CN110407715A - A kind of synthetic method of pregabalin intermediate - Google Patents
A kind of synthetic method of pregabalin intermediate Download PDFInfo
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- CN110407715A CN110407715A CN201910584908.4A CN201910584908A CN110407715A CN 110407715 A CN110407715 A CN 110407715A CN 201910584908 A CN201910584908 A CN 201910584908A CN 110407715 A CN110407715 A CN 110407715A
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- Prior art keywords
- ammonium
- synthetic method
- sodium
- methylhexanoic acid
- pregabalin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of synthetic methods of pregabalin intermediate, belong to technical field of medicine preparation.The present invention is using the solids such as ammonium chloride, ammonium hydrogen carbonate, ammonium carbonate, ammonium sulfate, ammonium oxalate, ammonium formate, ammonium bromide, ammonium iodide, ammonium hydroxide, formamide, acetamide, hydrazine hydrate or liquid substance as ammonia source, in the presence of alkali, (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid is reacted at room temperature, Pregabalin key intermediate (R) -3- (carbamoylmethyl) -5- methylhexanoic acid is generated.Operation of the present invention is simple, can obtain pregabalin intermediate under atmospheric pressure at room in high yield, and reaction condition is mild, economic and environment-friendly, is suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine preparation, and in particular to a kind of synthetic method of pregabalin intermediate.
Background technique
Pregabalin (Pregabalin；Trade name: Lyrica) be 3- aminomethyl -5- methylhexanoic acid C3Position absolute stereo
Chemistry is the isomers of S type, is a novel gamma-amino acid (GABA) receptor antagonist that Pfizer Inc. develops.2004
July in year is ratified to list in Britain for the first time, the treatment for the infull property epilepsy in adult patients part.In recent years, Pregabalin is suitable
It answers disease to be further expanded, can be used for treating periphery caused by generalized anxiety disorder and sociability anxiety disorder, diabetes
Neuralgia, postherpetic neuralgia and fibromyalgia syndrome etc. are the approvals of first acquisition U.S. FDA for treat two kinds with
The drug of epineural pain, and the medicine administration frequency is low, adverse reaction is few, causes people's extensive concern, becomes global smooth
One of medicine is sold, 2018 annual sales amounts are up to 5,200,000,000 dollars or more.
United States Patent (USP) US2014/0243412A1 provides a kind of Pregabalin key intermediate (R) -3- (carbamyl first
Base) -5- methylhexanoic acid [(R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid] synthetic method,
Reaction equation is as follows:
Ammonia source used is ammonia in the method, reaction need heat and ammonia pressurized conditions under complete, ammonia demand
Greatly, environmental protection pressure is big, and equipment requirement is high, is unfavorable for industrialized production.
Summary of the invention
The purpose of the present invention is synthesizing Pregabalin key intermediate (R) -3- (carbamoylmethyl)-for the prior art
The use of a large amount of ammonias is ammonia source in the technique of 5- methylhexanoic acid, needs pressure maintaining equipment, reaction time length, reacts incomplete, environment
The disadvantages of unfriendly, providing a kind of non-ammonia is ammonia source, it is easy to operate, reaction condition is mild, it is environmentally protective, be suitble to industrial metaplasia
The pregabalin intermediate synthetic method of production.
In order to achieve the above object, the synthetic method and reaction equation that the present invention uses are as follows:
Under ice-water bath and stirring condition, ammonia source is added in organic solvent, and alkali is added portionwise thereto, then in room
(S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid is added under temperature thereto, reaction is stirred at room temperature 4~12 hours, has reacted
After isolate and purify product, obtain pregabalin intermediate, i.e. (R) -3- (carbamoylmethyl) -5- methylhexanoic acid.
Above-mentioned ammonia source is selected from ammonium chloride, ammonium hydrogen carbonate, ammonium carbonate, ammonium sulfate, ammonium oxalate, ammonium formate, ammonium bromide, iodate
Ammonium, ammonium hydroxide, formamide, acetamide, any one or more in hydrazine hydrate；It is preferred that ammonium chloride, ammonium formate, ammonium iodide, ammonium hydroxide, first
Any one in amide, acetamide.
The additional amount in above-mentioned ammonia source is the 2.0~6.0 of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole
Times, preferably the additional amount in ammonia source is 3.0~5.0 times of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
Above-mentioned alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Sodamide, sodium hydride, first
Sodium alkoxide, sodium ethoxide, sodium tert-butoxide, any one or more in potassium tert-butoxide；It is preferred that sodium bicarbonate, Sodamide, sodium methoxide, tertiary fourth
Any one in sodium alkoxide, potassium tert-butoxide.
