the effective ejection preparation for treating pulmonary hypertension, and overseas clinical trial data are aobvious
Show that this product clinical efficacy is definite, safety is better than other prostacyclin analogs class drugs listed.In the U.S., plus take
Greatly, Australia and Europe listing many years, and in the multiple country's listings in Asia.This product stability is preferable, long half time, mainly
It is administered using subcutaneous continuous infusion mode, also sustainable intravenous infusion administration, transdermal delivery mechanisms are comparatively safe, can reduce
The risk of severe infections septicemia.
You are researched and developed by American Association drugmaker (United Therapeutics) to treprostinil, in states such as the U.S.
Family's listing, is the drug of prostanoid treatment pulmonary hypertension, and compound patent US4306075A is expired.1999
Year, United Therapeutics house journal application WO9921830A1 discloses a kind of method for preparing treprostinil that,
The synthetic route of report is as follows:
And periodical J.Org.Chem.2004,69,1890-1902 optimize the preparation process of WO9921830A1 report, and
Disclose the preparation method of side chain compound 6:
In the above preparation method, the difficult point of technique is the condensation reaction of compound 5 Yu compound 6, therefore, compound
8 be to prepare your key intermediate of treprostinil, is had the following deficiencies: in the preparation method
1, since in prepare compound 8, each intermediate is grease, and purifying products are difficult, column layer need to repeatedly be carried out
Analysis, solvent consumption is big, leads to cost increase and environmental protection pressure is big.
2, Claisen rearangement is reacted for pyroreaction, the unstability of aldehyde compound itself and is reacted for a long time in high temperature
A large amount of by-product macromolecule grease can be generated, it is necessary to it is chromatographed by column and removes grease, it is cumbersome.
3, the heavy metal that uses causes that environmental pollution is serious when PCC is aoxidized, and easily causes product heavy metals exceeding standard.
4, on the one hand use n-BuLi when prepare compound 6, and need -40 DEG C -- 50 DEG C of reactions, in addition use price compared with
Expensive trimethyl silicane propine, causes 6 cost of compound excessively high, severe reaction conditions, and industrial application value is low.
Summary of the invention
Of the existing technology in order to solve the problems, such as, inventor develops a kind of novel system in long-term R&D process
The method of standby your key intermediate (I) of treprostinil, reaction condition of the present invention is mild, technical maturity, and quality is stablized, and is very suitable for
Industrial application.
One aspect of the present invention provides a kind of preparation method of formula (I) compound, includes the following steps:
1) formula (II) compound reacts to obtain formula (IV) change in the presence of condensing agent with formula (III) compound or its acid salt
Close object；
2) formula (IV) compound reacts to obtain formula (I) compound with formula (V) compound, and reaction equation is as follows:
Wherein, R1、R2Independent is hydroxyl protection base.
As a preferred option, R1、R2It is independently selected from C1-8Alkyl, C1-8Alcoxyl C1-8Alkyl, halogen replace C1-8Alkane
Base, C3-8Naphthenic base, benzyl, C1-8Alkoxy substituted benzyl, THP trtrahydropyranyl ,-SiR3R4R5、-C(O)R3；R3、R4、R5Respectively solely
Vertical is selected from Cl-8Alkyl, C3-8Naphthenic base.
As scheme still more preferably, R1For benzyl, R2For 2- THP trtrahydropyranyl.
As a preferred option, the acid of formula (III) the compound acid salt refers to organic acid or inorganic acid, and described has
Machine acid is selected from or mixtures thereof trifluoroacetic acid, trichloroacetic acid, Loprazolam, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid；Inorganic acid is selected from
Or mixtures thereof hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, formic acid, acetic acid.
As scheme still more preferably, the acid of formula (III) the compound acid salt is selected from hydrochloric acid.
As a preferred option, the condensing agent be selected from DIC, DCC, HOBT, EDC.HCl, PyBOP, PyBroP,
Or mixtures thereof HATU, HCTU, DEPBT, EEDQ, CDI.
As a preferred option, the addition in step 2) is tried relative to the grignard of formula (IV) 0.5-10 times of mole of compound
Agent, the Grignard Reagent of preferably 1.0-2.0 times mole, the preferred methyl-magnesium-bromide of the Grignard Reagent, ethylmagnesium bromide, methyl chloride
Change magnesium, ethylmagnesium chloride.
Further, formula (II) compound can be prepared by the following procedure method and be made:
Wherein R1If formula (I) compound defines, R6Selected from C substituted or unsubstituted1-8Alkoxy, C substituted or unsubstituted3-8
Cycloalkyloxy, the substituent group are selected from halogen, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, 3-8 member are miscellaneous
Ring group, 3-8 circle heterocyclic ring base oxygroup, C5-10Aryl, C5-10Aryloxy, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup；It is described
Alkali be selected from sodium hydroxide, potassium hydroxide, or mixtures thereof lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate.
