CN1651430A - Synthesis method of saijiabin, its racemate and S-configuration, and preparation method of its amorphous powder - Google Patents
Synthesis method of saijiabin, its racemate and S-configuration, and preparation method of its amorphous powder Download PDFInfo
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- CN1651430A CN1651430A CN 200410102052 CN200410102052A CN1651430A CN 1651430 A CN1651430 A CN 1651430A CN 200410102052 CN200410102052 CN 200410102052 CN 200410102052 A CN200410102052 A CN 200410102052A CN 1651430 A CN1651430 A CN 1651430A
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Abstract
The present invention provides a making method for the gabitril, its racemic substance and its S-configuration, as well as the new prosoma and its making method. The way also can be used to make the racemic substance of the gabitril and the S-configuration of the enantiomer. The present invention also provides the making method of the actinic pure Beta-piperidine formic ether 12 and the S-configuration of the enantiomer. The synthetic route of the invention does not need the expensive special reagent, the reaction condition is mild and it can be made with industrial production.
Description
Technical field
The invention provides the novel synthesis of the diseases related medicine tiagabine (Tiagabine) of a kind of treatment epilepsy and GABA (γ-Aminobutyric acid) picked-up and the method for making of amorphous powder thereof.The present invention provides the preparation method of the tiagabine and the S-configuration tiagabine of racemization simultaneously.The present invention also provides the preparation method of the optically pure β of the required raw material of synthetic above-claimed cpd-piperidine carboxylic acid ester.
Background technology
Nielsen in 1991 etc. have reported that at first tiagabine (Tiagabine) has good spasmolytic effect,
Simultaneously still the fine inhibitor of GABA (γ-Aminobutyric acid) picked-up (EurJ.pharmacol., 1991,196 (3), 257-266).At present it has been developed into treatment epilepsy and GABA (the diseases related medicine (CN 1225094A, 1999,8,4) of picked-up of γ-Aminobutyricacid).Knud equals to report in 1993 its synthetic method (J.Med.Chem., 1993,36,1716-1725), but two kinds of synthetic methods of their usefulness have all been used the responsive especially and expensive organometallic reagent (Scheme 1) to air, therefore are unsuitable for suitability for industrialized production.
Summary of the invention
The problem to be solved in the present invention provides a kind of treatment epilepsy and GABA (γ-Aminobutyric acid) absorbs the novel synthesis of diseases related medicine tiagabine (Tiagabine) and the method for making of amorphous powder thereof.
The problem that the present invention also will solve provides the preparation method of the tiagabine and the S-configuration tiagabine of racemization.
The problem that the present invention also will solve provides the new precursor of synthetic tiagabine, and the preparation method that the optically pure β of the required raw material of synthetic tiagabine-piperidine carboxylic acid ester is provided.
The invention provides the novel method of a kind of synthetic tiagabine (Scheme 2) and precursor thereof, this method is equally applicable to the raceme of synthetic tiagabine and the compound of S-configuration thereof.
Its step is as follows:
1) makes the compound and the Ph of general formula 1
3P
+(CH
2)
3OYX-or (RO)
2PO (CH
2)
3The OY reaction,
In the formula, the Y representative
Or
X represents Cl, Br or I, and R represents C
1～C
5Alkyl;
2) compound of resulting following general formula 9, after the protecting group through sloughing hydroxyl compound 10, again and HX (X=Cl, Br, I), PX '
3(X '=Cl, Br), thionyl chloride or Tosyl chloride react the compound shown in the following general formula 11, in the formula, the Y definition is the same, Z represents OTs, Cl, Br or I,
3) make the compound of general formula 11, with the compound reaction of following formula 12 ', R ' represents C
1～C
5Alkyl;
4) compound of the resulting general formula 13 ' of conversion is the compound as the bottom right formula;
Described conversion can be with after the compound 13 ' hydrolysis again with hcl acidifying to PH1～3.Wherein when 12 ' is the R configuration, promptly
Be tiagabine by what above-mentioned conversion obtained; When 12 ' is raceme, the raceme that is tiagabine that obtains by above-mentioned conversion; When 12 ' is the S configuration, the S-configuration that is tiagabine that obtains by above-mentioned conversion.
Step 1) and step 1), 2 by above-mentioned synthetic method), the raceme and the S-configuration thereof that provide the new precursor of synthetic tiagabine, this precursor to be equally applicable to synthetic tiagabine, described precursor are promptly
In the formula
OTs, OH.
