CN101171228A - Pregabalin free of isobutylglutaric acid and a process for preparation thereof - Google Patents
Pregabalin free of isobutylglutaric acid and a process for preparation thereof Download PDFInfo
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- CN101171228A CN101171228A CNA2006800157622A CN200680015762A CN101171228A CN 101171228 A CN101171228 A CN 101171228A CN A2006800157622 A CNA2006800157622 A CN A2006800157622A CN 200680015762 A CN200680015762 A CN 200680015762A CN 101171228 A CN101171228 A CN 101171228A
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- 229960001233 pregabalin Drugs 0.000 title claims abstract description 117
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 112
- 238000000034 method Methods 0.000 title claims description 51
- UATSLDZQNXAKMA-UHFFFAOYSA-N 3-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(CC(O)=O)CC(O)=O UATSLDZQNXAKMA-UHFFFAOYSA-N 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 title description 19
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 72
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000003981 vehicle Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000013583 drug formulation Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000000203 mixture Substances 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 15
- 238000005406 washing Methods 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000012535 impurity Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 239000003513 alkali Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- -1 suspensoid Substances 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
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- 239000000843 powder Substances 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
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- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 4
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- 150000007530 organic bases Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 235000013162 Cocos nucifera Nutrition 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 2
- LHSAKGVBHJUEOV-UHFFFAOYSA-N 2-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(C(O)=O)CCC(O)=O LHSAKGVBHJUEOV-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000512259 Ascophyllum nodosum Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- FITPCXSHEGAMCJ-JJKGCWMISA-N ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] Chemical compound ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] FITPCXSHEGAMCJ-JJKGCWMISA-N 0.000 description 2
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
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- 229940043279 diisopropylamine Drugs 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- 239000008103 glucose Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
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- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A Pregabalin having a low level of 3-isobutylglutaric acid is provided.
Description
Related application
The application requires 60/679 of submission on May 10th, 2005,60/689 of submission on June 9th, No. 784 1,60/730 of submission on October 26th, No. 699 1,60/731 of submission on October 27th, No. 584 1, submit in No. 434 and on November 1st, 2005 60/732, the rights and interests of No. 745 U.S. Provisional Application, its whole content is incorporated this paper into.
Invention field
The Pregabalin and the preparation that the present invention relates to have low-level 3-isobutyl-pentanedioic acid have the method for the Pregabalin of low-level 3-isobutyl-pentanedioic acid.
Background of invention
(S)-Pregabalin, (S)-(+)-3-(amino methyl)-5-methylhexanoic acid, a kind of compound with following chemical structure,
(S)-Pregabalin
It is a kind of γ-An Jidingsuan or (S)-3-isobutyl-(GABA) analogue.Find (S)-Pregabalin activation GAD (L-L-Glutamic decarboxylase).(S)-Pregabalin has the dose-dependently protective effect to epilepsy, and is a kind of CNS-active compound.(S)-and Pregabalin is used for anticonvulsant therapy, and reason is its activation GAD, quickens GABA and produces, and this GABA is the main inhibitory nerve mediator of a kind of brain, release during its brain 30% is outstanding.
(S)-Pregabalin has pain relieving, anticonvulsion and anxiety is active.(S)-Pregabalin is a Pfizer company with trade(brand)name LYRICA , with 25,50,75,150,200 and the tablet listing of 300mg dosage.
(S)-and Pregabalin is disclosed in DRUGS OF THEFUTURE from the preparation of 3-isobutyl-pentanedioic acid, and 24 (8), in 862-870 (1999) and the United States Patent (USP) 5,616,793, and describe by following scheme:
Therefore, by handling, the 3-isobutyl-pentanedioic acid of compound 1 is changed into the acid anhydrides of corresponding compounds 2 with acetic anhydride.This acid anhydrides and NH
4The pentanedioic acid monoamine of the reacting generating compound 3 of OH, it splits with (R)-1-phenylethylamine, obtains (R)-phenylethylamine salt of (R)-3-(carboxamide methyl)-5-methylhexanoic acid, compound 3-salt.This salt and acidifying are closed and are discharged the R enantiomorph, compound 4.At last, use Br
2/ NaOH carries out Hofmann degradation and obtains (S)-Pregabalin.
In the aforesaid method, compound 3-isobutyl-pentanedioic acid (referring to the CMH-diacid) has following array structure:
The isobutyl-pentanedioic acid
Be used as the precursor of the 3-carbamyl methyl-5-methylhexanoic acid-racemoid (referring to the CMH-racemoid) of formula 3, its generation (S)-Pregabalin.