Further, method can be prepared by the following procedure again and be made for formula (Ⅸ) compound:
Wherein R1If formula (I) compound defines, R6Single step reaction Chinese style (Ⅸ) compound as above is defined；The alkali
For organic base or inorganic base, the organic base is selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, the nothing
Machine alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, vinegar
Or mixtures thereof sour sodium；
Further, method can be prepared by the following procedure again and be made for formula (VIII) compound:
Wherein R6Single step reaction Chinese style (Ⅸ) compound as above is defined, preferably methoxyl group, ethyoxyl；X is halogen, preferably
Bromine.
Further, formula (V) compound can be prepared by the following procedure method and be made: using formula (Ⅺ) compound as raw material
The formula (V) compound is prepared, the preparation method is as follows:
Alternatively,
Alternatively,
Wherein R2、R3、R4、R5If formula (I) compound defines, X is halogen
Further, formula (Ⅺ) compound can be prepared by the following procedure method and be made:
Another aspect of the present invention provides a kind of method with (S) -1,2- oxepane for raw material preparation formula (V) compound,
Include the following steps:
Wherein R2As formula (I) compound defines；X is halogen.
As preferential scheme, work as R2When selected from 2- THP trtrahydropyranyl (THP), it is specific the preparation method is as follows:
Another aspect of the present invention provides a kind of method with (S) -1,2- oxepane for raw material preparation formula (V) compound,
Include the following steps:
Wherein R2、R3、R4、R5As formula (I) compound defines.
As preferential scheme, work as R2When selected from 2- THP trtrahydropyranyl, it is specific the preparation method is as follows:
Another aspect of the present invention provides a kind of method with (S) -1,2- oxepane for raw material preparation formula (V) compound,
Include the following steps:
Wherein R2As formula (I) compound defines；X is halogen.
As preferential scheme, work as R2When selected from 2- THP trtrahydropyranyl, it is specific the preparation method is as follows:
Another aspect of the invention provides a kind of novel intermediates formula (IV) compound of preparation formula (I) compound:
Wherein, R1Selected from C1-8Alkyl, C1-8Alcoxyl C1-8Alkyl, halogen replace C1-8Alkyl, C3-8Naphthenic base, benzyl, C1-8Alkane
Oxygroup substituted benzyl, THP trtrahydropyranyl ,-SiR3R4R5、-C(O)R3；R3、R4、R5It is independently selected from selected from Cl-8Alkyl, C3-8
Naphthenic base.
As preferential scheme, R1Selected from methyl, ethyl, tert-butyl or benzyl.
Compared with prior art, present invention has the advantage that
1, the present invention prepares treprostinil that intermediate (I) using two-step reaction, and reaction condition is mild, and intermediate (I) is pure
Degree is greater than 95% or more, and prospects for commercial application is wide.
2, Claisen rearangement byproduct of reaction of the present invention can be removed by subsequent hydrolysis, the subsequent hydroxyl of formula (VIII) compound
Obtaining formula (II) compound after base protection, ester hydrolysis is solid, is easy recrystallization purifying, avoids column chromatography, and pure after purification
Degree is conducive to the progress of subsequent reactions up to 98% or more.
3, a noval chemical compound i.e. formula (IV) compound is obtained when the present invention prepares your intermediate (I) of treprostinil.
4, the present invention, which is reacted using weber amide with alkynes anion, directly obtains ketone compound (I), avoids the prior art
It is middle to use environmental pollution caused by heavy metal (PCC oxidant).
5, weber amide of the present invention can be by Grignard Reagent in condition (room temperature as mild as a dove with reacting for alkynes anion
To 45 DEG C) under react, avoid industrial more difficult ultralow temperature reaction, simplify operation, greatly reduce energy consumption.
6, the present invention provides three kinds of different method preparation formulas by raw material of (S) -1,2- oxepane formula (Ⅺ) compound
(V) compound obtains single substituent using epoxide selectivities necleophilic reaction open loop, and reaction condition is mildly easy to operate
Safety, raw material is simple and easy to get and cheap with reagent, and products obtained therefrom GC purity is up to 90% or more, much higher than prior art report
GC purity is suitble to industrial application.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and below (such as embodiment)
It can be combined with each other between each technical characteristic of middle specific descriptions, to constitute new or preferred technical side
Case.Due to space limitations, I will not repeat them here.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there is following contain with term in the specification and in the claims
Justice.
“C1-8Alkyl " refers to that straight chained alkyl and containg branched alkyl radical including 1 to 8 carbon atom, alkyl refer to the aliphatic hydrocarbon of saturation
Group, C0-8Refer to not carbon atoms or C1-8Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl,
2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate
Base, 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- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methyl
Hexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl,
3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethyl oneself
Base, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- second
Base amyl, 2- methyl -3- ethylpentyl or its various branched isomer etc..
Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be in any workable tie point
It is upper to be substituted, preferably one or more following groups, independently selected from halogen, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base,
C3-8Cycloalkyloxy, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, C5-10Aryl, C5-10Aryloxy, 5-10 unit's heteroaryl, 5-
Replaced the substituent group of 10 unit's heteroaryl oxygroups；
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, " C3-8Naphthenic base " refer to including 3 to
The naphthenic base of 8 carbon atoms, preferably monocyclic cycloalkyl, such as:
The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, ring
Hexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..
Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring." spiro cycloalkyl group ", which refers to, shares a carbon between monocycle
The polycyclic moiety of atom (claiming spiro-atom), these can be containing one or more double bonds, but none ring has total conjugated
Pi-electron system.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring
Base or more spiro cycloalkyl groups, the non-limiting embodiment of spiro cycloalkyl group includes:
" cycloalkyl " refers to the full carbon of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system
Polycyclic moiety, wherein one or more rings can be containing one or more double bonds, but none ring has the π electricity of total conjugated
Subsystem.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl can be divided into according to a group cyclic number, cycloalkyl it is unrestricted
Property embodiment includes:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, these can
To contain one or more double bonds, but none ring has the pi-electron system of total conjugated.It can be with according to group cyclic number
It is divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting embodiment of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure
Ring together is naphthenic base, and non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..
Naphthenic base can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, 3-8 circle heterocyclic ring base, 3-8
Circle heterocyclic ring base oxygroup, C5-10Aryl, C5-10Aryloxy, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup；
" cycloalkyloxy " refers to and-O- (unsubstituted naphthenic base), and wherein naphthenic base is as defined above.C3-8Cycloalkanes oxygen
Base refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting embodiment includes cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, hexamethylene oxygen
Base etc..
Alkoxy can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, 3-8 circle heterocyclic ring base, 3-8
Circle heterocyclic ring base oxygroup, C5-10Aryl, C5-10Aryloxy, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup；
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, wherein one or more annular atoms
Hetero atom selected from nitrogen, oxygen or S (O) r (wherein r is integer 0,1,2), but do not include the ring portion of-O-O- ,-O-S- or-S-S-
Point, remaining annular atom is carbon." 5-10 circle heterocyclic ring base " refers to the ring group comprising 5 to 10 annular atoms, and " 3-8 circle heterocyclic ring base ", which refers to, includes
The ring group of 3 to 8 annular atoms.
" aryl " refers to full carbon monocycle or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, has conjugation
Polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of pi-electron system, " C5-10Aryl " refers to the full carbon containing 5-10 carbon
Aryl, " 5-10 member aryl " refer to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthalene.The aryl rings can condense in
On heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limiting embodiment with the ring that precursor structure links together
Include:
" heteroaryl " refers to comprising 1 to 4 heteroatomic heteroaromatic system, and the hetero atom includes nitrogen, oxygen and S (O) r (its
Middle r is integer 0,1,2) hetero atom, and 5-7 unit's heteroaryl refers to the heteroaromatic system containing 5-7 annular atom, 5-10 unit's heteroaryl
Refer to the heteroaromatic system containing 5-10 annular atom, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals,
Pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring,
The ring wherein to link together with precursor structure is heteroaryl ring, and non-limiting embodiment includes:
" halogen " refers to fluorine, chlorine, bromine or iodine.
“-SiR3R4R5" refer to trialkyl silyl, preferably trimethyl silicane, triethyl group silicon, tert-butyldimethyl silyl etc..
Term " condensing agent " refers to the reagent that can cause condensation reaction.Condensation reaction refers to two or more organic molecule phases
A macromolecular is synthesized with covalently bonded after interaction, while losing water or other are fairly simple inorganic or small organic molecule
Reaction.Small-molecule substance therein is usually water, hydrogen chloride, methanol or acetic acid etc..The abbreviation of various condensing agents is right in the present invention
The Chinese answered is as shown in table 1.
The corresponding Chinese of abbreviation of the various condensing agents of table 1
| Referred to as | Chinese |
| DIC | N, N- diisopropylcarbodiimide |
| DCC | N, N- dicyclohexylcarbodiimide |
| HOBT | I-hydroxybenzotriazole |
| EDC.HCl | 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride |
| PyBOP | Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl |
| PyBroP | Tripyrrole alkane base phosphonium bromide hexafluorophosphate |
| HATU | 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester |
| HCTU | 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester |
| DEPBT | 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone |
| EEDQ | 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline |
| CDI | Carbonyl dimidazoles |
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention by no means, the present invention
Also it is not intended to be limited to the content of embodiment.
The compound of the present invention structure is determined by nuclear magnetic resonance (NMR) or/and LC-MS chromatography (LC-MS)
's.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).The measurement of NMR is with Bruker AVANCE-400 core
Magnetic instrument, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3) and deuterated chloroform (CDCl OD3) in be designated as
Tetramethylsilane (TMS).
The measurement of LC-MS chromatography LC-MS Agilent 1200Infinity Series mass spectrograph.The measurement of HPLC
Use Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatographic column) and Waters 2695-
2996 high pressure liquid chromatographs (Gimini C18150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC is used is
0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography generally uses cigarette
200~300 mesh silica gel of platform Huanghai Sea silica gel is carrier.
Starting material in the embodiment of the present invention is known and can be commercially available, or can use or press
It is synthesized according to methods known in the art.
