CN112939809A - Preparation method of 1-cyano-3-methyl diethyl butylmalonate - Google Patents
Preparation method of 1-cyano-3-methyl diethyl butylmalonate Download PDFInfo
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Abstract
The application provides a preparation method of 1-cyano-3-methyl diethyl butylmalonate (CNDE), which belongs to the technical field of medical technology (organic synthesis), and has the technical key points that: the method comprises the following steps: (1) carrying out Knoevenagel condensation reaction on isovaleraldehyde, diethyl malonate and a solvent in the presence of a catalyst, namely dipropylamine and acetic acid to obtain a CNDE01 product; (2) adding CNDE01, sodium cyanide, water and solvent into a closed kettle, and reacting under the action of carbon dioxide to obtain CNDE product. The application aims to provide a preparation method of 1-cyano-3-methyl diethyl butylmalonate (CNDE), overcomes the defects of the existing production process, and has the advantages of low raw material cost, high product purity and yield, less three wastes and the like.
Description
Technical Field
The application relates to a preparation method of 1-cyano-3-methyl diethyl butylmalonate (CNDE), belonging to the field of medical technology (organic synthesis).
Background
The english name of diethyl 1-cyano-3-methylbutyl malonate (CNDE) is: propanedioic acid, 2- (1-cyano-3-methylbutanyl) -1, 3-dimethyl ester; CAS #: 186038-82-4; the structural formula is as follows:
CNDE is a key intermediate for the synthesis of Pregabalin (published: org. Process Res. Dev.2008, 12(3), 392-398 Development of a Chemoenzymatic Manufacturing Process for Pregabalin).
Pregabalin (trade name: Lyrica), chemical name: (3S) -3-aminomethyl-5-methylhexanoic acid, a gamma-aminobutyric acid (GABA) receptor antagonist developed by Warner-Lambert corporation. Registration applications were filed in the united states by the company pfeir in 2003; in 12 months 2004, the FDA approved pregabalin as a drug for the treatment of diabetic neuralgia and postherpetic neuralgia. Pregabalin was the first approved drug in the united states and europe to be simultaneously indicated for the treatment of both of these pains. Pregabalin was approved for the adjuvant treatment of adult seizures in 6 months 2005. Pregabalin was rated as one of the ten medical advances in 2007 by the era periodicals in the united states in 2007. Pregabalin, which has a global cumulative sale of over $ 150 billion, was approved in 2010 into china.
At present, the synthetic routes of CNDE mainly include the following 3:
the first mode is as follows: the methods provided by patents such as US5840956A and CN101497578A are that isovaleraldehyde and diethyl malonate are used as raw materials, and are subjected to knoevenagel reaction and then subjected to addition reaction with sodium cyanide to generate CNDE.
The reaction process is as follows:
the route is a large-scale production process route adopted at home and abroad at present, but the defects of more impurities of condensation products, difficult separation and purification and low product purity and yield are generally existed. Especially, after the sodium cyanide addition reaction, a large amount of waste water is generated, and the waste water can be discharged after being qualified, so that the pollution is very serious.
The second mode is as follows: CN105061234A and CN 103450045a provide addition methods with hydrocyanic acid, but hydrocyanic acid is toxic and has the disadvantage of inconvenient use and storage. For production enterprises with hydrocyanic acid resources, the route has certain raw material cost advantage, and the route has no significance for other enterprises.
The reaction is as follows:
the third mode is as follows: shenyangmei fine chemical company, Inc., in CN101948406A patent, discloses a novel synthetic route, which comprises reacting isovaleraldehyde, sodium cyanide and benzenesulfonyl chloride, and reacting with potassium bromide to obtain 2-bromo-4-methylpentanenitrile; finally, the CNDE product is obtained by condensation with diethyl malonate in the presence of strong base.
The reaction is as follows:
the intermediate 2-bromo-4-methyl valeronitrile in the route is easy to have elimination reaction under alkaline conditions, so that the product purity is poor, and olefin impurities are difficult to purify and remove. Meanwhile, the potassium bromide, the sodium hydride, the benzene sulfonyl chloride and other high-price reagents are used, so that the raw material cost of the CNDE is greatly increased.
In conclusion, finding a CNDE production route with the advantages of low raw material cost, high product purity and yield and less three wastes becomes a technical problem to be solved urgently.
Disclosure of Invention
The object of the present application is to provide a novel method for preparing CNDE, which addresses the above-mentioned deficiencies of the prior art.