(S)-and impurity in the Pregabalin, as CMH-diacid and other, the impurity in perhaps any active pharmaceutical ingredient (API) is unwanted, and under extreme case, even may be deleterious to the patient with the formulation treatment that contains API.
Except that stability, it is a factor in the API shelf-lives, and the purity of the API that produces in commercial manufacturing process is undoubtedly a business-like prerequisite.The impurity of introducing during the commercial manufacturing process must be restricted to very little amount, and does not preferably exist basically.For example, product amount by regulation raw material in manufacturing processed, control process parameter such as temperature, pressure, time and stoichiometric ratio, and comprise purification step such as crystallization, distillation and liquid-liquid extraction, the ICHQ7A guide of API manufacturers requires process impurity to remain on below the setting limit.
The product mixtures of chemical reaction seldom is one and has enough purity to meet the simplification compound of pharmacy standard.In most of the cases, employed auxiliary reagent also will be present in the product mixtures in the by product of reaction and secondary product and the reaction.Some stage during API is as (S)-Pregabalin preparation process, must analyze its purity, analyze by HPLC or TLC usually, to determine whether the suitable preparation that continues, finally be used for pharmaceutical products.It is definitely purified that API needs not to be, because absolute purity is a kind of theoretical imagination that is difficult to usually reach.Yet setting purity rubric is not have impurity as far as possible in order to ensure API, thereby, be safe as far as possible for clinical application.Just as discussed above, in the U.S., the amount that food and medicine Surveillance Authority guide is recommended to limit some impurity is lower than 0.1%.
Usually, by product, secondary product and auxiliary reagent (general designation " impurity ") be through spectrography and/or with another kind of physical method discriminating, related with a point on for example peak position in color atlas or the TLC plate then (Strobel p.953, Strobel, H.A.; Heineman, W.R., ChemicalInstrumentation:A Systematic Approach, the 3rd edition. (Wiley﹠amp; Sons:NewYork 1989)).After this, can differentiate impurity by for example its relative position in color atlas, wherein the number of minutes of measuring between the detector is normally passed at sample injection post and wash-out specific components in the position of this in color atlas.Relative position in the color atlas is called " retention time ".
Such as is known to persons skilled in the art, by understanding its chemical structure and route of synthesis, and, can improve the processing of method impurity greatly by distinguishing the parameter that influences the amount of impurity in the end product.
Thereby, the present technique field need contain the Pregabalin of low-level CMH-diacid and (S)-Pregabalin with and preparation method thereof.
Summary of the invention
On the one hand, the invention provides and contain 0.15% the Pregabalin of having an appointment to the CMH-diacid of the following structure of HPLC method detectability.
The CMH-diacid
On the other hand, the invention provides and contain 0.10% the Pregabalin of having an appointment to the CMH-diacid of HPLC method detectability.
More on the other hand, the invention provides and contain 0.07% the Pregabalin of having an appointment to the CMH-diacid of HPLC method detectability.
On the one hand, the invention provides formula of medicine, it comprises and contains 0.15% (S)-Pregabalin and the pharmaceutically acceptable vehicle to the CMH-diacid of HPLC method detectability of having an appointment.
In another embodiment, the invention provides the method for preparing formula of medicine, comprise and mixing containing 0.15% (S)-Pregabalin and the pharmaceutically acceptable carrier that arrives the CMH-diacid of HPLC method detectability of having an appointment.
In another embodiment again, the invention provides and contain 0.15% the application of (S)-Pregabalin in pharmaceutical compositions of having an appointment to the CMH-diacid of HPLC method detectability.
Detailed Description Of The Invention
As used herein, unless otherwise indicated, term " CMH " is meant R enantiomorph ((R)-CMH) or the CMH racemic modification of CMH.
R-CMH CMH
As used herein, unless otherwise indicated, term " Pregabalin " is meant the S enantiomorph ((S)-Pregabalin) or the Pregabalin racemic modification of Pregabalin.
(S)-pregabalin
As used herein, unless otherwise indicated, when using the CMH racemic modification, obtain the Pregabalin racemic modification.
As used herein, unless otherwise indicated, when using (R)-CMH, obtain (S)-Pregabalin.
The invention provides and contain 0.15% the Pregabalin of having an appointment to the CMH-diacid of the following structure of HPLC method detectability.
The CMH-diacid
Preferably, Pregabalin of the present invention contains the 0.15% CMH-diacid to about 0.03%HPLC area of having an appointment.
The present invention further provides and contained 0.10% the Pregabalin of having an appointment to the CMH-diacid of HPLC method detectability.
Preferably, Pregabalin of the present invention contains the 0.10% CMH-diacid to about 0.03%HPLC area of having an appointment.
The present invention also provides and has contained 0.07% Pregabalin to the CMH-diacid of HPLC method detectability of having an appointment.
