CN107602402B - A method of Pregabalin is prepared using ion-exchange - Google Patents
A method of Pregabalin is prepared using ion-exchange Download PDFInfo
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Abstract
The invention belongs to technical field of compound preparation, are related to a kind of method for preparing Pregabalin using ion-exchange, include the following steps (1) S, the dissociation of S- salt: in the presence of solvent, S, S- salt are dissociated by anion exchange resin, obtain Pregabalin solution；(2) preparation of Pregabalin: the Pregabalin solution that upper step is obtained is concentrated, and the first organic solvent crystallization is added, obtains Pregabalin；This method has many advantages, such as that product purity height, high income, mandelic acid residual quantity is low, ash content is few, environmentally protective, easy to operate, economic and practical.
Description
Technical field
The present invention relates to field of compound preparation, and in particular to a kind of side that Pregabalin is prepared using ion-exchange
Method.
Background technique
Pregabalin, (S)-(+) -3-aminomethyl-5-methyl-hexanoic acid are a kind of novel GABA receptor inhibition
Agent, for treating nerve pain, post-herpetic neuralgia, fibre caused by diabetic peripheral neuropathy change or spinal cord injury
Tie up myalgia and epilepsy.
Pregabalin is the analogue of inhibitory neurotransmitter GABA.Pregabalin does not make sodium channel directly
With it passes through the unitransport channel of transhipment leucine, isoleucine and valine, special through the cell membrane of blood-brain barrier
Anisotropic and P/Q type valtage-gated calcium channel α2-δSubunit combines；Ca can be reduced2+Interior stream, that reduces mankind's Cerebral cortex slice goes first
Adrenaline release, makes overwrought neuron restore normal condition.In the hippocampal cell of mouse, Pregabalin can also prolong
Long ATP dependence K+The open hour in channel.The research of transcranial magnetic stimulation prompts, Pregabalin to the effect of motor cortex with
GABA reuptaking inhibitor is similar.
The industrialization generation method of Pregabalin mainly has 3 kinds at present, referring to Organic Process Research &
Development 1997,1,26-38 and Organic Process Research&Development 2008,12,392-
398, starting material is 3- isobutylglutaric acid or cyanogen diester.
First method is referring to Organic Process Research&Development 1997,1,26-38, with 3-
Isobutylglutaric acid, through acetic anhydride cyclization, aminolysis open loop obtains racemization amic acid, obtains optical voidness after α-phenylethylamine is split
Amic acid intermediate finally obtains Pregabalin by Hoffmann rearrangement or the amic acid of racemization is directly obtained through Hoffmann rearrangement
It to Pregabalin raceme, is split using S-MA, dissociates to obtain Pregabalin.
Second method is pair referring to Organic Process Research&Development 1997,1,26-38
The improvement of first method, using cyanogen diester as starting material, by hydrolysis, depickling, reduction obtains raceme Puri bar after acidification
Woods, dissociating after S-MA is split can be obtained Pregabalin.The route is the first generation Pregabalin of Pfizer's research and development
Industrialized production route.
The third method referring to Organic Process Research&Development 2008,12,392-398,
This method is improvement of the Pfizer to first generation Pregabalin industrialized production route, splits cyanogen by commercially viable esterase
Diester obtains optical voidness sodium salt, and Pregabalin can be obtained by decarboxylation, hydrolysis, reduction, acidification.
By the above method it is found that being split by S-MA is to obtain the important method of optical voidness Pregabalin, and S- is general
Auspicious Bahrain and the dissociation of the diastereomeric salt (pregabalin S-MA salt, i.e. S, S- salt) of S-MA formation are
Obtain the committed step of optical voidness Pregabalin；According to the regulation of existing pharmacopeia, S-MA is the pass of Pregabalin bulk pharmaceutical chemicals
The related substance of key, residual need strict control (area normalization is less than 0.1%), it can be seen that the dissociation of S, S- salt is chemical resolution
Method prepares the important process step of Pregabalin.
Current S reported in the literature, there are two types of the dissociating methods of S- salt, referring to Organic Process Research&
Synthesising process research [D] the Zhejiang University master of Development 1997,1,26-38 and Huang Yan Pregabalin, which graduates, to be discussed
Text, 2008.
