CN109824526A - Sarpogrelate hydrochloride intermediate 2-(3- dimethylamino -2- hydroxyl) propoxybenzaldehyde synthetic method - Google Patents
Sarpogrelate hydrochloride intermediate 2-(3- dimethylamino -2- hydroxyl) propoxybenzaldehyde synthetic method Download PDFInfo
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- CN109824526A CN109824526A CN201910212040.5A CN201910212040A CN109824526A CN 109824526 A CN109824526 A CN 109824526A CN 201910212040 A CN201910212040 A CN 201910212040A CN 109824526 A CN109824526 A CN 109824526A
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- hydroxyl
- dimethylamino
- propoxybenzaldehyde
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
Abstract
The invention discloses a kind of synthetic methods of sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde, it is related to drug technical field of organic synthesis, using salicylide as raw material, in the presence of acid binding agent, intermediate 2- (ethylene oxide -2- methoxyl group) benzaldehyde first is generated with etherified react of epoxychloropropane, then generates 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde through aminating reaction with dimethylamine.2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde is made by salicylide through two-step reaction in the present invention, reaction dissolvent is not added additionally, and the in line pollution on the environment of reaction dissolvent or reaction dissolvent is avoided to recycle increased energy consumption investment while reducing reaction dissolvent input cost.
Description
Technical field:
The present invention relates to drug technical field of organic synthesis, and in particular to a kind of sarpogrelate hydrochloride intermediate 2- (3- bis-
Methylamino -2- hydroxyl) propoxybenzaldehyde synthetic method.
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.
To solve the above-mentioned problems, we have redesigned the synthetic route of object Sarpogrelate, with first between being easy to get
Oxygroup benzyl diethyl phosphite 6 and 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde 7 are raw material, are reacted in obtaining
Mesosome 8 restores the progress olefin oxidation of intermediate 8 to obtain intermediate 5, then obtains mesh at salt with succinic anhydride esterification, hydrochloric acid
Mark product 1.
Summary of the invention:
Technical problem to be solved by the present invention lies in provide a kind of simplified synthetic operation, reduce cost and guarantee that palladium carbon is urged
The synthetic method of sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde of agent recycled.
The following technical solution is employed for the technical problems to be solved by the invention to realize:
The synthetic method of sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde, with bigcatkin willow
Aldehyde is as raw material, in the presence of acid binding agent, first generates intermediate 2- (ethylene oxide -2- first with etherified react of epoxychloropropane
Oxygroup) benzaldehyde, then 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde is generated through aminating reaction with dimethylamine.
The acid binding agent is selected from one of organic base, inorganic base or sodium salt of organic acid.
The organic base is selected from one of triethylamine, diisopropyl ethyl amine, pyridine.
The inorganic base is selected from one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide.
The sodium salt of the organic acid is selected from one of sodium formate, sodium acetate, spy's acid sodium, sodium benzoate.
The dimethylamine is 30% dimethylamine agueous solution.
The beneficial effects of the present invention are:
(1) with epoxychloropropane etherification reaction, epoxy chlorine occur for the present invention under acid binding agent effect using salicylide as raw material
Propane makees reaction dissolvent simultaneously, generates intermediate 2- (ethylene oxide -2- methoxyl group) benzaldehyde, then in dimethylamine agueous solution instead
It should obtain sarpogrelate hydrochloride synthetic intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde；This two-step reaction does not have
Additional addition reaction dissolvent, avoided while reducing reaction dissolvent input cost the in line pollution on the environment of reaction dissolvent or
Reaction dissolvent recycles and increased energy consumption is put into；And post-processing operation is simple and easy, and gained is intermediate after conventional extracting operation
The purity of body and final product is all 90% or more, to be conducive to the synthesis of subsequent sarpogrelate hydrochloride.
(2) 2- obtained (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde and meta-methoxy benzyl phosphorous acid are utilized
Diethylester reacts synthetic hydrochloric acid Sarpogrelate, and the synthesis cost of sarpogrelate hydrochloride is reduced while simplifying route；Avoid original
The protection of phenolic hydroxyl group and deprotection reaction in material simplify synthesis step, and prevent during deprotection because micro phosphorus remains
And so that hydrogenating reduction is poisoned with palladium-carbon catalyst, to guarantee the recycled of palladium-carbon catalyst, reduce the investment of catalyst at
This.