Preferably, Pregabalin of the present invention contains the 0.07% CMH-diacid to about 0.03%HPLC area of having an appointment.
The detectability of HPLC method is meant any HPLC method that is used to measure Pregabalin purity, and especially measures the HPLC method of the amount be used for measuring Pregabalin CMH-diacid.Preferably, described detectability is the detectability of the HPLC method used among the present invention or the detectability of any other equivalent means.
The CMH that is used to prepare Pregabalin does not contain from the synthetic CMH-diacid in stage early; Yet when being converted into Pregabalin, CMH is hydrolyzed and obtains impurity CMH-diacid.The CMH-diacid is the major impurity in the Pregabalin, it very difficulty remove.Therefore, it is useful controlling its formation method and its purification process.The present invention includes a kind of method of the CMH-of control diacid level, this method is kept alkali metal hydroxide aqueous solution at low temperatures by when mixing with R-CMH and when dropwise adding bromine.Therefore, thus the amount of the CMH-diacid that the temperature during control adds formed between the control reaction period.This method also comprises the purifying Pregabalin, the selective extraction of the Pregabalin acid-salt that its solvent by using careful selection and/or solvent mixture carry out, and subsequent crystallisation obtains purified basically Pregabalin thus.
The method of CMH-diacid level comprises mixing water and a kind of alkali metal hydroxide that is selected from following compounds in the control Pregabalin: sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide; Under about 20 ℃ temperature, add CMH at about 0 ℃, and under about 25 ℃ temperature, dropwise add bromine at about 0 ℃.Join CMH in the alkali aqueous solution and the reaction of bromine and CMH, water and alkali metal mixture is heat release.Therefore, by dropwise adding bromine and cooling off with the temperature between the control reaction period, promote to regulate the amount of the CMH-diacid that the CMH hydrolysis forms under alkaline condition by lasting.
The Pregabalin that contains the CMH-diacid of 0.15% to the HPLC method detectability of having an appointment can prepare by following steps: mixing water and a kind of alkali metal hydroxide; Under about 20 ℃ temperature, add CMH at about 0 ℃; Under about 25 ℃ temperature, dropwise add bromine at about 0 ℃; Be heated to about 40 ℃ and arrive about 100 ℃ temperature; React with strong inorganic acid; Use C
4-8The alcohol extraction; Mix with alkali; And from C
4-8The alcohol crystallization.
The Pregabalin that contains the CMH-diacid of 0.07% to the HPLC method detectability of having an appointment can prepare by following steps: mixing water and a kind of alkali metal hydroxide that is selected from following compounds: sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide; Under about 10 ℃ temperature, add CMH at about 5 ℃; Under about 10 ℃ temperature, dropwise add bromine at about 5 ℃; Be heated to about 40 ℃ and arrive about 100 ℃ temperature; With the strong inorganic acid reaction that is selected from following compounds: H
2SO
4, HCl, HBr and H
3PO
4With the C that is selected from following compounds
4-8Alcohol extraction: butanols, isopropylcarbinol, 2-butanols, amylalcohol or primary isoamyl alcohol; Mix with the alkali that is selected from following compounds: Diisopropylamine and propylamine, Tributylamine, triethylamine, sodium hydroxide, potassium hydroxide, cesium hydroxide, yellow soda ash, sodium bicarbonate and salt of wormwood; And from being selected from the C of following compounds
4-8Alcohol crystallization: butanols, isopropylcarbinol, 2-butanols, amylalcohol or primary isoamyl alcohol.
As mentioned above, the preparation of Pregabalin can illustrate by following scheme:
CMH can obtain according to for example United States Patent (USP) 5,616,793 disclosed methods.
The Pregabalin that the inventive method obtains contains the CMH-diacid.The Pregabalin that obtains can contain the 0.15% CMH-diacid to about HPLC method detectability, preferably, for about 0.15% to about 0.03%HPLC area, perhaps 0.10% to HPLC method detectability, preferably, about 0.10% to about 0.03% HPLC, perhaps 0.07% to HPLC method detectability, preferably, about 0.07% to about 0.03% HPLC.
Preferably, alkali metal hydroxide is a sodium hydroxide.Preferably, alkali metal hydroxide uses with the form of the aqueous solution.
Usually, the pH that the mixture that obtains behind mixed C MH and the alkali metal hydroxide has is at least about 13, preferably is at least about 14.
Preferably, bromine adds with the amount of 1 molar equivalent to about 1.4 molar equivalents/molar equivalent CMH.Preferably, dropwise added more preferably about 30 to about 45 minutes to about 180 minutes time with about 12 minutes.