First method obtains Pregabalin crude product with tetrahydrofuran-water mixed solvent, through thermal decomposition, low temperature crystallization, is
The dissociating method of most important S, S- salt, this method main problem is solvent consumption is big, dissociation is not thorough, S-MA in crude product
Residual needs further subtractive process, and reaction yield only 60% or so needs additional resolving agent removal process, technique is opposite
It is complicated.
Huang Yan etc. has used common soda acid to dissociate method in its paper, i.e., to S, a certain amount of hydrochloric acid, which is added, in S- salt makes it
Dissociation, Pregabalin are dissolved in the water with hydrochloride form, and ethyl acetate extracts S-MA, realize Pregabalin and S- almond
The separation of acid, the Pregabalin hydrochloride in water phase are adjusted to isoelectric point precipitation, the advantages of this method by the way that sodium hydroxide is added
It is that a technical process realizes S, the dissociation of S- salt and the recycling of resolving agent, main problem is product packet after neutralizing
Containing a large amount of sodium chloride, product assay and ash content are unqualified.
In conclusion at present there are some problems in S reported in the literature, the dissociating method of S- salt.Therefore, exploitation one is green
Colour circle guarantor, easy to operate, economic and practical, with high purity, high income, ash content are small, by S, method that S- salt prepares Pregabalin
It is new issue to be resolved at present.
Summary of the invention
The purpose of the present invention is to provide a kind of method for preparing Pregabalin using ion-exchange, this method, which has, to be produced
Object purity is high, the advantages that high income, mandelic acid residual quantity is low, ash content is few, environmentally protective, easy to operate, economic and practical.
The object of the present invention is achieved like this: a method of Pregabalin, the side are prepared using ion-exchange
Method the following steps are included:
(1) dissociation of S, S- salt
In the presence of solvent, S, S- salt are dissociated by anion exchange resin, obtain Pregabalin solution；
(2) preparation of Pregabalin
The Pregabalin solution concentration that upper step is obtained, is added the first organic solvent crystallization, obtains Pregabalin；
The S, S- salt are the diastereomeric salt that pregabalin and S-MA are formed；
The anion exchange resin is selected from basic anionic resin, and the basic anionic resin is selected from
Dowex-SBR-P alkalescence anion-exchange resin, Duolite-A101 alkalescence anion-exchange resin, Dowex-IRA-401 alkali
One of property anion exchange resin, Lewatit M500 alkalescence anion-exchange resin；In the step (1), S, S-
Salt is 20-100 DEG C by the temperature that anion exchange resin is dissociated, and preferable temperature is 60-80 DEG C, and more preferable temperature is
60-70℃；In the step (1), S, S- salt is 0.5-2 hours by the time that anion exchange resin is dissociated, excellent
Selecting the time is 1-2 hours；In the step (1), the solvent is the mixed solvent of water and the second organic solvent, described the
Two organic solvents are selected from one or more of methanol, ethyl alcohol, isopropanol and tetrahydrofuran；The water and the second organic solvent
Volume ratio is 1:1 to 10:1, is preferably in a proportion of 10:3；The ratio of the quality of the S, S- salt and the volume of second organic solvent
For 2-5:3, it is preferably in a proportion of 32:30, the unit of the quality is gram that the unit of the volume is milliliter；In the step (2)
In, first organic solvent is selected from one or more of methanol, ethyl alcohol or isopropanol；The Pregabalin solution and first
The volume ratio of organic solvent is 1:1-5, preferred volume ratio 1:3；It further include dissociate to by anion exchange resin
To S-MA recycled the step of: the anion exchange resin after dissociation in step (1) is washed with aqueous slkali, will be washed
It when washing liquid and being adjusted with acid to pH to 1-3, is extracted with third organic solvent, concentration organic phase obtains S-MA crude product, S- almond
Acid crude is by being recrystallized to give S-MA；The aqueous slkali is selected from sodium hydrate aqueous solution, potassium hydroxide aqueous solution, carbon
Sour hydrogen sodium water solution or ammonium hydroxide, the concentration of the aqueous slkali are 1-10%, preferred concentration 5%；The acid is selected from hydrochloric acid, sulfuric acid
One of, the concentration of the acid is 5-8mol/L, and the concentration of preferred acid is 6mol/L；The third organic solvent is selected from methyl
Tertbutyl ether, the solvent of the recrystallization are toluene, and the time of the recrystallization is 24 hours, and the temperature of the recrystallization is 0
℃。
It is of the invention to be characterized by a kind of method that Pregabalin is prepared using ion-exchange, principle are as follows: (1) originally
The process of inventive method is as follows:
The solution of S, S- salt (Formula II), pH 6.08.The pK of free S-MAaIt is 5.28, in S, S- salting liquid
In the form of S-MA anion (formula III) exist can be adsorbed by alkalescence anion-exchange resin, and Pregabalin (Formulas I) its
pKaIt is 4.2, existing in the form of carboxylic acid molecules can not be adsorbed in the solution by alkalescence anion-exchange resin.In temperature appropriate
Under degree and dicyandiamide solution, S, S- salt is dissociated, the OH on S-MA anion and alkalescence anion-exchange resin-Exchange,
It is adsorbed on skeleton, Pregabalin is free；Since S-MA anion is constantly adsorbed on resin matrix, promote S, S-
The dissociation equilibrium of salt is constantly mobile to positive direction, so that the dissociation of S, S- salt is complete.