A preparation method of CNDE comprises the following steps:
s1, preparation of CNDE 01: isovaleraldehyde, diethyl malonate and a solvent react to obtain CNDE 01;
s2, preparation of CNDE:
s2-1, adding CNDE01, sodium cyanide, water and a solvent into a closed kettle, and reacting under the action of carbon dioxide to obtain a sodium bicarbonate/carbonic acid buffer solution of a target product CNDE;
s2-2, after the reaction is finished, adding hexane to filter and remove solids (adding hexane to the reaction mass to filter and remove solids);
and S2-3, recovering the solvent from the organic layer to obtain the CNDE (removing the solvent from the filtrate under reduced pressure to obtain a CNDE finished product).
The reaction formula is as follows:
further, step S1 specifically includes:
s1-1: putting isovaleraldehyde, diethyl malonate, dipropylamine, acetic acid and a solvent into a reaction kettle, heating to reflux by oil bath, and performing azeotropic water distribution until the raw materials are consumed until the content of diethyl malonate/(isovaleraldehyde + diethyl malonate + CNED01) is less than or equal to 4% (GC area normalization); after the reaction is finished, cooling to 20-40 ℃, and adding water for washing; wherein dipropylamine and acetic acid are both catalysts;
s1-2: the organic layer was subjected to reduced pressure to recover the solvent, thereby obtaining CNDE 01.
Further, in step S1-1, the solvent is any one of cyclohexane, methylcyclohexane, hexane, and heptane.
Further, step S2-1 specifically includes: adding CNDE01, water, solvent and sodium cyanide into a closed kettle, heating to 30-150 ℃ for reaction, introducing carbon dioxide, controlling the pressure in the kettle to be 0.1-10 atmospheric pressure, reacting until CNDE01/(CNDE01+ CNED02) is less than 3% (GC area normalization), and finishing the reaction.
Further, the solvent used in step s2-1 is DMF, ethanol, isopropanol, dimethyl sulfoxide, preferably ethanol.
Further, in step S2-1, CNDE01, water, solvent and sodium cyanide are put into a closed kettle, and the temperature is raised to 40-60 ℃ for reaction.
Further, in step S2-1, carbon dioxide is introduced, and the pressure in the kettle is controlled to be 1-5 atmospheres.
The beneficial effect of this application:
firstly, the application provides a new cyano-group addition technology, carbon dioxide and water are used for in-situ generation of carbonic acid, and therefore hydrocyanic acid is generated in situ to carry out cyano-group addition reaction. Meanwhile, the generated sodium bicarbonate solid is removed by filtering after the reaction, so that the generation of waste water is greatly reduced.
Secondly, the team of inventors, in studying the preparation of CNDE, unexpectedly found that: by using carbonic acid generated in situ by carbon dioxide gas and water, hydrocyanic acid is generated in situ to be added with CNDE01, and carbonic acid can also effectively acidify sodium salt of 1-cyano-3-methyl diethyl butylmalonate generated by reaction, thereby reducing the alkalinity of the reaction system. Compared with the traditional production method for preparing the CNDE (such as the patent reports of WO2008062460A1 and US 5840956A: the reaction with sodium cyanide is firstly carried out, and then the neutralization is carried out with acetic acid), the product yield and the quality of the CNDE are reduced because the sodium cyanide has strong alkalinity, and side reactions such as hydrolysis, decarboxylation and the like of raw materials or product ester are easily caused in the reaction process; and the carbon dioxide can maintain weak acidity in a reaction system, so that side reactions such as ester hydrolysis and the like are avoided, and the yield and the purity of the product are greatly improved.
Specifically, it is to be noted that: carbon dioxide is a safe and inexpensive gas that is converted to carbonic acid in water; the saturated aqueous carbon dioxide solution is maintained at a pH of 5.6 to 5.8 at room temperature. If the pressure of the carbon dioxide is increased to 5 atmospheres, the pH of the saturated aqueous carbon dioxide solution is maintained at 3.8 to 4.0, which is comparable to the pH of acetic acid.
The production process in the prior art comprises the following steps:
wherein: m is sodium or potassium.