The additional amount of above-mentioned alkali is 2.0~8.0 times of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole,
It is preferred that the additional amount of alkali is 3.0~6.0 times of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
Above-mentioned organic solvent is selected from methanol, ethyl alcohol, tetrahydrofuran, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), 1,4- dioxy
Six rings, methylene chloride, chloroform, carbon tetrachloride, acetonitrile, benzene, any one or more in toluene；It is preferred that methanol, tetrahydro furan
It mutters, any one in methyl tertiary butyl ether(MTBE), methylene chloride, carbon tetrachloride.
In above-mentioned synthetic method, the preferably described isolation and purification method are as follows: reaction system is concentrated under reduced pressure after react and is removed
Remove organic solvent, be subsequently placed in ice-water bath, under stirring to its be added water to solid be completely dissolved, then with concentrated hydrochloric acid adjust pH to
4~5, a large amount of white solids are precipitated, filters after the further crystallisation by cooling of ice-water bath, is dried after filter cake is washed with water.
Beneficial effects of the present invention are as follows:
The present invention is using solid or liquid substance as ammonia source, in the presence of alkali, makes (S) -3- (ethyoxyl formyl methyl) -5-
Methylhexanoic acid room temperature reaction, generates Pregabalin key intermediate (R) -3- (carbamoylmethyl) -5- methylhexanoic acid.Present invention behaviour
Make simply, pregabalin intermediate can be obtained under atmospheric pressure at room in high yield, reaction condition is mild, economic and environment-friendly, is suitble to industry
Metaplasia produces.
Detailed description of the invention
Fig. 1 is that embodiment 1 obtains (R) -3- (carbamoylmethyl) -5- methylhexanoic acid1H-NMR figure.
Fig. 2 is the liquid phase figure that embodiment 1 obtains (R) -3- (carbamoylmethyl) -5- methylhexanoic acid.
Fig. 3 is the mass spectrogram that embodiment 1 obtains (R) -3- (carbamoylmethyl) -5- methylhexanoic acid.
Specific embodiment
The present invention is described in more detail with reference to the accompanying drawings and examples, but protection scope of the present invention is not limited only to
These embodiments.
Embodiment 1
198g (3.7mol) ammonium chloride, 1200mL tetrahydrofuran are added into 5L there-necked flask, there-necked flask is placed in ice-water bath,
386g (4.6mol) sodium bicarbonate is added under stirring altogether in batches, control system temperature is no more than 20 DEG C, adds recession deicing water
Bath protection, be added at one time after being stirred at room temperature 30 minutes 200g (0.92mol) (S) -3- (ethyoxyl formyl methyl) -5- methyl oneself
Sour (ee=99%), TLC detects fully reacting after stirring 8 hours at room temperature.System is concentrated under reduced pressure under 40 DEG C of heating water baths,
Tetrahydrofuran is removed, is subsequently placed in ice-water bath, distilled water to remaining solid is added under stirring thereto and is completely dissolved, with dense salt
Sour (37%w/w) adjusts pH to 4~5, a large amount of white solids is precipitated and after the further crystallisation by cooling of ice-water bath, and water is used in filtering
Filter wash cake 2 times, naturally dry obtains product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 149.5g, and yield 86.34% is pure
Degree is greater than 96%, enantiomeric purity ee=99%.The structural characterization result of products obtained therefrom is as shown in Figures 1 to 3.
Embodiment 2
29.6g (554mmol) ammonium chloride, 120mL methanol are added into 5L there-necked flask, there-necked flask is placed in ice-water bath, is stirred
It mixes down and 31g (370mmol) sodium bicarbonate is added altogether in batches, control system temperature is no more than 20 DEG C, adds recession deicing water-bath
Protection, is stirred at room temperature and is added at one time 20g (92.5mmol) (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid after twenty minutes
(ee=99%), TLC detects fully reacting after stirring 4 hours at room temperature.System is concentrated under reduced pressure under 40 DEG C of heating water baths, is removed
Methanol is removed, is subsequently placed in ice-water bath, distilled water to remaining solid is added thereto under stiring and is completely dissolved, uses concentrated hydrochloric acid
(37%w/w) adjusts pH to 4~5, a large amount of white solids is precipitated and after the further crystallisation by cooling of ice-water bath, and filtering is washed with water
Filter cake 2 times, naturally dry obtains product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 11g, and yield 60.3%, purity is greater than
96%, enantiomeric purity ee=99%.