Preferably, be heated to about 60 ℃ and arrive about 85 ℃ temperature.Preferably, before adding strong inorganic acid, heating was carried out more preferably from about 15 minutes to 1 hour about 15 minutes to about 4 hours.
Preferably, before adding strong inorganic acid, be cooled to about 40 ℃ and arrive about 20 ℃ temperature.Preferably, strong inorganic acid is H
2SO
4
Preferably, when adding strong inorganic acid, can obtain the salt of Pregabalin and strong inorganic acid.This salt is by using C
4-8Alcohol selective extraction and separating with the CMH-diacid.This extraction is optionally, because the different solubility of this salt in water is in the solubleness of CMH-diacid in water.Preferred C
4-8Alcohol is isopropylcarbinol.
Preferably, the organic phase that obtains from extraction process is mixed with alkali, to obtain the throw out of Pregabalin.Preferably, described alkali is organic bases or mineral alkali.Preferred organic bases is secondary amine or tertiary amine.Preferably, secondary amine is Diisopropylamine or dipropyl amine.Preferred tertiary amine is Tributylamine or triethylamine.More preferably, described organic bases is a Tributylamine.Preferably, mineral alkali is alkali metal hydroxide or alkaline carbonate.Preferred alkali metal hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide.Preferred alkaline carbonate is yellow soda ash, sodium bicarbonate or salt of wormwood.Preferred alkali is organic bases, most preferably is tertiary amine, even and be more preferably Tributylamine.
Preferably, more preferably be heated to about 60 ℃ to about 110 ℃ by the gained throw out being heated to about 50 ℃ to about 110 ℃, most preferably be heated to about 90 ℃ to about 110 ℃, to obtain a solution, to be cooled to again being lower than about 25 ℃ temperature, preferably be cooled to about 25 ℃ to-10 ℃ approximately, more preferably be cooled to about 10 ℃ to about 2 ℃, to obtain the precipitate of pregabalin thing, Pregabalin can be by crystallization, wherein, the CMH-diacid still is dissolved in the solution.The precipitate of pregabalin thing can be by filtering, wash and dry separation the in vacuum drying oven.
The Pregabalin that is used as parent material in crystallisation process can contain the CMH-diacid at least about the 0.15%HPLC area.The also available Pregabalin that contains at least about the CMH-diacid of 0.10%HPLC area, and, the also available Pregabalin that contains at least about the CMH-diacid of 0.07%HPLC area.
Measuring the level of CMH-diacid in the Pregabalin can be undertaken by using the HPLC method, and it comprises Pregabalin sample and about 1: 1: 8 acetonitrile of ratio: methyl alcohol: buffer solution mixture mixes, to obtain a solution; Solution is injected 250 * 4.6mm Inertsil ODS 3V (or similarly) post, use acetonitrile subsequently: methyl alcohol: damping fluid (1: 1: 8) (being called elutriant A) and acetonitrile (being called elutriant B) are as elutriant, when about 50min,, and measure CMH-two acid contents (preferably at the 210nm place) in the relevant sample with the UV detector with sample wash-out from post.
The present invention also provides formula of medicine, and it comprises and contains 0.15% (S)-Pregabalin and the pharmaceutically acceptable vehicle to the CMH-diacid of HPLC method detectability of having an appointment.
The invention provides the method for preparing formula of medicine, comprise and mixing containing 0.15% (S)-Pregabalin and a kind of pharmaceutically acceptable carrier that arrives the CMH-diacid of HPLC method detectability of having an appointment.
The present invention further provides and contained 0.15% application of (S)-Pregabalin in pharmaceutical compositions of arriving the CMH-diacid of HPLC method detectability of having an appointment.
As used herein, term " pharmaceutical composition " comprises tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository or injection.Described pharmaceutical composition does not preferably use the acidic excipient preparation.The pharmaceutical composition that contains Pregabalin of the present invention can be by using thinner or auxiliary material such as filling agent, weighting agent, tackiness agent, wetting agent, disintegrating agent, tensio-active agent and lubricant preparation.The various modes that give of pharmaceutical composition of the present invention can be selected according to therapeutic purpose, for example tablet, pill, powder agent, liquid agent, suspensoid, emulsion, granule, capsule, suppository or injection.