The process of the application is as follows:
third, the inventors searched: "diethyl methylbutylmalonate or CNDE" and isovaleraldehyde and diethyl malonate, after the search in CNTXT and EPO, the search results are: 0.
meanwhile, "diethyl methylbutylmalonate or CNDE" and "carbon dioxide or CO2"cntext and EPO were searched for, and the search results were: 0.
therefore, the mode proposed by the application is pioneering. For the scheme of the present application, however, the reaction conditions are: putting CNDE01, water, solvent and sodium cyanide into a closed kettle, heating to 40-60 ℃ for reaction, introducing carbon dioxide, controlling the pressure in the kettle to be 0.1-10 atmospheric pressure, and reacting until the CNDE01 is less than 3% (which is a core index for judging when the reaction stops); adding hexane into the reaction material, filtering to remove solids, and removing the solvent from the filtrate under reduced pressure to obtain a CNDE finished product', which is also one of the core inventive concepts of the application.
Drawings
FIG. 1 is a CNDE structure confirmation of example 11H NMR spectrum;
FIG. 2 is a CNDE structure confirmation of example 113C NMR spectrum;
FIG. 3 is an HPLC chromatogram of CNDE purity measurement of example 1.
Detailed Description
The following examples will help researchers understand the gist of the present application, but are not intended to limit the present application.
The basic idea of the application is as follows:
a preparation method of 1-cyano-3-methyl diethyl butylmalonate (CNDE) (1) comprises the steps of carrying out Knoevenage1 condensation reaction on isovaleraldehyde, diethyl malonate and a solvent in the presence of a catalyst, namely dipropylamine and acetic acid, so as to obtain a CNDE01 product; (2) adding CNDE01, sodium cyanide, water and a solvent into a closed kettle, and reacting under the action of carbon dioxide to obtain a CNDE product:
the above reaction formula is as follows:
the method comprises the following specific steps:
step 1: putting isovaleraldehyde, diethyl malonate, dipropylamine, acetic acid and a solvent (the solvent adopts cyclohexane, methylcyclohexane, hexane and heptane; preferably methylcyclohexane) into a reaction kettle, heating to reflux by oil bath, and carrying out azeotropic water distribution until the raw materials are consumed until the content of diethyl malonate/(isovaleraldehyde + diethyl malonate + CNED01) is less than or equal to 4% (GC area is normalized). After the reaction is finished, cooling to 20-40 ℃, and adding water for washing. And recovering the solvent from the organic layer under reduced pressure to obtain a CNDE01 product.
Step 2: putting CNDE01, water, solvent (the solvent is any one of DMF, ethanol, isopropanol and dimethyl sulfoxide; ethanol is preferred) and sodium cyanide into a closed kettle, heating to 30-150 ℃ (40-60 ℃ is preferred) for reaction, introducing carbon dioxide (carbon dioxide and water in the system generate carbonic acid in situ, the pressure of the carbon dioxide is 0.1-10 atm, 1-5 atm is preferred), controlling the pressure in the kettle to be 0.1-10 atm, and reacting until CNDE01/(CNDE01+ CNED02) is less than 3% (GC area is normalized); adding hexane into the reaction material, filtering to remove solids, and removing the solvent from the filtrate under reduced pressure to obtain a CNDE finished product.
Example 1:
step 1: preparation of CNDE01
138.5g of diethyl malonate, 78.1g of isovaleraldehyde, 4.5g of dipropylamine, 5.5g of acetic acid and 200g of methylcyclohexane are sequentially added into a 500mL reaction kettle, and the temperature is raised to reflux for water diversion; at the beginning, the internal temperature is about 80 ℃, then the temperature is gradually increased to 105 ℃ for about 10 hours, almost no water drops are extracted from the water separator, the sampling is controlled in the middle (the content of diethyl malonate is controlled to be less than or equal to 4%), the temperature of the system is reduced to be below 40 ℃ after the reaction is finished, 150g of water is added into the reaction materials for washing, the reaction materials are kept stand for layering, an organic layer is separated, the organic phase is decompressed and desolventized at 50 ℃, 200.2g of crude product is obtained, the yield is 93.7%, and the purity is 92.4%.