In the case where no specified otherwise, all reactions of the invention under the stirring of continuous magnetic, in drying nitrogen or
It is carried out under argon atmospher, solvent is dry solvent.
In the case where no specified otherwise, the solution in embodiment refers to aqueous solution.The temperature of reaction is room temperature.Room temperature is
Optimum reaction temperature is 20 DEG C~30 DEG C.
Chromatography (LC-MS) or gas phase is used in conjunction using thin-layered chromatography (TLC), liquid matter in the monitoring of reaction process in embodiment
Chromatography (GC), which reacts used solvent system, to be had: methylene chloride and methanol system, n-hexane and ethyl acetate system, stone
The volume ratio of oily ether and ethyl acetate system, acetone, solvent can be adjusted according to the polarity difference of compound.
The system of the eluant, eluent of column chromatography includes: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system,
C: methylene chloride and ethyl acetate system, D: ethyl acetate and methanol, the volume ratio of solvent it is different according to the polarity of compound and
It is adjusted, a small amount of ammonium hydroxide and acetic acid etc. can also be added and be adjusted.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art
Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong
The preferred implement methods and materials are for illustrative purposes only.
Embodiment one
1000ml methanol is added under nitrogen protection into reaction flask, compound 3- hydroxy-benzoic acid is sequentially added under stirring
Methyl ester 200.0g (1.314mol), potassium carbonate 218.0g (1.580mol), sodium iodide 20.0g (0.133mol), bromopropene
191.0g (1.579mol), is heated to flowing back；After being stirred to react 7-9 hours, TLC detects raw material end of reaction (solvent: petroleum
Ether: ethyl acetate=4:1), 25 DEG C are cooled to, reaction solution is filtered, is concentrated to dryness；500ml methyl is added to residue
Tertbutyl ether, filtering, filtrate washed once with 15% aqueous ammonium chloride solution 300ml, and anhydrous sodium sulfate dries, filters, and filtrate subtracts
Pressure be concentrated to dryness light yellow oil 3- allyloxy-benzoic acid methyl ester 243.5g (1.267mol, molar yield:
96.4%, HPLC purity 96.5%).
Embodiment two
3- allyloxy-benzoic acid methyl ester 243.5g (1.267mol) is placed in a reaction flask, 220 DEG C of reactions are warming up to
1.0~3.0 hours, it is cooled to 60 DEG C；500ml methyl tertiary butyl ether(MTBE) and 844ml 1mol/L are sequentially added into above-mentioned reaction flask
Lithium hydroxide aqueous solution, temperature adjustment is stirred to react overnight to 30-40 DEG C, is cooled to 0~5 DEG C, the reaction of 117ml concentrated hydrochloric acid tune is added dropwise
Liquid pH=1~2, with 700ml methyl tertiary butyl ether(MTBE) extract, organic phase successively through saturated sodium bicarbonate aqueous solution (700ml × 2),
Saturated sodium-chloride water solution (500ml) washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness light yellow partly solid
Body 2- allyl -3- hydroxy-benzoic acid methyl ester 193.8g (1.008mol, molar yield 79.6%, HPLC purity 96.4%).
Embodiment three
2- allyl -3- hydroxy-benzoic acid methyl ester 193.8g (1.008mol) is placed in a reaction flask, 3000ml is added
Then acetone adds sodium iodide 14.8g (0.099mol), cesium carbonate 393.4g (1.207mol), benzyl bromine 190.6g
(1.112mol) is warming up to reflux.It is stirred to react 1-2 hours, TLC analyzes raw material end of reaction (solvent: petroleum ether: acetic acid
Ethyl ester=4:1), it is cooled to room temperature, filters, is concentrated to dryness；300mL n-hexane is added, is washed with water (200ml*3), nothing
Aqueous sodium persulfate dries, filters, and is concentrated to dryness give light yellow oil 2- allyl -3- benzyloxy-benzoic acid methyl ester
279.8g (0.991mol, molar yield 98.3%, HPLC purity 91.1%).
Example IV
2- allyl -3- benzyloxy-benzoic acid methyl ester 279.8g (0.991mol) is placed in a reaction flask, successively plus
Enter 3000ml tetrahydrofuran, 1000ml methanol, 15% potassium hydroxide aqueous solution 1115.3g (2.981mol) is heated to flowing back；Instead
After answering 4 hours, TLC analyzes raw material end of reaction (solvent: petroleum ether: ethyl acetate=4:1), is cooled to 50 DEG C, depressurizes dense
Contracting removes methanol and tetrahydrofuran.It remains water phase to be extracted with methyl tertiary butyl ether(MTBE) (600mL*3), separates water layer, 3.0mol/ is added dropwise
L dilute hydrochloric acid (about 860mL) adjusts pH=1~2, drips off and is stirred to react 1 hour, filters, and filter cake is beaten with 1500ml petroleum ether and is stirred
It mixes 0.5 hour, filters, 60 DEG C of filter cake obtain off-white powder 2- allyl -3- benzyloxy-benzoic acid in vacuum drying 3 hours
222.8g (0.830mol, yield 83.8%, HPLC purity 99.0%).