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
150g epoxychloropropane is put into 100g salicylide, is stirred, 120g Anhydrous potassium carbonate is put under nitrogen protection, is risen
Temperature reacts 5h, after epoxychloropropane is recovered under reduced pressure, raffinate is poured into 300mL ice water, separates organic layer, is obtained to 80 ± 2 DEG C
143g intermediate, yield 98%, purity 96%.
Under nitrogen protection, 143g intermediate is put into 30% dimethylamine agueous solution of 429g, and 25 ± 2 DEG C are stirred to react
12h, reaction terminate, and with dilute hydrochloric acid tune pH=7, stratification obtains oil reservoir, washes 2 times, and anhydrous magnesium sulfate is dry, obtain yellowish-brown
Oily liquids obtains 155g 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde, purity 92.3%, yield 86%.
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 (6)
1. the synthetic method of sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde, feature exist
In: using salicylide as raw material, in the presence of acid binding agent, intermediate 2- (epoxy first is generated with etherified react of epoxychloropropane
Ethane -2- methoxyl group) benzaldehyde, then 2- (3- dimethylamino -2- hydroxyl) propoxyl group benzene first is generated through aminating reaction with dimethylamine
Aldehyde.
2. sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde according to claim 1
Synthetic method, it is characterised in that: the acid binding agent is selected from one of organic base, inorganic base or sodium salt of organic acid.
3. sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde according to claim 2
Synthetic method, it is characterised in that: the organic base be selected from one of triethylamine, diisopropyl ethyl amine, pyridine.
4. sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde according to claim 2
Synthetic method, it is characterised in that: the inorganic base be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide
One of.
5. sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde according to claim 2
Synthetic method, it is characterised in that: the sodium salt of the organic acid is in sodium formate, sodium acetate, spy's acid sodium, sodium benzoate
It is a kind of.
6. sarpogrelate hydrochloride intermediate 2- (3- dimethylamino -2- hydroxyl) propoxybenzaldehyde according to claim 1
Synthetic method, it is characterised in that: the dimethylamine be 30% dimethylamine agueous solution.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910212040.5A CN109824526A (en) | 2019-03-18 | 2019-03-18 | Sarpogrelate hydrochloride intermediate 2-(3- dimethylamino -2- hydroxyl) propoxybenzaldehyde synthetic method |
| CN202210091162.5A CN114394905A (en) | 2019-03-18 | 2019-03-18 | Synthetic method of sarpogrelate hydrochloride intermediate 2- (3-dimethylamino-2-hydroxy) propoxybenzaldehyde |
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| CN201910212040.5A CN109824526A (en) | 2019-03-18 | 2019-03-18 | Sarpogrelate hydrochloride intermediate 2-(3- dimethylamino -2- hydroxyl) propoxybenzaldehyde synthetic method |
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| CN202210091162.5A Pending CN114394905A (en) | 2019-03-18 | 2019-03-18 | Synthetic method of sarpogrelate hydrochloride intermediate 2- (3-dimethylamino-2-hydroxy) propoxybenzaldehyde |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356012A (en) * | 2014-09-23 | 2015-02-18 | 山东齐都药业有限公司 | Preparation method of sarpogrelate hydrochloride photodegradation impurities |
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| CN103242179B (en) * | 2013-05-08 | 2014-12-17 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
| CN105906486B (en) * | 2016-04-20 | 2018-04-20 | 安徽修一制药有限公司 | The synthetic method of Sarpogrelate intermediate 2 [2 (3 methoxyphenyl) ethyl] phenol |
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- 2019-03-18 CN CN201910212040.5A patent/CN109824526A/en active Pending
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356012A (en) * | 2014-09-23 | 2015-02-18 | 山东齐都药业有限公司 | Preparation method of sarpogrelate hydrochloride photodegradation impurities |
Non-Patent Citations (2)
| Title |
|---|
| 王振 等: "盐酸沙格雷酯合成工艺及其质量研究", 《中国医药工业杂志》 * |
| 范石虎: "盐酸沙格雷酯合成工艺改进", 《中国药物化学杂志》 * |
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