Step 2: preparation of CNDE
Putting 100.1g of CNDE01, 115g of ethanol, 10g of water and 20.1g of sodium cyanide into a stainless steel closed kettle, heating to 30-40 ℃ for reaction, introducing carbon dioxide gas, controlling the pressure level in the kettle to be 1-2atm, and keeping sampling and central control for 2 hours (controlling the CNDE01 to be less than or equal to 3 percent); adding 200g of hexane into the reaction mass, filtering to remove solids (safety operation is noted, waste contains a small amount of cyanide, and hydrogen peroxide and alkali are used for quenching cyanide ions), removing most of solvent from filtrate (hexane layer) at normal pressure, keeping the temperature below 80 ℃, then cooling to 50 ℃, and carrying out vacuum desolventizing until the vacuum degree is-0.09 to-0.1 MPa until no fraction is collected, thus obtaining 104.7g of CNDE product with the nominal content of 94.6%, the product purity of 95.2% and the yield of 87.6%.
1H NMR(CDCl3)，400MHz，δ4.28(m，4H)，3.54(d，J＝8.2Hz，1H)，3.31(m，1H)，1.91(m，1H)，1.68(m，1H)，1.31(m，1H)，1.31(dt，J＝13.3，7.1Hz，6H)，0.98(t，J＝6.3Hz，6H).
13C NMR(CDCl3)，100MHz δ166.18，119.34，62.42，53.86，38.86，29.46，26.15，23.10，20.94， 14.01
Of products1H-NMR and13HPLC spectra for C-NMR and purity detection are shown in figure 1, figure 2 and figure 3.
The product purity test of the present application employs the following HPLC conditions:
example 2:
step 1: preparation of CNDE01
138.5g of diethyl malonate, 78.1g of isovaleraldehyde, 4.5g of dipropylamine, 5.5g of acetic acid and 150g of cyclohexane are sequentially added into a 500mL reaction kettle, and the temperature is raised to reflux for water diversion; at the beginning, the internal temperature is about 70 ℃, then the temperature is gradually increased to 85 ℃ for about 10 hours, almost no water drops are extracted from the water separator, the sampling is controlled in the middle (the content of diethyl malonate as the raw material is controlled to be less than or equal to 4%), the temperature of the system is reduced to be below 40 ℃ after the reaction is finished, 150g of water is added into the reaction material for washing, the reaction material is kept stand for layering, an organic layer is separated, the organic phase is decompressed and desolventized at 45 ℃, 198.6g of crude product is obtained, the yield is 90.7%, and the purity is 90.2%.
Step 2: preparation of CNDE
Putting 100g of CNDE01, 115g of DMF, 10g of water and 20.1g of sodium cyanide into a stainless steel closed kettle, heating to 150 ℃ for reaction, introducing carbon dioxide gas, controlling the pressure level in the kettle to be 5atm, and keeping sampling and central control for 2 hours (controlling the CNDE01 as a raw material to be less than or equal to 3%); adding 200g of hexane into the reaction materials, filtering to remove solids (safety operation is noted, waste contains a small amount of cyanide, and hydrogen peroxide and alkali are used for quenching cyanide ions), removing most of solvent from filtrate at normal pressure, cooling to 50 ℃, reducing pressure until the vacuum degree is-0.09 to-0.1 MPa, and desolventizing until no fraction is collected, thus obtaining 98.3g of CNDE product with the nominal content of 92.8 percent, the product purity of 91.0 percent and the yield of 80.6 percent.
Example 3:
step 1: preparation of CNDE01
138.5g of diethyl malonate, 78.1g of isovaleraldehyde, 5.0g of dipropylamine, 5.5g of acetic acid and 160g of heptane are sequentially added into a 500mL reaction kettle, and the temperature is raised to reflux for water diversion; at the beginning, the internal temperature is about 80 ℃, then the temperature is gradually increased to about 98 ℃ for about 8 hours, almost no water drops are extracted from the water separator, the sampling is controlled in a middle way (the content of diethyl malonate as a raw material is controlled to be less than or equal to 4%), after the reaction is finished, the system is cooled to be below 40 ℃, 150g of water is added into the reaction material for washing, the reaction material is kept stand for layering, an organic layer is separated, the organic phase is decompressed and desolventized at 45 ℃, 201.5g of crude product is obtained, the yield is 91.3%, and the purity is 89.5%.
Step 2: preparation of CNDE
Putting 100g of CNDE01, 130g of isopropanol, 10g of water and 20.1g of sodium cyanide into a stainless steel closed kettle, heating to 40-60 ℃ for reaction, introducing carbon dioxide gas, controlling the pressure level in the kettle to be 10atm, and keeping sampling and central control for 2 hours (controlling the CNDE01 to be less than or equal to 3%); adding 200g of heptane into the reaction material, filtering to remove solids (safety operation is noted, waste contains a small amount of cyanide, and hydrogen peroxide and alkali are used for quenching cyanide ions), removing most of solvent from filtrate under normal pressure, cooling to 50 ℃, carrying out vacuum desolventizing until the vacuum degree is-0.09 to-0.1 MPa, and no fraction is collected to obtain 101.5g of CNDE product, wherein the nominal content is 93.8%, the product purity is 93.4%, and the yield is 84.2%.