The method of the compound of above-mentioned synthetic tiagabine and raceme thereof and S-configuration can specifically describe as follows:
Compound 8 (can be with reference to J.Org.Chem., 1979,44,3760～3764) be dissolved in the organic solvent, add alkali, after the reflux, return time is recommended as 10～60 minutes, and adding the compound 1 that is dissolved in the above-mentioned solvent (can be with reference to J.Med.Chem., 1993,36,1716-1725), recommend to get compound 9 in 1～24 hour in 0～110 ℃ of reaction.Described organic solvent is recommended as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), ether, acetonitrile, dioxane, benzene or toluene etc.Described alkali is recommended C
nH
2n+1OM (n=1～5, M=Na, K), potassium hydroxide, sodium hydroxide or salt of wormwood.Wherein the consumption of compound 8 and alkali is recommended as equivalent, and compound 8 is recommended as 1～1.5 with the consumption mol ratio of compound 1: 1.
Compound 9 is dissolved in the organic solvent; described organic solvent comprises acetone, tetrahydrofuran (THF), dioxane or acetonitrile; in the acid of 1～6N for example under the effect of hydrochloric acid, sulfuric acid or phosphoric acid; recommend in 0～50 ℃ of reaction 1～10 hour; the protecting group of hydroxyl can be removed compound 10; compound 10 is dissolved in the organic solvent; described organic solvent is methylene dichloride, trichloromethane, 1; 2-ethylene dichloride, tetrahydrofuran (THF), ether, acetonitrile, dioxane, acetone, benzene or toluene etc.; and then and HX (X=C1; Br, I), PX '
3(X '=Cl, Br), thionyl chloride or Tosyl chloride react compound 11, (X=Cl, Br I) are recommended as dense HX to used HX, and its concentration is recommended as 1～12N.
Compound 11 is dissolved in the organic solvent solvent, with compound 12 reactions, is recommended in 0～50 ℃ of reaction 10～72 hours under the effect of alkali and potassiumiodide, gets compound 13.Described organic solvent is recommended as acetone, acetonitrile or tetrahydrofuran (THF) etc.Described alkali is mineral alkali such as salt of wormwood, perhaps organic bases such as pyridine or triethylamine etc.
Compound 13 is dissolved in hydrolysis in the organic solvent, and organic solvent is recommended as ethanol, recommends potassium hydroxide or sodium hydroxide hydrolysis with 1～15N; Be 1～3 can get the target compound tiagabine with hcl acidifying to PH again, recommending to be acidified to PH is 1～2.
The crystal of tiagabine (Tiagabine) is water-soluble, and freeze-drying gets amorphous powder.
Replace (R)-β-piperidine carboxylic acid ester 12 with the β-piperidine carboxylic acid ester of racemization and (S)-β-piperidine carboxylic acid ester, utilize aforesaid method can get the tiagabine and the S-configuration tiagabine of racemization respectively.
Reaction formula is for example:
(wherein R ' represents C to compound 12
1～C
5Alkyl) and the preparation method of enantiomorph (S)-β-piperidine carboxylic acid ester recommend as follows: salify and the crystallization in 50～100% pure and mild ether mixed solvent (recommending 75%～100% the ethanol and the mixed solvent of ether) of the L-tartrate of racemization β-piperidine carboxylic acid ester and 0.5～3 equivalent (being recommended as equivalent), used alcohol is recommended as methyl alcohol, ethanol, propyl alcohol or Virahol, used ether is recommended as methyl ether, ether, glycol dimethyl ether or ethylene glycol diethyl ether, the gained crystal again in 50～100% alcohol (recommending 75%～100% ethanol) recrystallization can get optical purity for twice more than or equal to 95% compound 12, specifically: used alcohol is recommended as methyl alcohol, ethanol, propyl alcohol or Virahol, behind the recrystallization that the gained crystal is soluble in water, inorganic base aqueous solution with 1～10N modulates 9～14 with pH value, used mineral alkali is recommended as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, use organic solvent extraction again, the recommendation organic solvent is a methylene dichloride, trichloromethane, 1, the 2-ethylene dichloride, ether or ethyl acetate promptly get optical purity more than or equal to 95% compound 12; It is soluble in water that the crystalline mother liquor concentrates the gained resistates for the first time, dissociate with the inorganic base aqueous solution of 1～10N and to have part optically active (S)-β-piperidine carboxylic acid ester, specifically: it is soluble in water that the crystalline mother liquor