Embodiment five
Under nitrogen protection, by 2- allyl -3- benzyloxy-benzoic acid 40.0g (0.149moL) and N, O- dimethyl hydroxyl
Amine hydrochlorate 22.0g (0.224mol) is placed in a reaction flask, and 80mL n,N-Dimethylformamide is then added, under stirring successively
HOBT20.1g (0.149mol), EDCI44.3g (0.224mol), n,N-diisopropylethylamine 67.4g (0.552mol) is added,
Reaction 20 hours is stirred at room temperature, TLC analyzes raw material end of reaction (solvent: petroleum ether: ethyl acetate=4:1), it is cooled to 0~
5 DEG C, 400mL methyl tertiary butyl ether(MTBE) is added, 3% sodium hydrate aqueous solution 335g is then added dropwise, it is small that 0.5 is stirred after being added dropwise
When, upper organic layer is separated, water layer is added the extraction of 400ml methyl tertiary butyl ether(MTBE), merges organic phase；Organic phase successively passes through
1.2mol/L dilute hydrochloric acid (500ml × 2) washing, saturated sodium bicarbonate aqueous solution (300ml × 1) washing, anhydrous sodium sulfate is dry,
Filtering, 45~50 DEG C are concentrated to dryness to obtain yellow oil 2- allyl -3- benzyloxy-N- methoxy-. N-methyl-benzene first
Amide 45.3g (0.145mol, molar yield 97.6%, HPLC purity 98.1%).
1H NMR (400MHz, DMSO-d6): δ 7.48-7.31 (m, 5H), 7.25 (t, J=8Hz, 1H), 7.12 (d, J=
8Hz, 1H), 6.87 (d, J=7.6Hz, 1H), 5.88-5.79 (m, 1H), 5.15 (s, 2H), 4.96-4.91 (m, 2H), 3.44
(br,3H),2.29-3.31(m,2H),3.22(br,3H).
Embodiment six
Nitrogen protection under room temperature, sequentially adds (6S) -6- ((tetrahydro -2H- pyranose -2- base) oxygroup)-decyl- 9- alkynes
35.6g (0.149mol) and 60mL tetrahydrofuran stir lower dropwise addition 3.0mol/L ethyl magnesium bromide etherate into reaction flask
50.8mL (0.152mol) is added dropwise 35~40 DEG C of temperature control, is stirred to react 1.5-2.0 hours.Then temperature adjustment is added to 25 DEG C
The tetrahydrofuran (60mL) of 2- allyl -3- benzyloxy-N- methoxy-. N-methyl benzamide 45.3g (0.145mol) is molten
Liquid finishes and is warming up to back flow reaction 1 hour, and TLC detects raw material end of reaction (solvent: petroleum ether: ethyl acetate=4:1),
0 °~5 DEG C are cooled to, 100ml saturated aqueous ammonium chloride quenching reaction is added；It is extracted with methyl tertiary butyl ether(MTBE) (200mL × 2)
Mixed liquor merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated to dryness, and column separation obtains light yellow oil
(6S) -1- (2- allyl -3- (benzyloxy) phenyl) -6- ((tetrahydro -2H- pyranose -2- base) oxygen)-undecyl -2- alkynes -
1- ketone 55.2g (0.113mol, yield 77.9%, HPLC purity 98.1%).
1H NMR(400MHz,CDCl3):δ7.78-7.73(m,1H),7.44-7.31(m,5H),7.29-7.24(m,1H),
7.10 (dd, J=7.6,1.6Hz, 1H), 6.05-5.96 (m, 1H), 5.11 (s, 2H), 5.03-4.95 (m, 2H), 4.66-4.61
(m,1H),3.92-3.84(m,3H),3.76-3.71(m,1H),3.50-3.45(m,1H),2.64-2.59(m,1H),2.50
(t, J=7.6Hz, 1H), 1.92-1.25 (m, 16H), 0.88 (t, J=6.8Hz, 3H)
Embodiment seven
Magnesium chips 144.0g (6.0mol), 2000ml anhydrous tetrahydro furan, a small amount of iodine are added in reaction flask, are heated to 50
DEG C, it is added dropwise bromination of n-butane 548.1g (4.0mol), initiation reaction during dropwise addition, dark brown solution becomes colourless solution, controls
Rate of addition processed maintains 55 DEG C -60 DEG C of temperature, and drop finishes within 60 minutes.Room temperature (25 DEG C) is down to be stirred to react 2 hours.It stands, nitrogen
Supernatant is separated under protection, obtains 2000ml grey black normal-butyl magnesium bromide tetrahydrofuran solution (about 2.0mol/L), for use.