Embodiment 3
40g (277.5mmol) ammonium iodide, 120mL tetrahydrofuran are added into 5L there-necked flask, there-necked flask is placed in ice water
Bath, is added 11g (277.5mmol) Sodamide altogether in batches under stirring, control system temperature is no more than 20 DEG C, adds recession deicing
Water-bath protection, is stirred at room temperature and is added at one time 20g (92.5mmol) (S) -3- (ethyoxyl formyl methyl) -5- methyl after twenty minutes
Caproic acid (ee=99%), TLC detects fully reacting after stirring 4 hours at room temperature.System is depressurized under 40 DEG C of heating water baths dense
Contracting removes tetrahydrofuran, is subsequently placed in ice-water bath, and distilled water to remaining solid is added thereto under stiring and is completely dissolved,
PH to 4~5 is adjusted with concentrated hydrochloric acid (37%w/w), a large amount of white solids are precipitated and after the further crystallisation by cooling of ice-water bath, mistake
Filter, is washed with water filter cake 2 times, naturally dry, obtains product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 15g, yield
86.7%, purity is greater than 96%, enantiomeric purity ee=99%.
Embodiment 4
16mL (277.5mmol, 30w/w) ammonium hydroxide, 120mL tetrahydrofuran are added into 5L there-necked flask, there-necked flask is placed in
Ice-water bath, is added 15g (277.5mmol) sodium methoxide altogether in batches under stirring, control system temperature is no more than 20 DEG C, adds recession
Deicing water-bath protection, is stirred at room temperature and is added at one time 20g (92.5mmol) (S) -3- (ethyoxyl formyl methyl) -5- after twenty minutes
Methylhexanoic acid (ee=99%), TLC detects fully reacting after stirring 4 hours at room temperature.System is subtracted under 40 DEG C of heating water baths
Pressure concentration, removes tetrahydrofuran, is subsequently placed in ice-water bath, and it is completely molten to remaining solid that distilled water is added thereto under stiring
Solution adjusts pH to 4~5 with concentrated hydrochloric acid (37%w/w), a large amount of white solids is precipitated and after the further crystallisation by cooling of ice-water bath,
Filtering, is washed with water filter cake 2 times, naturally dry, obtains product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 13g, yield
75%, purity is greater than 96%, enantiomeric purity ee=99%.
Embodiment 5
In the present embodiment, with the ammonium iodide in equimolar formamide alternative embodiment 3, is replaced and implemented with equimolar sodium methoxide
Sodamide in example 3, with the tetrahydrofuran in isometric methanol alternative embodiment 3, other steps are same as Example 3, obtain
Product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 12g, yield 70%, purity are greater than 96%, enantiomeric purity ee=
99%.
Embodiment 6
In the present embodiment, with the ammonium iodide in equimolar formamide alternative embodiment 3, replaced with equimolar sodium tert-butoxide real
The Sodamide in example 3 is applied, with the tetrahydrofuran in isometric methanol alternative embodiment 3, other steps are same as Example 3, obtain
To product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 14g, yield 81%, purity is greater than 96%, enantiomeric purity ee=
99%.
Embodiment 7
In the present embodiment, with the ammonium iodide in equimolar formamide alternative embodiment 3, replaced with equimolar sodium bicarbonate real
The Sodamide in example 3 is applied, with the tetrahydrofuran in isometric methylene chloride alternative embodiment 3, other steps and 3 phase of embodiment
Together, product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 13g, yield 75% are obtained, purity is greater than 96%, enantiomeric purity
Ee=99%.
Embodiment 8
In the present embodiment, with tetrahydrofuran in isometric methylene chloride alternative embodiment 4, other steps and 4 phase of embodiment
Together, product (R) -3- (carbamoylmethyl) -5- methylhexanoic acid 11g, yield 63% are obtained, purity is greater than 96%, enantiomeric purity
Ee=99%.
Claims (9)
1. a kind of synthetic method of pregabalin intermediate, it is characterised in that:
Under ice-water bath and stirring condition, ammonia source is added in organic solvent, and alkali is added portionwise thereto, then at room temperature
(S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid is added thereto, reaction is stirred at room temperature 4~12 hours, divides after having reacted
From purified product, pregabalin intermediate is obtained, i.e. (R) -3- (carbamoylmethyl) -5- methylhexanoic acid；
Above-mentioned ammonia source be selected from ammonium chloride, ammonium hydrogen carbonate, ammonium carbonate, ammonium sulfate, ammonium oxalate, ammonium formate, ammonium bromide, ammonium iodide,
Ammonium hydroxide, formamide, acetamide, any one or more in hydrazine hydrate；
Above-mentioned organic solvent is selected from methanol, ethyl alcohol, tetrahydrofuran, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), 1,4- dioxy six
Ring, methylene chloride, chloroform, carbon tetrachloride, acetonitrile, benzene, any one or more in toluene.
