CN109824527A - A kind of synthetic method of sarpogrelate hydrochloride - Google Patents
A kind of synthetic method of sarpogrelate hydrochloride Download PDFInfo
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- CN109824527A CN109824527A CN201910212039.2A CN201910212039A CN109824527A CN 109824527 A CN109824527 A CN 109824527A CN 201910212039 A CN201910212039 A CN 201910212039A CN 109824527 A CN109824527 A CN 109824527A
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- sarpogrelate hydrochloride
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- synthetic method
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- hydrochloric acid
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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 invention discloses a kind of synthetic methods of sarpogrelate hydrochloride, it is related to drug technical field of organic synthesis, using meta-methoxy benzyl diethyl phosphite 6 and 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde 7 as raw material, intermediate 8 is generated through condensation reaction, hydrogenated reduction reaction generates intermediate 5 to intermediate 8 again, and intermediate 5 and succinic anhydride obtain sarpogrelate hydrochloride 1 through esterification, hydrochloric acid salt-forming reaction.Synthetic route of the invention is relatively easy, and second step hydrogenating reduction olefinic double bonds do not need hydroxyl protection base benzyl, thus it is not stringent to catalyst requirement, catalyst poisoning is prevented without the phosphorus residual of strict control intermediate 8；5 purity of midbody product obtained simultaneously is preferable, is easy to lower step and obtains the target product of high-purity.
Description
Technical field:
The present invention relates to drug technical field of organic synthesis, and in particular to a kind of synthetic method of sarpogrelate hydrochloride.
Background technique:
Sarpogrelate hydrochloride, entitled succinic acid list [2- (dimethylamino) -1- [[2- [2- (3- methoxyphenyl) second of chemistry
Base] phenoxy group] methyl] ethyl] ester hydrochloride is a day 5-HT2 receptor antagonist and blood for Honda side drugmaker, Mitsubishi research and development
Platelet assembles antagonist, is clinically used for Chronic Thrombotic obliterans.
Currently, there are many route of synthetic hydrochloric acid Sarpogrelate, include following synthetic routes:
The route, which is reacted first with adjacent benzyloxy benzyl diethyl phosphite 2 with m-methoxybenzaldehyde 3, generates alkene
Intermediary, then with palladium-carbon catalyst hydrogenating reduction, and Deprotection obtains intermediate 4,4 and epoxy chloropropionate cyclic ethers, then with two
First ammonia spirit open loop obtains intermediate 5, and last diethyl succinate and intermediate 5 are esterified, and hydrochloric acid obtains target product at salt
Sarpogrelate hydrochloride 1.
It is expensive using intermediate 3 in the technology；And manufacturing process is cumbersome, pollution is very big.Alkene intermediates are adding
High to the purity requirement of alkene intermediates when hydrogen reduction takes off benzyloxy protecting group, micro phosphorus residual is just easily catalyzed palladium carbon
Agent poisoning.In order to reduce cost, recycled palladium-carbon catalyst needs to control phosphorus residual in alkene intermediates, process it is cumbersome and
Increase cost.From the point of view of entire technology, route is longer, process complexity and uncontrollable, higher cost.
Summary of the invention:
Technical problem to be solved by the present invention lies in a kind of synthetic method of sarpogrelate hydrochloride is provided, this method is selected
Raw material cheap and easy to get, hydrogenating reduction catalyst poisoning caused by capable of preventing phosphorus from remaining, and made sarpogrelate hydrochloride is pure
Degree can reach 99.7%.
The following technical solution is employed for the technical problems to be solved by the invention to realize:
A kind of synthetic method of sarpogrelate hydrochloride, with meta-methoxy benzyl diethyl phosphite 6 and 2- (3- diformazan ammonia
Base -2- hydroxyl) propoxybenzaldehyde 7 is used as raw material, intermediate 8, the hydrogenated reduction reaction again of intermediate 8 are generated through condensation reaction
Generation intermediate 5, intermediate 5 and succinic anhydride obtain sarpogrelate hydrochloride 1 through esterification, hydrochloric acid salt-forming reaction.
The catalyst of the hydrogenation reduction selects palladium carbon.
The reaction dissolvent of the hydrogenation reduction selects methanol.
The reaction dissolvent of the esterification selects acetone.
The beneficial effects of the present invention are: synthetic route of the invention is relatively easy, second step hydrogenating reduction olefinic double bonds,
Hydroxyl protection base benzyl is not needed, thus it is not stringent to catalyst requirement, it remains without the phosphorus of strict control intermediate 8
Prevent catalyst poisoning；5 purity of midbody product obtained simultaneously is preferable, is easy to lower step and obtains the target product of high-purity, most
The purity of made product hydrochloric acid Sarpogrelate reaches 99.7% eventually.
Specific embodiment:
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below
Specific embodiment is closed, the present invention is further explained.