By (S)-epoxychloropropane 350g (3.78mol), cuprous iodide 72.37g (0.38mol) and the anhydrous tetrahydro of 1000ml
Furans is added in another reaction flask bottle, is cooled to 0 DEG C and is stirred 10 minutes.The normal-butyl magnesium bromide tetrahydrofuran prepared is molten
Liquid is slowly dropped in above-mentioned reaction solution, and control rate of addition makes interior temperature lower than 10 DEG C, and about 2h drop finishes, and is warming up to room temperature (25 DEG C)
16 hours are stirred to react, fully reacting.It is cooled to 0 DEG C.15% ammonia spirit (600ml) that ammonium chloride saturation is slowly added dropwise is quenched
Reaction, control temperature are lower than 25 DEG C, finish, stir 0.5 hour, filter, and filter cake is washed with 1000ml ethyl acetate, merging filtrate
Organic phase successively uses NH415% ammonia spirit (400ml) of Cl saturation, saturation NaCl aqueous solution (400ml) respectively washed once.
50 DEG C are concentrated to dryness to obtain grease (S) -1- chloroheptane -2- alcohol crude product 638.4g (GC purity 75.32%).
(S) -1- chloroheptane -2- alcohol crude product (638.4g), 2000ml methyl tertiary butyl ether(MTBE) are added in another reaction flask,
NaOH solid 370g (9.25mol) slowly is added portionwise, room temperature (25 DEG C) is stirred to react 18 hours, and raw material fundamental reaction is complete,
It filters, filtrate successively respectively washed once with water (400ml), saturated salt solution (200ml), and anhydrous sodium sulfate is dry, 40 DEG C of decompressions
It is concentrated to dryness, concentration gained grease decompression is steamed again, pressure -0.95mPa collects 70-75 DEG C of fraction, obtains colorless oil
(S) -1,2- oxepane 265.8g (2.329mol, molar yield 61.6%, GC purity 86.37%).
Embodiment eight
Under the conditions of nitrogen protection, by (S) -1,2- oxepane 80.0g is added in reaction flask, sequentially adds 400ml tetra-
Hydrogen furans and CuI 13.4g (0.07mol) are cooled to 0~5 DEG C, and 515ml 1.7mol/L allylmgcl tetrahydro furan is added dropwise
Mutter solution (0.876mol), and control rate of addition keeps reacting liquid temperature to be no more than 5 DEG C, is added dropwise within about 2 hours, keeps the temperature 0 DEG C
Stirring 1 hour.GC detects raw material fully reacting.The saturation NH of 15% ammonium hydroxide is slowly added dropwise4Cl solution (800ml) quenching reaction,
It controls temperature and is no more than 30 DEG C.It is added dropwise, a large amount of solids is precipitated, filter, filter cake is washed with 1000ml ethyl acetate, filtrate point
Water layer is removed, organic phase successively uses the saturation NH of 15% ammonium hydroxide4Cl solution (400mL), saturated common salt aqueous solution (200mL) washing are each
Washed once, anhydrous sodium sulfate is dry, be concentrated to dryness grease (S)-octyl- 1- alkene -5- alcohol 108.8g (GC purity:
78.0%).
Embodiment nine
(S)-octyl- 1- alkene -5- alcohol 108.8g is added in reaction flask, then addition 550ml methylene chloride, stirring and dissolving,
Sequentially add 3,4- dihydro -2H- pyrans (DHP) 181.4g (2.16mol), para-methylbenzenepyridinsulfonate sulfonate (PPTs) 9.01g
(0.03mol), room temperature (25 DEG C) are stirred to react 16-24 hours, and raw material fundamental reaction is complete, and reaction solution is successively with saturation NaHCO3
Solution (200ml × 2), saturation NaCl solution (200mL × 1) washing, anhydrous sodium sulfate is dry, filters, is concentrated to dryness
Grease 2- (((S)-octyl- 1- alkene -5- base) oxygen) tetrahydro -2H- pyrans 146.0g (GC purity: 69.0%).
Embodiment ten
By 2- (((S)-octyl- 1- alkene -5- base) oxygen) tetrahydro -2H- pyrans 146.0g, 700ml methylene chloride and pyridine 52.8g
(0.670mol0 is added in reaction flask, and reaction solution is cooled to 0~5 DEG C, pyridinium tribromide 213.8g is added portionwise under stirring
(0.670mol), control temperature are no more than 5 DEG C, and addition in about 1 hour finishes, and 0-5 DEG C of heat preservation is stirred to react 2 hours, and GC detection is former
Expect fully reacting, 450ml saturated sodium thiosulfate quenching reaction, branch vibration layer are added dropwise at 0~5 DEG C of temperature control, organic phase is successively used
250ml saturated sodium thiosulfate solution, 250ml saturated salt solution respectively washed once, and anhydrous sodium sulfate is dry, filter filtrate decompression
It is concentrated to dryness to obtain oily residue.