Example 4:
step 1: preparation of CNDE01
138.5g of diethyl malonate, 78.1g of isovaleraldehyde, 5.0g of dipropylamine, 5.5g of acetic acid and 180g of hexane are sequentially added into a 500mL reaction kettle, and the temperature is raised to reflux for water diversion; at the beginning, the internal temperature is about 70 ℃, then the temperature is gradually increased to about 78 ℃, about 8 hours, almost no water drops are extracted from the water separator, the sampling is controlled in the middle (the content of diethyl malonate is controlled to be less than or equal to 4%), after the reaction is finished, the system is cooled to be below 40 ℃, 150g of water is added into the reaction materials for washing, the reaction materials are kept stand for layering, an organic layer is separated, the organic phase is decompressed and desolventized at 45 ℃, 202.3g of crude product is obtained, the yield is 90.7%, and the purity is 88.5%.
Step 2: preparation of CNDE
Putting 100.1g of CNDE01, 200g of 95% ethanol and 28.1g of potassium cyanide into a stainless steel closed kettle, heating to 40-60 ℃ for reaction, introducing carbon dioxide gas, controlling the pressure level in the kettle to be 4-6atm, and keeping sampling and central control for 3 hours (controlling the CNDE01 to be less than or equal to 3%); adding 200g of heptane into the reaction material, filtering to remove solids (safety operation is noted, waste contains a small amount of cyanide, and hydrogen peroxide and alkali are used for quenching cyanide ions), removing most of solvent from filtrate under normal pressure, cooling to 50 ℃, carrying out vacuum desolventizing until the vacuum degree is-0.09 to-0.1 MPa, and no fraction is collected to obtain 99.6g of CNDE product, wherein the nominal content is 92.1%, the product purity is 89.7%, and the yield is 81.3%.
Example 5:
step 1: preparation of CNDE01
138.5g of diethyl malonate, 78.1g of isovaleraldehyde, 5.0g of di-n-propylamine, 6.0g of acetic acid and 160g of heptane are sequentially added into a 500mL reaction kettle, and the temperature is raised until reflux and water diversion are carried out; at the beginning, the internal temperature is about 80 ℃, then the temperature is gradually increased to about 95 ℃, about 9 hours, almost no water drops are extracted from the water separator, the sampling is controlled in the middle (the content of diethyl malonate is controlled to be less than or equal to 4%), after the reaction is finished, the system is cooled to be below 40 ℃, 150g of water is added into the reaction materials for washing, the reaction materials are kept stand for layering, an organic layer is separated, the organic phase is decompressed and desolventized at 45 ℃, and 196.5g of crude product with the yield of 92.7 percent and the purity of 92.2 percent is obtained.
Step 2: preparation of CNDE
Putting 100.1g of CNDE01, 160g of dimethyl sulfoxide, 20g of water and 19.8g of sodium cyanide into a stainless steel closed kettle, heating to 60 ℃ for reaction, introducing carbon dioxide gas, controlling the pressure in the kettle to be 9-10atm, and keeping sampling and central control (controlling the CNDE01 to be less than or equal to 3 percent) for 2 hours; adding 200g of hexane into the reaction materials, filtering to remove solids (safety operation is noted, waste contains a small amount of cyanide, and hydrogen peroxide and alkali are used for quenching cyanide ions), removing most of solvent from filtrate at normal pressure, cooling to 50 ℃, reducing pressure until the vacuum degree is-0.09 to-0.1 MPa, and desolventizing until no fraction is collected, thus obtaining 100.7g of CNDE product with the nominal content of 91.5%, the product purity of 92.3% and the yield of 82.4%.