On the basis of S, S- salt dissociation, realize that Pregabalin is separated with S-MA by filtering, purified washing
After washing, Pregabalin is in aqueous solution form, and S-MA is adsorbed in tree with S-MA anionic form, i.e. formula III compound
On rouge skeleton.
Precipitation obtains the Pregabalin product of high-purity after isopropanol is added in the aqueous solution of Pregabalin.
Formula III compound is dissociated from resin matrix after resin regeneration, is dissolved in the water, by recycling almond after acidification
Sour (formula IV) compound.
The beneficial effects of the present invention are:
It (1) is the separation for realizing Pregabalin and S-MA by simple filter process.
(2) Pregabalin and S-MA being prepared have very high yield and purity.
(3) consumption of organic solvent is few in route, environmentally protective, and ion exchange resin reclaiming is simple, it is easy to accomplish big
Scale continuous operation.
(4) remaining mandelic acid and content of ashes are few in the Pregabalin that the method for the present invention is prepared.
Specific embodiment
It will be helpful to understand the present invention by implementation method in detail below, but be not intended to limit the contents of the present invention.This field
It should be understood to the one skilled in the art that equivalent replacement made by technical characteristic of the invention, or be correspondingly improved, still fall within of the invention
Within protection scope.
Embodiment one
1, the dissociation of S, S- salt
32g S is added into the 500mL four-hole bottle equipped with thermometer, the water and 30mL methanol of S- salt and 100mL are added
100g pretreated Dowex-SBR-P alkalescence anion-exchange resin (OH type, DOW/ DOW Chemical, gel-type, styrene-two
Ethenylbenzene is copolymerized matrix skeleton), it is heated to 60-70 DEG C of heat preservation 1h, is filtered, resin washs get Pu Ruiba with 100mL deionized water
Woods solution for standby.
2, the preparation of Pregabalin
The Pregabalin solution that upper step obtains is concentrated into about 60mL, 180mL isopropanol is added, system is heated to 80-85
DEG C, 5% (w/w) active carbon is added, keeps the temperature 15-20min, filters while hot, filtrate continues to dissolve by heating all solids, delays under water-bath
Slowly 20 DEG C are cooled to, are cooled further to 0-5 DEG C, keep the temperature 4h, filtering, filter cake is with the washing of 100mL isopropanol, 55 DEG C of vacuum drying
4h obtains white 11.3 g of Pregabalin finished product, two step total recoverys 70%.
Pregabalin prevailing quality data are as follows: HPLC content (Pregabalin standard items external standard method) 99.7%, S- almond
Acid residual (area normalization) 0.08%, ash content 0.17%.
Embodiment two
1, the dissociation of S, S- salt
32g S is added into the 500mL four-hole bottle equipped with thermometer, the water and 30mL methanol of S- salt and 100mL are added
The selection situation of the pretreated resin of 100g, resin is shown in Table 1, is heated to 60-70 DEG C of heat preservation 1h, and filtering, resin is gone with 100mL
Ion water washing obtains Pregabalin solution for standby.