Any vehicle known in this field and widely used all can be used in the pharmaceutical composition.The carrier that uses includes but not limited to lactose, white sugar, sodium-chlor, glucose, urea, starch, lime carbonate, kaolin, Microcrystalline Cellulose, silicic acid etc.The tackiness agent that uses includes but not limited to water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, Xylo-Mucine, shellac, methylcellulose gum, dipotassium hydrogen phosphate, polyvinylpyrrolidone etc.The disintegrating agent that uses includes but not limited to the fatty acid ester of dry starch, sodium alginate, agar powder, kelp (laminalia) powder, sodium bicarbonate, lime carbonate, polyoxyethylene sorbitan, Sulfuric acid,monododecyl ester, sodium salt, stearic acid monoglyceride, starch, lactose etc.The disintegration inhibitor that uses comprises but is not limited to white sugar, tristearin, coconut grease, hydrogenation wet goods.The absorption enhancer that uses includes but not limited to quaternary ammonium hydroxide, Sulfuric acid,monododecyl ester, sodium salt etc.The wetting agent that uses includes but not limited to glycerine, starch etc.The sorbent material that uses includes but not limited to starch, lactose, kaolin, wilkinite, colloid silicic acid etc.The lubricant that uses includes but not limited to talcum powder, stearate, boric acid powder, polyoxyethylene glycol etc.Tablet can be further with known coating material dressing, as coated tablet, gelatin film garment piece, enteric coated tablet, film coated tablet, double-layer tablets and multilayer tablet.
When pharmaceutical composition is made pill, any known vehicle that can use this area to use.For example, carrier includes but not limited to, lactose, starch, coconut grease, hard vegetables oil, kaolin, talcum powder etc.The tackiness agent that uses includes but not limited to gummi arabicum pulveratum, tragacanth gum powder, gelatin, ethanol etc.The disintegrating agent that uses includes but not limited to agar, kelp etc.
For pharmaceutical composition is formed suppository, any known vehicle that can use this area to use.For example, vehicle includes but not limited to, the ester of polyoxyethylene glycol, coconut grease, higher alcohols and higher alcohols, gelatin and semisynthetic glyceryl ester.
When preparation during Injectable composition, solution and suspension sterilizes, and preferably make and blood etc.Injection can use carrier well known in the art.For example, the carrier that is used for injection includes but not limited to, the fatty acid ester of the isooctadecanol of water, ethanol, propylene glycol, ethoxylation, the isooctadecanol of polyoxyization and polyoxyethylene sorbitan.A those of ordinary skill of this area can be at an easy rate with a little test or without testing the requirement of determining sodium-chlor, glucose or glycerine, to prepare isoosmotic injectable formulation.
Can add the interpolation sexual element, as solvating agent, buffer reagent and pain killer.If desired, tinting material, sanitas, spices, perfume compound, sweeting agent and other medicines can also be joined in the preparation that needs.
The amount that is used for the treatment of the Pregabalin that contains in the schizoid pharmaceutical composition should be enough to treat, improve or alleviate the symptom relevant with schizophrenia.Preferably, Pregabalin exists with about 1% amount to about 70% weight of dosage, and more preferably about 1% of dosage to about 30% weight.
According to patient's age, sex and symptom, pharmaceutical composition of the present invention can give by the whole bag of tricks.For example, but tablet, pill, solution, suspensoid, emulsion, granule and capsule orally give.Injection can individually or with the injection transfusion give as glucose solution and amino acid solution mixed venous.If desired, but injection intramuscular, intracutaneous, subcutaneous or intraperitoneal give.But the suppository rectum gives.
The dosage that is used for the treatment of schizoid pharmaceutical composition according to the present invention will depend on using method, patient's age, sex and the patient's condition.Preferably, Pregabalin gives to the amount of about 10mg/kg body weight/day with about 0.1mg/kg.More preferably, in dosage, can contain the Pregabalin of 1mg of having an appointment to 200mg.
The present invention also comprises the method for preparing formula of medicine, and it comprises Pregabalin and a kind of pharmaceutically acceptable mixed with excipients.As used herein, term " formula of medicine " comprises tablet, pill, powder agent, liquid agent, suspensoid, solution, emulsion, granule, capsule, suppository or injection.
Describe the present invention with reference to some embodiment preferred, those skilled in the art are according to the understanding of this specification sheets, and other embodiment will be conspicuous.The present invention is further illustrated by the embodiment with reference to following detailed description The compounds of this invention preparation.The multiple change of material and method will be that significantly these changes can be implemented in being no more than scope of the present invention for a person skilled in the art.
Embodiment
Carry out the analysis of isobutyl-pentanedioic acid in the Pregabalin crude product (CMH-diacid) by following method:
HPLC Inertsil?ODS?3V，250*4.6mm，5μ.C.N?5020-01802
Elutriant A:80%0.04M (NH
4)
2HPO
4, it uses H
3PO
4Be adjusted to pH=6.5
10% acetonitrile
10% methyl alcohol
Elutriant B: acetonitrile
Stand-by time 50min
Gradient time (min) elutriant A (%) the elutriant B (%) of elutriant
0 100 0
6 100 0
50 65 35
Starting time 10min
Flow velocity 0.8ml/min
Detector 210nm
Volumetric injection 20 μ L
Diluent elutriant A
25 ℃ of column temperatures
5 ℃ of automatic sampling actuator temperatures
The quantitative limit of described method is 0.03%.