Above-mentioned alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Sodamide, sodium hydride, methanol
Sodium, sodium ethoxide, sodium tert-butoxide, any one or more in potassium tert-butoxide.
2. the synthetic method of pregabalin intermediate according to claim 1, it is characterised in that: the ammonia source is selected from chlorine
Change ammonium, ammonium formate, ammonium iodide, ammonium hydroxide, formamide, any one in acetamide.
3. the synthetic method of pregabalin intermediate according to claim 1 or 2, it is characterised in that: the ammonia source adds
Enter 2.0~6.0 times that amount is (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
4. the synthetic method of pregabalin intermediate according to claim 3, it is characterised in that: the additional amount in the ammonia source
It is 3.0~5.0 times of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
5. the synthetic method of pregabalin intermediate according to claim 1, it is characterised in that: the alkali is selected from carbonic acid
Hydrogen sodium, Sodamide, sodium methoxide, sodium tert-butoxide, any one in potassium tert-butoxide.
6. the synthetic method of pregabalin intermediate according to claim 1 or 5, it is characterised in that: the addition of the alkali
Amount is 2.0~8.0 times of (S) -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
7. the synthetic method of pregabalin intermediate according to claim 6, it is characterised in that: the additional amount of the alkali is
(S) 3.0~6.0 times of -3- (ethyoxyl formyl methyl) -5- methylhexanoic acid mole.
8. the synthetic method of pregabalin intermediate according to claim 1, it is characterised in that: the organic solvent is selected from
Methanol, tetrahydrofuran, methyl tertiary butyl ether(MTBE), methylene chloride, any one in carbon tetrachloride.
9. the synthetic method of pregabalin intermediate according to claim 1, it is characterised in that the side isolated and purified
Method is: reaction system is concentrated under reduced pressure after having reacted and removes organic solvent, is subsequently placed in ice-water bath, water is added to it under stirring
It is completely dissolved to solid, then adjusts pH to 4~5 with concentrated hydrochloric acid, a large amount of white solids are precipitated, through the further crystallisation by cooling of ice-water bath
After filter, dried after filter cake is washed with water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302963A (en) * | 2020-03-24 | 2020-06-19 | 合肥医工医药股份有限公司 | Method for preparing 3-aminomethyl-5-methylhexanoic acid |
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| WO2007139933A2 (en) * | 2006-05-24 | 2007-12-06 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation of r-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof |
| CN101965328A (en) * | 2007-12-26 | 2011-02-02 | 基因里克斯(英国)有限公司 | Process to pregabalin |
| US20140243412A1 (en) * | 2013-02-28 | 2014-08-28 | Dr. Reddy's Laboratories Ltd. | Process for preparation of pregabalin |
| CN104496832A (en) * | 2014-11-21 | 2015-04-08 | 浙江美诺华药物化学有限公司 | Synthetic method of pregabalin |
| CN108912004A (en) * | 2018-08-01 | 2018-11-30 | 宏冠生物药业有限公司 | A kind of synthetic method of pregabalin intermediate |
| WO2018221604A1 (en) * | 2017-05-31 | 2018-12-06 | 住友化学株式会社 | Method for producing 3-arylpropionamide compound and 3-arylpropionic acid ester compound |
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2019
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007139933A2 (en) * | 2006-05-24 | 2007-12-06 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation of r-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof |
| CN101965328A (en) * | 2007-12-26 | 2011-02-02 | 基因里克斯(英国)有限公司 | Process to pregabalin |
| US20140243412A1 (en) * | 2013-02-28 | 2014-08-28 | Dr. Reddy's Laboratories Ltd. | Process for preparation of pregabalin |
| CN104496832A (en) * | 2014-11-21 | 2015-04-08 | 浙江美诺华药物化学有限公司 | Synthetic method of pregabalin |
| WO2018221604A1 (en) * | 2017-05-31 | 2018-12-06 | 住友化学株式会社 | Method for producing 3-arylpropionamide compound and 3-arylpropionic acid ester compound |
| CN108912004A (en) * | 2018-08-01 | 2018-11-30 | 宏冠生物药业有限公司 | A kind of synthetic method of pregabalin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302963A (en) * | 2020-03-24 | 2020-06-19 | 合肥医工医药股份有限公司 | Method for preparing 3-aminomethyl-5-methylhexanoic acid |
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Application publication date: 20191105 |