2, the preparation of Pregabalin
The Pregabalin solution that upper step obtains is concentrated into about 60mL, 180mL isopropanol is added, system is heated to 80-85
DEG C, 5% (w/w) active carbon is added, keeps the temperature 15-20min, filters while hot, filtrate continues to dissolve by heating all solids, delays under water-bath
Slowly 20 DEG C are cooled to, are cooled further to 0-5 DEG C, keep the temperature 4h, filtering, filter cake is with the washing of 100mL isopropanol, 55 DEG C of vacuum drying
4h obtains white Pregabalin finished product, and Pregabalin product yield and quality condition are shown in Table 1:
Influence of the 1 different model resin of table to Pregabalin finished product
| Serial number | Resin model | Yield | HPLC content | Mandelic acid residual | Ash content |
| 1 | Dowex-SBR-P (styrene type) | 70% | 99.7% | 0.08% | 0.17% |
| 2 | Duolite-A101 (styrene type) | 71% | 98.5% | 0.11% | 0.18% |
| 3 | Dowex-IRA-401 (styrene type) | 68% | 95.1% | 0.2% | 1.9% |
| 4 | Lewatit M500 (styrene type) | 60% | 98.7% | 0.09% | 0.23% |
Embodiment three
1, the dissociation of S, S- salt
The addition 32g S into the 500mL four-hole bottle equipped with thermometer, the water and 30mL organic solvent of S- salt and 100mL,
The selection situation of organic solvent is shown in Table 2, be added the pretreated Dowex-SBR-P alkalescence anion-exchange resin of 100g (OH type,
DOW/ DOW Chemical), it is heated to 60-70 DEG C of heat preservation 1h, is filtered, resin washs to obtain Pregabalin solution with 100mL deionized water
It is spare.
2, the preparation of Pregabalin
The Pregabalin solution that upper step obtains is concentrated into about 60mL, 180mL isopropanol is added, system is heated to 80-85
DEG C, 5% (w/w) active carbon is added, keeps the temperature 15-20min, filters while hot, filtrate continues to dissolve by heating all solids, delays under water-bath
Slowly 20 DEG C are cooled to, are cooled further to 0-5 DEG C, keep the temperature 4h, filtering, filter cake is with the washing of 100mL isopropanol, 55 DEG C of vacuum drying
4h obtains white Pregabalin finished product, and Pregabalin product yield and quality condition are shown in Table 2:
Influence of 2 different organic solvents of table to Pregabalin finished product
| Serial number | Solvent | Yield | HPLC content | Mandelic acid residual | Ash content |
| 1 | Methanol | 70% | 99.7% | 0.08% | 0.17% |
| 2 | Ethyl alcohol | 68% | 98.5% | 0.10% | 0.19% |
| 3 | Acetone | 30% | 97.5% | 0.21% | 0.11% |
| 4 | Tetrahydrofuran | 60% | 99.1% | 0.29% | 0.15% |
Example IV
1, the dissociation of S, S- salt
32g S is added into the 500mL four-hole bottle equipped with thermometer, the water and 30mL methanol of S- salt and 100mL are added
The pretreated Dowex-SBR-P alkalescence anion-exchange resin of 100g (OH type, DOW/ DOW Chemical), heating, the heating reach
To temperature range be shown in Table 3, keep the temperature 1h, filtering, resin washs to obtain Pregabalin solution for standby with 100 mL deionized waters.
2, the preparation of Pregabalin
The Pregabalin solution that upper step obtains is concentrated into about 60mL, 180mL isopropanol is added, system is heated to 80-85
DEG C, 5% (w/w) active carbon is added, keeps the temperature 15-20min, filters while hot, filtrate continues to dissolve by heating all solids, delays under water-bath
Slowly 20 DEG C are cooled to, are cooled further to 0-5 DEG C, keep the temperature 4h, filtering, filter cake is with the washing of 100mL isopropanol, 55 DEG C of vacuum drying
4h obtains white Pregabalin finished product, and Pregabalin product yield and quality condition are shown in Table 3:
Influence of 3 different temperatures of table to Pregabalin finished product
| Serial number | Temperature range | Yield | HPLC content | Mandelic acid residual | Ash content |
| 1 | 20-30℃ | 95% | 50% | 43% | 0.19% |
| 2 | 40-45℃ | 85% | 68% | 18% | 0.21% |
| 3 | 50-55℃ | 80% | 79% | 15% | 0.19% |
| 4 | 60-70℃ | 70% | 99.7% | 0.08% | 0.17% |
| 5 | 70-80℃ | 68% | 98.9% | 0.07% | 0.18% |
Embodiment five
1, the dissociation of S, S- salt
32g S is added into the 500mL four-hole bottle equipped with thermometer, the water and 30mL methanol of S- salt and 100mL are added
The pretreated Dowex-SBR-P alkalescence anion-exchange resin of 100g (OH type, DOW/ DOW Chemical) is heated to 60-70 DEG C of guarantor
Temperature, the time of the heat preservation are shown in Table 4, and filtering, resin washs to obtain Pregabalin solution for standby with 100mL deionized water.