concentrates the gained resistates for the first time, inorganic base aqueous solution with 1～10N modulates 9～14 with pH value, used mineral alkali is recommended as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, use organic solvent extraction again, the recommendation organic solvent is a methylene dichloride, trichloromethane, 1, the 2-ethylene dichloride, ether or ethyl acetate, get final product to such an extent that part optically active (S)-β-piperidine carboxylic acid ester arranged, D-tartrate recrystallization in 50～100% alcohol (recommending 75%～100% ethanol) of itself and 0.5～3 equivalent (being recommended as equivalent) can be got enantiomorph (S)-β-piperidine carboxylic acid ester of optical purity more than or equal to 95% compound 12 for twice, specifically: used alcohol is recommended as methyl alcohol, ethanol, propyl alcohol or Virahol, to there be D-tartrate twice gained crystal of recrystallization in 50～100% alcohol (recommending 75%～100% ethanol) of part optically active (S)-β-piperidine carboxylic acid ester and 0.5～3 equivalent (being recommended as equivalent) soluble in water, inorganic base aqueous solution with 1～10N modulates 9～14 with pH value, used mineral alkali is recommended as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, use organic solvent extraction again, the recommendation organic solvent is a methylene dichloride, trichloromethane, 1, the 2-ethylene dichloride, ether or ethyl acetate, get final product optical purity more than or equal to enantiomorph (S)-β-piperidine carboxylic acid ester of 95% compound 12.
The invention provides the amorphous powder of a kind of tiagabine (Tiagabine), the amorphous powder of described tiagabine has following characteristics:
(a) in the analysis of X-ray powder diffraction, be the haloing figure of a no diffraction peak (2 θ); And
(b) 1700cm that in infrared absorption spectrum, has an appointment
-1With 3200～3500cm
-1Characteristic absorbance.
The amorphous powder of tiagabine provided by the invention can prepare by the following method: the pure product of compound tiagabine (Tiagabine) are water-soluble, and cooling (being recommended as-70 ℃～50 ℃) freeze-drying gets amorphous powder.
The synthetic route that the present invention proposes need not expensive special reagent, and the reaction conditions gentleness is suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is the polycrystalline crystalline X line powder diagram of tiagabine;
Fig. 2 is the monocrystalline crystalline X line powder diagram of the amorphous powder of tiagabine
Embodiment
To help further to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
The preparation of compound 9 (Y=OTHP, wherein THP represents THP trtrahydropyranyl)
9.7 gram (20mmol) compound 8 (Ph
3P
+(CH2) 3OTHPBr
-) be suspended in 200 milliliters of dry benzene, add 2.24 gram (20mmol) potassium tert.-butoxides, reflux half an hour once adds and is dissolved in 3 in 10 milliliters of dry benzene and digests compound 1, reflux after 5 hours raw material disappear, stop heating, add 200 ml waters and 150 milliliters of ether, separatory, organic phase washing (2 * 100 milliliters), get 3.1 gram products, productive rate 65% with silica gel column chromatography.
1HNMR(CDCl
3)δ：1.5～1.9(8H，m)，2.03(3H，s)，2.07(3H，s)，2.40～2.48(2H，m)，3.49(2H，m)，3.82(2H，m)，4.61(1H，m)，6.12(1H，t，7.5Hz)，6.76(1H，d，J＝5.4Hz)，6.85(1H，d，J＝5.1Hz)，7.06(1H，d，J＝4.8Hz)，7.22(1H，d，J＝4.8Hz)。
Embodiment 2
(Z=OTs, wherein Ts represents CH to compound 11
3C
6H
4SO
2 -) preparation
1.2 gram (3.4mmol) compound 9 (Y=OTHP) is dissolved in 30 milliliters of tetrahydrofuran (THF)s, add 24 milliliter of 5% hydrochloric acid, stirring at room is after 4 hours, solvent evaporated, add extracted with diethyl ether (3 * 20ml), the organic phase washing (3 * 20ml), anhydrous sodium sulfate drying, solvent evaporated gets needle-like crystal 0.84 gram, it is compound 10, put it into 100 milliliters of there-necked flasks of another exsiccant, add 20 milliliters of no alcoholic acid trichloromethanes, stir, add 1.54 milliliters of dry pyridines, dropping is dissolved in the gram of 2.43 in 40 milliliters of no ethanol trichloromethanes Tosyl chloride, after dropwising, stirs 48 hours at 40～45 ℃, solvent evaporated, add 30 milliliters of ethyl acetate and 30 ml waters, separatory, 20 milliliters of washings of organic phase, saturated common salt washing (2 * 30ml), anhydrous sodium sulfate drying, silica gel column chromatography get 1.21 grams 11, productive rate 82%.