Grease is added in another reaction flask, the dissolution of 1000ml tetrahydrofuran is added, is slowly added under nitrogen protection
Sodamide 441.2g (weight in wet base contains dimethylbenzene), is heated to back flow reaction 5~6 hours, and GC detects raw material fully reacting, will
Reaction solution is cooled to 0 DEG C, and 680ml saturated ammonium chloride solution quenching reaction is added dropwise, and has a large amount of solids to be precipitated, is added into mixed liquor
600ml ethyl acetate and 600ml water, stirring to Quan Rong, liquid separation, water phase are extracted with 500ml ethyl acetate, merge organic phase, according to
It is secondary to be saturated NaHCO with 300ml3Solution, 300ml saturated salt solution respectively washed once, and anhydrous sodium sulfate is dry, filter, and filtrate adds
Pressure is concentrated to dryness, and purified on silica obtains grease (6S) -6- ((tetrahydro -2H- pyranose -2- base) oxygen)-decyl- 9- alkynes
95.3g (0.400mol, eight, nine, ten total moles yield 65.8% of embodiment, GC purity: 94.9%).
1H NMR(400MHz,CDCl3):δ4.65-4.68(m,1H),3.87-3.94(m,1H),3.69-3.74(m,1H),
3.47-3.52 (m, 1H), 2.31-2.37 (m, 1H), 2.24 (dt, J=2.8,7.2Hz, 1H), 1.92-1.95 (m, 1H),
1.68-1.79 (m, 4H), 1.47-1.59 (m, 6H), 1.28-1.36 (m, 6H), 0.89 (t, J=7.0Hz, 3H)
Embodiment 11
1- trimethyl silicon substrate propine 78.7g (0.701mol) is dissolved in 560mL anhydrous tetrahydro furan under nitrogen protection, it is cold
But to -40 DEG C -- 50 DEG C, 2.5mol/L n-BuLi hexane solution 280mL is added dropwise, control temperature is lower than -35 DEG C, about 30 points
Clock drop finishes, and -40 DEG C of heat preservation is stirred to react 3 hours, and (S) -1,2- oxepane 40.0g dissolved with 100mL tetrahydrofuran is added dropwise
(preparation of embodiment seven), control temperature are lower than -20 DEG C, and drop finishes within 30 minutes, and -40 DEG C of heat preservation is stirred to react 2 hours, and GC detects raw material
100mL saturated aqueous ammonium chloride quenching reaction is added dropwise in fully reacting.200mL water and 500mL ethyl acetate, liquid separation, which is added, to be had
Machine mutually washed once with 100mL saturated salt solution, and anhydrous sodium sulfate is dry, be concentrated to dryness grease 105.7g (GC is pure
Degree: 74.9%).
Above-mentioned grease is dissolved in 800mL ethyl alcohol, 40gNaOH is added, room temperature (25 DEG C) is stirred to react 2 hours, GC inspection
Raw material fully reacting is surveyed, reduced pressure boils off solvent, and 500mL water and 1000mL ethyl acetate, liquid separation is added, and organic phase is used
100mL*2 saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated to dryness to obtain brown oil (S)-octyl- 1- alkynes -5- alcohol
73.9g (GC purity: 68.4%).
Embodiment 12
(S)-octyl- 1- alkynes -5- alcohol 73.9g is dissolved in 1500ml methylene chloride, is added 3,4- dihydro -2H- pyrans (DHP)
88.3g (1.050mol) and para-methylbenzenepyridinsulfonate sulfonate (PPTs) 8.8g (0.035mol), it is small that room temperature (25 DEG C) is stirred to react 24
When, GC detects raw material fully reacting, and 100mL is added and is saturated NaHCO3With 250mL methylene chloride, liquid separation, organic phase is satisfied with 100mL
It is primary with brine It.Anhydrous sodium sulfate is dry, is concentrated to dryness, purified on silica obtains grease (6S) -6-
((tetrahydro -2H- pyranose -2- base) oxygen)-decyl- 9- alkynes 56.2g (0.236mol, embodiment 11,12 total moles yields
67.3%, GC purity: 93.6%).
Embodiment 13
Under nitrogen protection, by magnesium rod 31.5g (1.312moL), HgCl2(6) 2.5g (9.2mmol), iodine grain addition reactions
In bottle, 300ml ether is then added, is stirred, 36 DEG C of reflux is heated to, the initiation reaction of 5ml propargyl bromide, temperature 30- is first added
It 35 DEG C, keeps that 95ml propargyl bromide is added dropwise again at 0~10 DEG C of temperature, is added dropwise within about 1.0 hours, continues to be stirred to react 1.0 hours,
It is kept for 0~10 DEG C of temperature, adds (S) -1,2- oxepane 50.0g (preparation of embodiment seven), add within about 0.5 hour, continue to stir
1.0 hour.Be cooled to -10 DEG C, 10% aqueous ammonium chloride solution 100ml be added dropwise at 25 DEG C of control, adds within about 0.5 hour, finish after
Continuous stirring 0.5 hour, filtering, liquid separation, organic phase successively respectively washed once through water (150ml), saturated salt solution (150ml), nothing
Aqueous sodium persulfate dries, filters, and is concentrated to dryness to obtain yellow oil (S)-octyl- 1- alkynes -5- alcohol 62.9g (GC purity
75.7%).