2, the preparation of Pregabalin
The Pregabalin solution that upper step obtains is concentrated into about 60mL, 180mL isopropanol is added, system is heated to 80-85
DEG C, 5% (w/w) active carbon is added, keeps the temperature 15-20min, filters while hot, filtrate continues to dissolve by heating all solids, delays under water-bath
Slowly 20 DEG C are cooled to, are cooled further to 0-5 DEG C, keep the temperature 4h, filtering, filter cake is with the washing of 100mL isopropanol, 55 DEG C of vacuum drying
4h obtains white Pregabalin finished product, and Pregabalin product yield and quality condition are shown in Table 4:
Influence of the different soaking times of table 4 to Pregabalin finished product
| Serial number | Soaking time | Yield | HPLC content | Mandelic acid residual | Ash content |
| 1 | 0.5 hour | 75% | 80% | 12.9% | 0.18% |
| 2 | 1 hour | 70% | 99.7% | 0.08% | 0.17% |
| 3 | 2 hours | 59% | 99.1% | 0.09% | 0.19% |
Embodiment six
The recycling of S-MA
By the anion exchange resin after being washed with deionized in one step 1 of embodiment with 5% hydroxide of 50mL*3
Sodium solution washing, collects mother liquor and is cooled to 0 DEG C, adjusts pH to 2 with 6mol/L HCl, is extracted with 600mL methyl tertiary butyl ether(MTBE),
After organic phase concentration S-MA crude product, the crude product with the re crystallization from toluene of 10 times of volumes, 0 DEG C crystallization 24 hours, it is flat to obtain S-
Peach acid 11.6g, yield 75%.
The S-MA qualitative data of recycling is as follows: HPLC content 98%, and 133-134 DEG C of fusing point, 155.1 ° of (c of optical activity
=2, H2O)。
Comparative example
The dissociation (hydrochloric acid method) of S, S- salt
7.6g S is added into the 100m L single port bottle equipped with thermometer, the water of S- salt and 22.8mL is heated to 40 DEG C, with
HCl solution regulation system pH to 1 keeps the temperature 1h, after system is cooling, with the extraction of 150mL ethyl acetate, water phase transfer, with 50%
NaOH solution adjusts pH to weakly acidic pH, is concentrated to give white solid, which is added 7.5mL isopropanol and the water recrystallization of 2.5mL,
Slow cooling is cooled further to 0-5 DEG C to 20 DEG C under water-bath, keeps the temperature 4h, filtering, for filter cake with the washing of 1mL isopropanol, 55 DEG C true
The dry 4h of sky, obtains white Pregabalin finished product 2.1g, total recovery 54%.
It is as follows to prepare Pregabalin prevailing quality data using salt acid dissociation method: HPLC content is (outside Pregabalin standard items
Mark method) 95.2%, S-MA remains (area normalization) 0.69%, ash content 1.19%.
Claims (12)
1. a kind of method for preparing Pregabalin using ion-exchange, which is characterized in that the described method comprises the following steps:
(1) dissociation of S, S- salt
In the presence of solvent, S, S- salt are dissociated by anion exchange resin, obtain Pregabalin solution；
(2) preparation of Pregabalin
The Pregabalin solution concentration that upper step is obtained, is added the first organic solvent crystallization, obtains Pregabalin；
The S, S- salt are the diastereomeric salt that pregabalin and S-MA are formed；
The anion exchange resin is selected from basic anionic resin, and the basic anionic resin is selected from Dowex-SBR-
P alkalescence anion-exchange resin, Duolite-A101 alkalescence anion-exchange resin, Dowex-IRA-401 alkali anion are handed over
Change one of resin, Lewatit M500 alkalescence anion-exchange resin.