1HNMR(CDCl
3)δ：1.98(6H，m)，2.44(3H，s)，2.46～2.51(2H，m)，4.06～4.11(2H，m)，5.91(1H，m)，6.76(1H，m)，6.82(1H，m)，7.06(1H，m)，7.21(1H，m)，7.32(2H，m)，7.78(2H，m)ppm；IR(KBr)：2923，1598，1360，1177cm
-1；EI-MS(m/z)：418[M]
+。
Embodiment 3
(R)-preparation of β-piperidine carboxylic acid ester 12 and enantiomorph (S)-β-piperidine carboxylic acid ester thereof (R '=C
2H
5) 71.16 gram racemization β-piperidine ethyl formates are dissolved in 350 milliliter 95% the ethanol, add 67 gram L-tartrate, be heated to dissolving, the cooling back adds 50 milliliters of ether, put into refrigerator overnight, filter next day, the gained crystal is washed with 15 milliliters of cold dehydrated alcohols, gained crystal recrystallization in 95% ethanol can get 38 tartrates that digest compound 6 for twice, gained salt is dissolved in 300 ml waters, and ice bath cooling transfers to 11～12 with the NaOH of 3N with pH value, chloroform extraction (3 * 300ml), combining extraction liquid, saturated common salt washing (2 * 200ml), steam behind the anhydrous sodium sulfate drying desolventize 15 gram (R)-β-piperidine ethyl formates 12, optical purity 98% (HPLC detects, chirality AD post); The concentrated gained resistates of the above-mentioned crystalline mother liquor first time is dissolved in 200 ml waters, NaOH with 3N transfers to 11～12 with pH value, chloroform extraction (3 * 200ml), combining extraction liquid, saturated common salt washing (2 * 200ml), steam behind the anhydrous sodium sulfate drying and desolventize to such an extent that optically active (S)-β-piperidine ethyl formate of part arranged, with the D-tartrate of itself and equivalent in 95% ethanol twice in salify and recrystallization the D-tartrate of 20 gram (S)-β-piperidine ethyl formates, as stated above it freely can be got 8 gram (S)-β-piperidine ethyl formates with the NaOH of 3N, optical purity is 95% (HPLC detects, chirality AD post)
Embodiment 4
The preparation of compound 13 (R '=C
2H
5)
0.209 gram (0.5mmol) compound 10 (Z=OTs) is dissolved in 10 milliliters of acetone, add 0.16 milliliter (1mmol) (R)-β-piperidine ethyl formate 12,17 milligrams of (0.1mmol) potassiumiodides, 0.138 gram (1mmol) salt of wormwood, stirring at room 72 hours, stopped reaction, the filtering insolubles, evaporate to dryness filtrate, resistates are dissolved in 10 milliliters of ethyl acetate, wash with 10 milliliter of 10% aqueous tartaric acid solution, saturated common salt washing (2 * 30ml), anhydrous sodium sulfate drying, silica gel column chromatography get 0.11 gram product, productive rate 55%.
1HNMR(CDCl
3)δ：1.21(3H，m)，1.37～1.72(3H，m)，1.93(2H，m)，2.02(3H，s)，2.05(3H，s)，2.09～2.17(1H，m)，2.34(2H，m)，2.54(3H，m)，2.73(1H，m)，2.96(1H，m)，4.07～4.15(2H，q，t＝7.2Hz)，6.03(1H，t，J＝7Hz)，6.76(1H，d，J＝4.8Hz)，6.84(1H，d，J＝4.8Hz)，7.06(1H，d，J＝4.5Hz)，7.22(1H，d，J＝4.8Hz)。
Embodiment 5
The preparation of amorphous Tiagabine
Digest compound 13 with 0.79 and be dissolved in 8 milliliters of dehydrated alcohols, drip the aqueous sodium hydroxide solution of 0.33 milliliter of 12N, stirring at room 48 hours, stopped reaction, the ice bath cooling transfers to 1～2 with 4N hydrochloric acid with pH value, uses dichloromethane extraction, organic phase saturated common salt washing (2 * 30ml), anhydrous sodium sulfate drying boils off solvent, is separated out by solid, use ethanol: methylene dichloride: the mixed solvent recrystallization of ether=1: 0.1: 4 gets 0.6 gram straight product, productive rate 75%.The gained crystal is dissolved in 30 ml waters, and freeze-drying gets amorphous powder.