Comparative example 1:
adding 20.0g of sodium cyanide, 100g of CNDE01 and 120g of absolute ethyl alcohol into the flask, and heating to an internal temperature of 50-55 ℃; after 2 hours, sampling and detecting (controlling CNDE01 to be less than 3 percent). Cooling to 20-25 ℃, and dropwise adding 27.5g of glacial acetic acid, wherein a small amount of bubbles are generated in the dropwise adding process and stirring is kept for 0.5 hour; 87.6g of tap water is added dropwise, the mixture is stirred for half an hour after the addition is finished, and the mixture is kept stand for demixing. Extracting the water layer with 56.5g hexane, standing for layering, and mixing the organic layers; the combined organic layers were washed 2 times with 100mL x 2 tap water and the aqueous layer was separated (note: the aqueous layers were combined and the cyano groups were quenched with hydrogen peroxide + base); and decompressing the organic layer at 60 ℃ until the vacuum degree is-0.09 to-0.1 MPa, and desolventizing until no fraction is extracted to obtain 96.3g of CNDE product with the nominal content of 83.5%, the product purity of 84.6% and the yield of 71.2%.
The above-mentioned embodiments are merely preferred embodiments of the present application, which are not intended to limit the present application in any way, and it will be understood by those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present application.
Claims (7)
1. The preparation method of 1-cyano-3-methyl diethyl butylmalonate is characterized by comprising the following steps:
s1, preparation of CNDE 01: isovaleraldehyde, diethyl malonate and a solvent react to obtain CNDE 01;
s2, preparation of CNDE, namely preparation of diethyl 1-cyano-3-methylbutyl malonate:
s2-1, adding CNDE01, sodium cyanide, water and a solvent into a closed kettle, and reacting under the action of carbon dioxide to obtain CNDE;
s2-2, after the reaction is finished, adding hexane and filtering to remove solids;
s2-3, recovering the solvent from the organic layer to obtain CNDE;
the reaction formula of the preparation method is as follows:
2. the method for preparing diethyl 1-cyano-3-methylbutyl malonate according to claim 1, characterized in that step S1 specifically comprises:
s1-1: putting isovaleraldehyde, diethyl malonate, dipropylamine, acetic acid and a solvent into a reaction kettle, heating to reflux by oil bath, and performing azeotropic water diversion until the raw materials are consumed until the content of diethyl malonate/(isovaleraldehyde, diethyl malonate and CNED01) is less than or equal to 4%; after the reaction is finished, cooling to 20-40 ℃, and adding water for washing; wherein dipropylamine and acetic acid are both catalysts;
s1-2: the organic layer was subjected to reduced pressure to recover the solvent, thereby obtaining CNDE 01.
3. The method for preparing diethyl 1-cyano-3-methylbutyl malonate according to claim 2, characterized in that in step S1-1, the solvent is any one of cyclohexane, methylcyclohexane, hexane, heptane.
4. The method for preparing diethyl 1-cyano-3-methylbutyl malonate according to any one of claims 1 to 3, characterized in that step S2-1 specifically comprises: adding CNDE01, water, solvent and sodium cyanide into a closed kettle, heating to 30-150 ℃ for reaction, introducing carbon dioxide, controlling the pressure in the kettle to be 0.1-10 atmospheric pressure, reacting until the CNDE01/(CNDE01+ CNED02) is less than 3%, and finishing the reaction.
5. The method for preparing diethyl 1-cyano-3-methylbutyl malonate according to any of the claims 4, characterized in that the solvent used in step S2-1 is any of DMF, ethanol, isopropanol, and dimethyl sulfoxide.
6. The method of claim 4, wherein in step S2-1, CNDE01, water, solvent, and NaCN are charged into a closed vessel, and the temperature is raised to 40-60 ℃ for reaction.
7. The method according to claim 4, wherein in step S2-1, carbon dioxide is introduced and the pressure in the tank is controlled to be 1 to 5 atmospheres.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5637767A (en) * | 1995-06-07 | 1997-06-10 | Warner-Lambert Company | Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
| WO2008062460A2 (en) * | 2006-10-06 | 2008-05-29 | Cadila Healthcare Limited | Crystalline forms of pregabalin |
| CN111333529A (en) * | 2018-12-19 | 2020-06-26 | 北京万全德众医药生物技术有限公司 | Preparation method of pregabalin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5637767A (en) * | 1995-06-07 | 1997-06-10 | Warner-Lambert Company | Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
| WO2008062460A2 (en) * | 2006-10-06 | 2008-05-29 | Cadila Healthcare Limited | Crystalline forms of pregabalin |
| CN111333529A (en) * | 2018-12-19 | 2020-06-26 | 北京万全德众医药生物技术有限公司 | Preparation method of pregabalin |
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