This detectability can be lower than 0.03%, because the peak of CMH-diacid can detect in color atlas.
Embodiment 1:(S)-preparation of Pregabalin
With pack in the reactor (0.2L) water (150ml) and NaOH (32.3g) to obtain a solution.This solution is cooled to 5 ℃, and adds (R)-CMH (30g).Dropwise add Br then
2(25.9g) (15min) keeps temperature to be lower than 10 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes, be cooled to room temperature then.Add isopropylcarbinol (90ml), add H subsequently
2SO
4Solution (66%) (32ml).To respectively be separated, water extracts with isopropylcarbinol (75ml).With Bu
3N (32.6ml) is added in the organic phase of this merging.This mixture heating up to dissolving, is cooled to 2 ℃, restir 1.5 hours then.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain 80.4% yield.Total purity: 99.7%HPLC area, CMH-diacid-be lower than 0.03%HPLC area.
Embodiment 2: the preparation of Pregabalin
With water (200ml) and the NaOH (34.7g) of packing in the reactor (1L).This solution is cooled to 5 ℃, and adds R-CMH (40g).Dropwise add Br
2(34.7g) (15min) keeps temperature to be lower than 10 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes be cooled to RT then.Add isopropylcarbinol (120ml), add H then
2SO
4-66% (40ml) solution (pH=3).With this mixture heating up to 33 ℃, will respectively be separated then, water is with isopropylcarbinol (100ml) extraction.Organic phase after merging is cooled to 2 ℃ reaches 2.5 hours, refilter to remove inorganic salt.Filtrate is heated to RT, and with Bu
3N (41.6g) joins in the organic phase.This mixture heating up to dissolving, is cooled to 2 ℃, restir 2 hours then.With solid filtering, and with filter cake i-BuOH (40ml) washing.The yield that calculates is 79.4%.CMH-diacid-0.07%HPLC area.
Embodiment 3:(S)-preparation of Pregabalin
With pack in the reactor (0.5L) water (175ml) and NaOH (37.6g) to obtain a solution.This solution is cooled to 10 ℃, and adds (R)-CMH (35g).During 0.5 hour with Br
2(30.24g) dropwise add, keep temperature to be lower than 25 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes, be cooled to room temperature then.This solution is divided into 2 parts.
Half of first part (equaled 5g (R)-CMH) and at room temperature stirred 5 hours, add isopropylcarbinol (15ml) and H then
2SO
4Solution (66%) (5ml).To respectively be separated, water extracts with isopropylcarbinol (12ml).With Bu
3N (5.2g) joins in the organic phase of merging.This solution is cooled to 2 ℃, restir 1.5 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.3%HPLC area, CMH-diacid-0.09%HPLC area.
With second part of following processing:
Add isopropylcarbinol (75ml), add H then
2SO
4Solution (66%) (25ml).To respectively be separated, water extracts with isopropylcarbinol (62ml).This solution is further divided into 2 parts (part A and B).
A certain amount of part A (is equaled 5g (R)-CMH) and at room temperature stirred 24 hours, add Bu
3N (2.6g), and this solution is cooled to 2 ℃, restir 1.5 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.07%HPLC area, CMH-diacid-0.03%HPLC area.
A certain amount of part A (is equaled 5g (R)-CMH) and at room temperature stirred 0.5 hour, add Bu
3N (2.6g), and this solution is cooled to room temperature, restir 24 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.67%HPLC area, CMH-diacid one is lower than the 0.03%HPLC area.
Embodiment 4:(S)-preparation of Pregabalin
With pack in the reactor (0.2L) water (150ml) and NaOH (32.3g) to obtain a solution.This solution is cooled to 15 ℃, and adds (R)-CMH (30g).With Br
2(25.9g) dropwise add (15min), keep temperature to be lower than 20 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes, be cooled to room temperature then.Add isopropylcarbinol (150ml), add H then
2SO
4Solution (66%) (30ml).To respectively be separated, water extracts with isopropylcarbinol (75ml).The organic phase that merges is divided into several parts.
1) adds Bu
3N (10.4ml), and this mixture is cooled to 2 ℃, restir 2 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.7%HPLC area, CMH-diacid-0.11%HPLC area.
2) add entry (10ml) and Bu
3N (10.4ml).This mixture is cooled to 2 ℃, restir 2 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.7%HPLC area, CMH-diacid-0.13%HPLC area.