1HNMR(CD
3OD)δ：1.29～2.20(4H，m)，2.40(3H，s)，2.42(3H，s)，2.64～3.01(5H，m)，3.22(2H，m)，3.50(1H，m)，3.67(1H，m)，6.00(1H，m)，6.59～6.65(2H，m)，6.77～6.85(2H，m)；ESI-MS(m/z)：377[M-Cl+H]
+；[α]
D 20＝-9.1(c＝1，H
2O)。
Claims (13)
1. the precursor of a tiagabine and raceme and S-configuration is characterized in that structural formula is as follows:
A=in the formula
Or OTs, OH
Tiagabine and raceme thereof and S-configuration with and the synthetic method of precursor, it is characterized in that comprising the steps 1), step 1), 2) or step 1), 2), 3), 4):
1) makes the compound and the Ph of general formula 1
3P
+(CH
2)
3OYX-or (RO)
2PO (CH
2)
3The OY reaction,
In the formula, the Y representative
Or
X represents Cl, Br or I, and R represents C
1～C
5Alkyl;
2) compound of resulting following general formula 9, behind the deprotection base compound 10, again and HX (X=Cl, Br, I), PX '
3(X '=Cl, Br), thionyl chloride or Tosyl chloride react the compound shown in the following general formula 11, in the formula, the Y definition is the same, Z represents OTs, Cl, Br or I,
3) make the compound of general formula 11, with the compound reaction of following formula 12 ', R ' represents C
1～C
5Alkyl;
4) compound of the resulting general formula 13 ' of conversion is the compound as the bottom right formula;
3. synthetic method according to claim 2 is characterized in that comprising the described step 1) of claim 2,2) and following steps 3), 4):
3) make the compound of general formula 11, with the compound reaction of following formula 12, R ' represents C
1～C
5Alkyl
4) compound of the resulting general formula 13 of conversion is a tiagabine
4, synthetic method according to claim 2, it is characterized in that described step 1): 1～1.5 normal compound 8 is dissolved in the organic solvent, the alkali that adds equivalent, after the reflux 10～60 minutes, add the 1 equivalent compound 1 that is dissolved in the above-mentioned solvent, got compound 9 in 1～24 hour in 0～110 ℃ of reaction.
5. synthetic method according to claim 4 is characterized in that described organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), ether, acetonitrile, dioxane, benzene or toluene etc., and described alkali is C
nH
2n+1OM, potassium hydroxide, sodium hydroxide or salt of wormwood, n=1～5 wherein, M=Na, K.
6. synthetic method according to claim 2; it is characterized in that the described method for preparing compound 10 by compound 9 is that compound 9 is dissolved in the organic solvent; described organic solvent comprises acetone; tetrahydrofuran (THF); dioxane or acetonitrile; hydrochloric acid at 1～6N; under the effect of sulfuric acid or phosphoric acid; in 0～50 ℃ of reaction 1～10 hour; the protecting group of hydroxyl can be removed compound 10; compound 10 is dissolved in the organic solvent; described organic solvent is a methylene dichloride; trichloromethane; 1; the 2-ethylene dichloride; tetrahydrofuran (THF); ether; acetonitrile; dioxane; benzene or toluene etc.; and then and HX (X=Cl, Br, I); PX '
3(X '=Cl, Br), thionyl chloride or Tosyl chloride react compound 11.
7. synthetic method according to claim 2, it is characterized in that the described method for preparing compound 13 by compound 11 is that compound 11 is dissolved in the organic solvent, under the effect of salt of wormwood, pyridine or triethylamine and potassiumiodide, reacted 10～72 hours at 0～50 ℃, get compound 13 with compound 12.Described organic solvent comprises acetone, acetonitrile or tetrahydrofuran (THF) etc.