2. a kind of method for preparing Pregabalin using ion-exchange according to claim 1, which is characterized in that in institute
It states in step (1), S, S- salt is 20-100 DEG C by the temperature that anion exchange resin is dissociated；In the step (1),
S, S- salt are 0.5-2 hours by the time that anion exchange resin is dissociated.
3. a kind of method for preparing Pregabalin using ion-exchange according to claim 2, which is characterized in that in institute
It states in step (1), S, S- salt is 60-80 DEG C by the temperature that anion exchange resin is dissociated；In the step (1),
S, S- salt are 1-2 hours by the time that anion exchange resin is dissociated.
4. a kind of method for preparing Pregabalin using ion-exchange according to claim 2, which is characterized in that in institute
It states in step (1), S, S- salt is 60-70 DEG C by the temperature that anion exchange resin is dissociated.
5. a kind of method for preparing Pregabalin using ion-exchange according to claim 1, which is characterized in that in institute
State in step (1), the solvent be water and the second organic solvent mixed solvent, second organic solvent selected from methanol,
One or more of ethyl alcohol, isopropanol and tetrahydrofuran；The volume ratio of the water and the second organic solvent is 1:1 to 10:1；
The ratio of the volume of the quality of the S, S- salt and second organic solvent is 2-5:3, and the unit of the quality is gram the body
Long-pending unit is milliliter.
6. a kind of method for preparing Pregabalin using ion-exchange according to claim 5, which is characterized in that in institute
It states in step (1), the volume ratio of the water and the second organic solvent is 10:3；The quality of the S, S- salt and described second organic
The ratio of the volume of solvent is 32:30, and the unit of the quality is gram that the unit of the volume is milliliter.
7. a kind of method for preparing Pregabalin using ion-exchange according to claim 1, which is characterized in that in institute
It states in step (2), first organic solvent is selected from one or more of methanol, ethyl alcohol or isopropanol；The Pregabalin
The volume ratio of solution and the first organic solvent is 1:1-5.
8. a kind of method for preparing Pregabalin using ion-exchange according to claim 7, which is characterized in that in institute
It states in step (2), the volume ratio of the Pregabalin solution and the first organic solvent is 1:3.
9. a kind of method for preparing Pregabalin using ion-exchange according to claim 1, which is characterized in that also wrap
Include the step of recycling to the S-MA dissociated by anion exchange resin: after dissociation in step (1)
Anion exchange resin washed with aqueous slkali, when cleaning solution is adjusted with acid to pH to 1-3, with third organic solvent extract,
Concentration organic phase obtains S-MA crude product, and S-MA crude product is by being recrystallized to give S-MA.
10. a kind of method for preparing Pregabalin using ion-exchange according to claim 9, which is characterized in that institute
The aqueous slkali stated is selected from sodium hydrate aqueous solution, potassium hydroxide aqueous solution, sodium bicarbonate aqueous solution or ammonium hydroxide, the aqueous slkali
Concentration is 1-10%；The acid is selected from one of hydrochloric acid, sulfuric acid, and the concentration of the acid is 5-8mol/L.
11. a kind of method for preparing Pregabalin using ion-exchange according to claim 10, which is characterized in that institute
The concentration for stating aqueous slkali is 5%；The concentration of the acid is 6mol/L.
12. a kind of method for preparing Pregabalin using ion-exchange according to claim 9, which is characterized in that institute
It states third organic solvent and is selected from methyl tertiary butyl ether(MTBE), the solvent of the recrystallization is toluene, and the time of the recrystallization is 24 small
When, the temperature of the recrystallization is 0 DEG C.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010061403A2 (en) * | 2008-11-26 | 2010-06-03 | Ind-Swift Laboratories Limited | Process to prepare highly pure (s)-pregabalin |
| CN105348124A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking oxopyrrolidine as intermediate |
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2017
- 2017-07-28 CN CN201710630743.0A patent/CN107602402B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010061403A2 (en) * | 2008-11-26 | 2010-06-03 | Ind-Swift Laboratories Limited | Process to prepare highly pure (s)-pregabalin |
| CN105348124A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking oxopyrrolidine as intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 普瑞巴林化学拆分过程研究;李雯 等;《郑州大学学报(工学版)》;20150731;第36卷(第4期);第33-36页 * |
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