Embodiment 5:(S)-preparation of Pregabalin
With pack in the reactor (0.1L) water (50ml) and NaOH (10.8g) to obtain a solution.This solution is cooled to 15 ℃, and adds (R)-CMH (10g).With Br
2(8.6g) dropwise add (15min), keep temperature to be lower than 20 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes, be cooled to room temperature then.Add isopropylcarbinol (60ml), add H subsequently
2SO
4Solution (66%) (10ml).To respectively be separated, water extracts with isopropylcarbinol (25ml).In the organic phase that merges, add Bu
3N (9.9g) is cooled to 2 ℃ with this mixture again, restir 2 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.88%HPLC area, CMH-diacid-0.12%HPLC area.
Embodiment 6:(S)-preparation of Pregabalin
With pack in the reactor (0.5L) water (165ml) and NaOH (35.5g) to obtain a solution.This solution is cooled to 15 ℃, and adds (R)-CMH (33g).With Br
2(28.51g) dropwise add (15min), keep temperature to be lower than 25 ℃ simultaneously.This mixture heating up to 60 ℃ is reached 15 minutes, be cooled to 15 ℃ then.Add isopropylcarbinol (100ml), add H then
2SO
4Solution (66%) (33ml).To respectively be separated, water extracts with isopropylcarbinol (83ml).In the organic phase that merges, add Bu
3N (34.2g), and this mixture is cooled to 2 ℃, restir 2 hours.With this solid filtering, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.86%HPLC area, CMH-diacid-0.14%HPLC area.
Embodiment 7:(S)-crystallization of Pregabalin
With the isopropylcarbinol (25ml) of packing in the flask (0.1L), water (10ml) and (S)-Pregabalin crude product (5g contains 0.44% CMH-diacid) to be to obtain a mixture.This mixture heating up is refluxed until dissolving.This solution is cooled to 2 ℃, and restir 1.5 hours is to bring out precipitation.This throw out is filtered, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.91%HPLC area, CMH-diacid-0.09%HPLC area.
Embodiment 8:(S)-crystallization of Pregabalin
(0.1L) in the flask packed into isopropylcarbinol (25ml), water (5ml) and (S)-Pregabalin crude product (5g contains the 0.44%CMH-diacid) to obtain a mixture.This mixture heating up is refluxed and stir 10 minutes to obtain a solution.This solution is cooled to 2 ℃, and restir 1.5 hours is to bring out precipitation.This throw out is filtered, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.85%HPLC area, CMH-diacid-0.07%HPLC area.
Embodiment 9:(S)-crystallization of Pregabalin
With the isopropylcarbinol (20ml) of packing in the flask (0.1L), water (10ml) and (S)-Pregabalin crude product (5g contains the 0.44%CMH-diacid) to be to obtain a mixture.This mixture heating up is refluxed until dissolving.This solution is cooled to 10 ℃, and restir 1.5 hours is to bring out precipitation.This throw out is filtered, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.72%HPLC area, CMH-diacid-0.1%HPLC area.
Embodiment 10:(S)-crystallization of Pregabalin
With the isopropylcarbinol (20ml) of packing in the flask (0.1L), water (10ml) and (S)-Pregabalin crude product (5g contains the 0.44%CMH-diacid) to be to obtain a mixture.This mixture heating up is refluxed until dissolving.This solution is cooled to 2 ℃, and restir 1.5 hours is to bring out precipitation.This throw out is filtered, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin crude product, total purity 99.91%HPLC area, CMH-diacid-be lower than 0.03%HPLC area.
Embodiment 11:(S)-crystallization of Pregabalin
With the isopropylcarbinol (16ml) of packing in the flask (0.1L), water (8ml) and (S)-Pregabalin crude product (4g contains the 0.37%CMH-diacid) to be to obtain a mixture.Mixture heating up is extremely refluxed until dissolving.This solution is cooled to 2 ℃, and restir 1 hour is to bring out precipitation.This throw out is filtered, washing, dry under 55 ℃ and vacuum again, obtain (S)-Pregabalin, total purity 99.72%HPLC area, CMH-diacid-0.08%HPLC area.
Claims (15)
1. the Pregabalin of following formula:
It contains the 0.15% CMH-diacid to the following formula of HPLC method detectability of having an appointment
The CMH-diacid.
2. the described Pregabalin of claim 1 contains the 0.15% CMH-diacid to about 0.03%HPLC area of having an appointment.
3. the described Pregabalin of claim 1 contains the 0.10% CMH-diacid to HPLC method detectability of having an appointment.
4. the described Pregabalin of claim 1 contains the 0.10% CMH-diacid to about 0.03%HPLC area of having an appointment.