Under nitrogen protection, (S)-octyl- 1- alkynes -5- alcohol 62.9g is added in reaction flask, 400ml methylene chloride is then added,
Stirring, is cooled to 0 DEG C, 3,4- dihydro -2H- pyrans (DHP) 102.9g (1.223mol) and para-methylbenzenepyridinsulfonate sulfonate (PPTs)
5.1g g (0.020mol) is kept for 20-25 DEG C of temperature and is stirred to react 24 hours, and GC detects raw material fully reacting, and reaction solution, which is used, to be added
Saturated sodium bicarbonate aqueous solution (400ml × 2) washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, and silica gel column chromatography is pure
Change yellow oil (6S) -6- ((tetrahydro -2H- pyranose -2- base) oxygen)-decyl- 9- alkynes 65.1g (0,273mol, embodiment ten
Three, 14 total moles yield 62.3%, GC purity: 96.6%).
It is finally it should be noted that of the invention the above examples are only used to illustrate the technical scheme of the present invention and are not limiting,
Although being described the invention in detail referring to preferred embodiment, those skilled in the art should understand that, it can be right
The technical solution of invention is modified or replaced equivalently, without departing from the spirit and scope of the technical solution of the present invention, should all
Cover in scope of the presently claimed invention.
Claims (14)
- The preparation method of formula 1. (I) compound, which comprises the steps of:1) formula (II) compound reacts to obtain formula (IV) compound in the presence of condensing agent with formula (III) compound or its acid salt；2) formula (IV) compound reacts to obtain formula (I) compound with formula (V) compound, and reaction equation is as follows:Wherein, R1、R2Independent is hydroxyl protection base.
- 2. preparation method according to claim 1, which is characterized in that R1、R2It is independently selected from C1-8Alkyl, C1-8Alkane Oxygen C1-8Alkyl, halogen replace C1-8Alkyl, C3-8Naphthenic base, benzyl, C1-8Alkoxy substituted benzyl, THP trtrahydropyranyl ,-SiR3R4R5 Or-C (O) R3；R3、R4、R5It is independently selected from selected from Cl-8Alkyl or C3-8Naphthenic base.
- 3. preparation method according to claim 1, which is characterized in that R1For benzyl, R2For 2- THP trtrahydropyranyl.
- 4. preparation method according to claim 1-3, which is characterized in that formula (III) the compound acid salt Acid refers to organic acid or inorganic acid, and the organic acid is selected from trifluoroacetic acid, trichloroacetic acid, Loprazolam, trifluoromethanesulfonic acid, right Or mixtures thereof toluenesulfonic acid, formic acid, acetic acid；Inorganic acid be selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or Its mixture.
- 5. preparation method according to claim 1, which is characterized in that the condensing agent be selected from DIC, DCC, HOBT, Or mixtures thereof EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI.
- 6. preparation method according to claim 1, which is characterized in that be added in step 2) relative to formula (IV) compound The Grignard Reagent of 0.5-10 times of mole.
- 7. preparation method according to claim 1, which is characterized in that be added in step 2) relative to formula (IV) compound The Grignard Reagent of 1.0-2.0 times of mole.
- 8. preparation method according to claim 6 or 7, which is characterized in that the Grignard Reagent is selected from methyl-magnesium-bromide, second Base magnesium bromide, methyl-magnesium-chloride or ethylmagnesium chloride.
- 9. preparation method according to claim 1, which is characterized in that formula (II) compound is by formula (IX) compound It is obtained in the presence of alkali,Wherein R1As defined in claim 1, R6Selected from C substituted or unsubstituted1-8Alkoxy, C substituted or unsubstituted3-8Cycloalkanes oxygen Base, the substituent group are selected from halogen, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, C5-10Aryl, C5-10Aryloxy, 5-10 unit's heteroaryl or 5-10 unit's heteroaryl oxygroup；The alkali is selected from or mixtures thereof sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate.
- 10. preparation method according to claim 9, which is characterized in that formula (Ⅸ) compound is changed by formula (VIII) It is obtained in the presence of alkali to close object,Wherein R1As defined in claim 1, R6As defined in claim 9；The alkali be organic base or inorganic base, it is described Organic base be selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, the inorganic base be selected from potassium carbonate, sodium carbonate, Or mixtures thereof cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate.
- 11. preparation method according to claim 10, which is characterized in that the preparation method of formula (VIII) compound is such as Under:Wherein R6As defined in claim 9；X is halogen.
- 12. preparation method according to claim 11, which is characterized in that R6Selected from methoxy or ethoxy；X is bromine.
- 13. preparation method according to claim 1, which is characterized in that prepare the formula using formula (Ⅺ) compound as raw material (V) compound, the preparation method is as follows:Alternatively,Alternatively,Wherein R2As defined in claim 1, R3、R4、R5As defined in claim 2, X is halogen.
- 14. preparation method according to claim 13, which is characterized in that the preparation method of formula (Ⅺ) compound is such as Under:
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| US20020099034A1 (en) * | 2001-01-05 | 2002-07-25 | Moriarty Robert M. | Process for stereoselective synthesis of prostacyclin derivatives |
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