8. synthetic method according to claim 2, it is characterized in that the described method for preparing tiagabine (Tiagabine) by compound 13 is that compound 13 is dissolved in the ethanol potassium hydroxide or sodium hydroxide hydrolysis with 1～15N, is 1～3 can get target compound tiagabine (Tiagabine) with hcl acidifying to PH again.
9. synthetic method according to claim 2 is characterized in that the preparation method of described compound 12 and S-configuration enantiomorph thereof, and wherein the R ' of compound 12 represents C
1～C
5Alkyl: racemization β-piperidine carboxylic acid ester and salify and the crystallization in 50～100% pure and mild ether mixed solvent of 0.5～3 normal L-tartrate, gained crystal again in 50～100% alcohol recrystallization can get compound 12 twice; It is soluble in water that the crystalline mother liquor concentrates the gained resistates for the first time, dissociating with the inorganic base aqueous solution of 1～10N to have part optically active (S)-β-piperidine carboxylic acid ester, itself and 0.5～3 normal D-tartrate recrystallization in 50～100% alcohol can be got enantiomorph (S)-β-piperidine carboxylic acid ester of compound 12 for twice.
10. synthetic method according to claim 9, it is characterized in that described alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol, described ether is methyl ether, ether, glycol dimethyl ether or ethylene glycol diethyl ether, described mineral alkali is recommended as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, described organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, ether or ethyl acetate.
11. synthetic method according to claim 9, the optical purity of enantiomorph (S)-β-piperidine carboxylic acid ester that it is characterized in that the compound 12 that obtains or compound 12 is more than or equal to 95%.
12. an amorphous tiagabine powder is characterized in that
(a) in the analysis of X-ray powder diffraction, be the haloing figure of a no diffraction peak (2 θ); And
(b) 1700cm that in infrared absorption spectrum, has an appointment
-1With 3200～3500cm
-1Characteristic absorbance.
13. the preparation method of the amorphous tiagabine powder of claim 12, it is characterized in that the pure product of compound tiagabine water-soluble, the cooling freeze-drying get amorphous powder.
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|---|---|---|---|
| CNA2003101227781A CN1554654A (en) | 2003-12-24 | 2003-12-24 | Synthetic method for thiagabine and its raceme and S-configuration and its method for preparing amorphous powder |
| CN200310122778.1 | 2003-12-24 | ||
| CNB2004101020526A CN1314684C (en) | 2003-12-24 | 2004-12-15 | Synthesis method of saijiabin, its racemate and S-configuration, and preparation method of its amorphous powder |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101209990B (en) * | 2006-12-26 | 2010-11-10 | 江苏天汁化学有限公司 | Resolution method for 3-piperidine formic acid ester |
| CN102827152A (en) * | 2012-09-17 | 2012-12-19 | 扬子江药业集团四川海蓉药业有限公司 | Method for preparing tiagabine and precursor compound of tiagabine |
| CN103351384A (en) * | 2013-07-16 | 2013-10-16 | 四川科瑞德凯华制药有限公司 | Preparing method for tiagabine hydrochloride |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK288385D0 (en) * | 1985-06-26 | 1985-06-26 | Novo Industri As | AMINO ACID DERIVATIVES |
| DK58291D0 (en) * | 1991-04-02 | 1991-04-02 | Novo Nordisk As | CRYSTALINE MATERIAL AND ITS PREPARATION |
| UA52661C2 (en) * | 1996-06-14 | 2003-01-15 | Ново Нордіск А/С | AN ANHYDROUS CRYSTALLINE FORM OF R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride |
-
2004
- 2004-12-15 CN CNB2004101020526A patent/CN1314684C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101209990B (en) * | 2006-12-26 | 2010-11-10 | 江苏天汁化学有限公司 | Resolution method for 3-piperidine formic acid ester |
| CN102827152A (en) * | 2012-09-17 | 2012-12-19 | 扬子江药业集团四川海蓉药业有限公司 | Method for preparing tiagabine and precursor compound of tiagabine |
| CN103351384A (en) * | 2013-07-16 | 2013-10-16 | 四川科瑞德凯华制药有限公司 | Preparing method for tiagabine hydrochloride |
| CN103351384B (en) * | 2013-07-16 | 2016-06-01 | 四川科瑞德凯华制药有限公司 | The preparation method of Tiagabine Hydrochloride |
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| Publication number | Publication date |
|---|---|
| CN1314684C (en) | 2007-05-09 |
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