5. the described Pregabalin of claim 1 contains the 0.07% CMH-diacid to HPLC method detectability of having an appointment.
6. the described Pregabalin of claim 1 contains the 0.07% CMH-diacid to about 0.03%HPLC area of having an appointment.
7. the described Pregabalin of claim 1, wherein said Pregabalin is following formula (S)-Pregabalin:
It contains the 0.15% CMH-diacid to HPLC method detectability of having an appointment.
8. described (the S)-Pregabalin of claim 7 contains the 0.15% CMH-diacid to about 0.03%HPLC area of having an appointment.
9. described (the S)-Pregabalin of claim 7 contains the 0.10% CMH-diacid to HPLC method detectability of having an appointment.
10. described (the S)-Pregabalin of claim 7 contains the 0.10% CMH-diacid to about 0.03%HPLC area of having an appointment.
11. described (the S)-Pregabalin of claim 7 contains the 0.07% CMH-diacid to HPLC method detectability of having an appointment.
12. described (the S)-Pregabalin of claim 7 contains the 0.07% CMH-diacid to about 0.03%HPLC area of having an appointment.
13. a pharmaceutical preparation, it comprises any described (S)-Pregabalin of claim 7～12 and pharmaceutically acceptable vehicle.
14. the method for useful in preparing drug formulations comprises any described (the S)-Pregabalin of claim 7～12 and pharmaceutically acceptable carrier is mixed.
15. the application of any described (the S)-Pregabalin of claim 7～12 in pharmaceutical compositions.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67978405P | 2005-05-10 | 2005-05-10 | |
| US60/679,784 | 2005-05-10 | ||
| US60/689,699 | 2005-06-09 | ||
| US60/730,584 | 2005-10-26 | ||
| US60/731,434 | 2005-10-27 | ||
| US60/732,745 | 2005-11-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101171228A true CN101171228A (en) | 2008-04-30 |
Family
ID=39391334
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800157533A Pending CN101171227A (en) | 2005-05-10 | 2006-04-11 | Pregabalin free of lactam and a process for preparation thereof |
| CNA2006800157622A Pending CN101171228A (en) | 2005-05-10 | 2006-05-10 | Pregabalin free of isobutylglutaric acid and a process for preparation thereof |
| CNA2006800157618A Pending CN101171229A (en) | 2005-05-10 | 2006-05-10 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
| CNA2006800157590A Pending CN101171225A (en) | 2005-05-10 | 2006-05-10 | Method for the preparation of pregabalin and salts thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800157533A Pending CN101171227A (en) | 2005-05-10 | 2006-04-11 | Pregabalin free of lactam and a process for preparation thereof |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800157618A Pending CN101171229A (en) | 2005-05-10 | 2006-05-10 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
| CNA2006800157590A Pending CN101171225A (en) | 2005-05-10 | 2006-05-10 | Method for the preparation of pregabalin and salts thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (4) | CN101171227A (en) |
| ES (1) | ES2351882T3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110174467A (en) * | 2018-10-25 | 2019-08-27 | 武汉武药制药有限公司 | A kind of method of high-efficient liquid phase chromatogram technique analysis separation 2,4- dicyano -3- isobutyl group glutaramide |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2518050A1 (en) * | 2009-12-25 | 2012-10-31 | Kaneka Corporation | Process for production of optically active 3-substituted glutaric acid monoamide |
| CN103922950B (en) * | 2014-04-08 | 2016-06-01 | 浙江美诺华药物化学有限公司 | The preparation method of a kind of lyrica |
| CN104086439B (en) * | 2014-06-30 | 2018-11-16 | 浙江华海药业股份有限公司 | A kind of recovery method of pregabalin intermediate resolving agent (R)-(+)-α-phenylethylamine |
-
2006
- 2006-04-11 CN CNA2006800157533A patent/CN101171227A/en active Pending
- 2006-05-10 CN CNA2006800157622A patent/CN101171228A/en active Pending
- 2006-05-10 ES ES06759589T patent/ES2351882T3/en active Active
- 2006-05-10 CN CNA2006800157618A patent/CN101171229A/en active Pending
- 2006-05-10 CN CNA2006800157590A patent/CN101171225A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110174467A (en) * | 2018-10-25 | 2019-08-27 | 武汉武药制药有限公司 | A kind of method of high-efficient liquid phase chromatogram technique analysis separation 2,4- dicyano -3- isobutyl group glutaramide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101171229A (en) | 2008-04-30 |
| ES2351882T3 (en) | 2011-02-11 |
| CN101171227A (en) | 2008-04-30 |
| CN101171225A (en) | 2008-04-30 |
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