Embodiment 1
The synthesis of intermediate 8:
Under nitrogen protection, in 1000mL glass reaction bottle, 300g intermediate 6 and 300g intermediate 7 is put into, is warming up to 120
± 2 DEG C, insulated and stirred 5h, reaction terminates.By in the reaction solution slowly ice water of falling 2000mL, off-white powder material is precipitated in stirring, is taken out
Filter is washed, drying.4 times of amount methanol crystallizations, obtain 371g off-white color intermediate 8, yield 85%, purity 98.6%.
The synthesis of intermediate 5:
371g intermediate 8 is dissolved in 1484g methanol, nitrogen displaced air, puts into 5% palladium carbon 11g, hydrogen displacement reaction
Nitrogen in bottle, and continue in 55 ± 2 DEG C of logical hydrogen, and maintain Hydrogen Vapor Pressure 2atm in reaction flask, and maintain until not inhaling hydrogen.
Reaction terminates, venting hydrogen, filters off palladium-carbon catalyst, and concentrated mother liquor obtains the faint yellow raffinate 5 of 375g, purity 98.8% to the greatest extent.
The synthesis of sarpogrelate hydrochloride 1:
Acetone 1500mL, succinic anhydride 170g, back flow reaction 2h are put into 375g intermediate 5, after steaming solution to the greatest extent, raffinate
It pours into 2000mL ice water, 5% liquid adjusting PH with base to 7, is extracted with 500mL*3 toluene.Under room temperature, through being passed through salt in toluene solution
Acid gas, obtains white crystal, 5 times of ethyl alcohol, and the purification of 1% activated carbon obtains 475g target product 1, purity 99.7%, yield
90%.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (4)
1. a kind of synthetic method of sarpogrelate hydrochloride, it is characterised in that: with meta-methoxy benzyl diethyl phosphite 6 and 2-
(3- dimethylamino -2- hydroxyl) propoxybenzaldehyde 7 is used as raw material, generates intermediate 8 through condensation reaction, intermediate 8 is again through adding
Hydrogen reduction reaction generation intermediate 5, intermediate 5 and succinic anhydride obtain hydrochloric acid sand Gray through esterification, hydrochloric acid salt-forming reaction
Ester 1.
2. the synthetic method of sarpogrelate hydrochloride according to claim 1, it is characterised in that: the hydrogenation reduction
Catalyst selects palladium carbon.
3. the synthetic method of sarpogrelate hydrochloride according to claim 1, it is characterised in that: the hydrogenation reduction
Reaction dissolvent selects methanol.
4. the synthetic method of sarpogrelate hydrochloride according to claim 1, it is characterised in that: the reaction of the esterification
Solvent selects acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201910212039.2A CN109824527A (en) | 2019-03-18 | 2019-03-18 | A kind of synthetic method of sarpogrelate hydrochloride |
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| CN201910212039.2A CN109824527A (en) | 2019-03-18 | 2019-03-18 | A kind of synthetic method of sarpogrelate hydrochloride |
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| CN109824527A true CN109824527A (en) | 2019-05-31 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239920A (en) * | 2007-02-05 | 2008-08-13 | 南京康然医药科技有限公司 | Method for preparing sarpogrelate hydrochloride |
| CN101279899A (en) * | 2008-05-22 | 2008-10-08 | 中国药科大学 | Preparation of phenol 2-[2-(3-methoxyphenyl) ethyl] |
| CN102875340A (en) * | 2011-07-12 | 2013-01-16 | 北大方正集团有限公司 | Sarpogrelate intermediate and preparation method thereof |
| CN103242179A (en) * | 2013-05-08 | 2013-08-14 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
| CN105906486A (en) * | 2016-04-20 | 2016-08-31 | 安徽禾益化学股份有限公司 | Synthetic method of sarpogrelate intermediate 2-[2-(3-methoxyphenyl)ethyl]phenol |
| CN107324979A (en) * | 2017-08-16 | 2017-11-07 | 北京奥得赛化学股份有限公司 | A kind of preparation method of sarpogrelate hydrochloride intermediate |
-
2019
- 2019-03-18 CN CN201910212039.2A patent/CN109824527A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239920A (en) * | 2007-02-05 | 2008-08-13 | 南京康然医药科技有限公司 | Method for preparing sarpogrelate hydrochloride |
| CN101279899A (en) * | 2008-05-22 | 2008-10-08 | 中国药科大学 | Preparation of phenol 2-[2-(3-methoxyphenyl) ethyl] |
| CN102875340A (en) * | 2011-07-12 | 2013-01-16 | 北大方正集团有限公司 | Sarpogrelate intermediate and preparation method thereof |
| CN103242179A (en) * | 2013-05-08 | 2013-08-14 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
| CN105906486A (en) * | 2016-04-20 | 2016-08-31 | 安徽禾益化学股份有限公司 | Synthetic method of sarpogrelate intermediate 2-[2-(3-methoxyphenyl)ethyl]phenol |
| CN107324979A (en) * | 2017-08-16 | 2017-11-07 | 北京奥得赛化学股份有限公司 | A kind of preparation method of sarpogrelate hydrochloride intermediate |
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Application publication date: 20190531 |
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