CN100417653C - Preparation method of thienotetrahydropyridinacetic acid and salt thereof - Google Patents
Preparation method of thienotetrahydropyridinacetic acid and salt thereof Download PDFInfo
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- CN100417653C CN100417653C CNB2005100607208A CN200510060720A CN100417653C CN 100417653 C CN100417653 C CN 100417653C CN B2005100607208 A CNB2005100607208 A CN B2005100607208A CN 200510060720 A CN200510060720 A CN 200510060720A CN 100417653 C CN100417653 C CN 100417653C
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Abstract
The present invention provides preparation process of thienotetrahydro pyridyl acetic acid and its salt as shown in the expression V. The preparation process of thienotetrahydro pyridyl acetate includes one step of alkaline hydrolyzing the compound shown in the expression IV in 20-50 wt% concentration alkali aqua under the action of phase transfer catalyst and at 60-130 deg.c to obtain the thienotetrahydro pyridyl acetate as shown in the expression V. The compound shown in the expression V may be further acidified simply to obtain thienotetrahydro pyridyl acetic acid. The present invention prepares thienotetrahydro pyridyl acetic acid and its salt as shown in the expression V in a simple process with high efficiency, and provides important intermediates for the preparation of clopidogrel and other methyl thienotetrahydro pyridyl acetate compounds.
Description
(1) technical field
The present invention relates to the preparation method of a kind of thienotetrahydropyriacidcetic acidcetic and salt thereof, belong to chemical pharmacy field.
(2) background technology
Thienotetrahydropyriacidcetic acidcetic and salt (V) thereof suc as formula (VI) are the important intermediate of preparation methyl thienotetrahydropyridinacetate such as clopidogrel.Recently, India Cardila Health Nursing Co., Ltd. discloses the preparation method (WO02059128 of a kind of formula (VI) compound and salt formula V thereof, CN1487943A), it is through type (IV) compound preparation formula (VII) compound under appropriate condition, near and the preparation formula of deriving (VI) compound and salt formula V thereof, this patent has been mentioned the method by formula (IV) compound direct preparation formula (VI) compound and salt formula V thereof, in the preparation example, the alkaline hydrolysis example is not provided, in fact we are by its method that provides and condition, can only preparation formula (VII) compound, perhaps the yield of formula (VI) compound and salt formula V thereof is too low and do not have the value of separating and producing, and acidic hydrolysis method that it provides and condition do not have competitive power because of yield too low (report 38%) yet.
Wherein X represents hydrogen, fluorine, chlorine, bromine or iodine atom, and M is an alkalimetal ion.
(3) summary of the invention
The invention provides a kind of technology is simple, yield is high preparation method suc as formula the thienotetrahydropyriacidcetic acidcetic and the salt (V) thereof of (VI).
Described thienotetrahydropyriacidcetic acidcetic salt (V) preparation method comprises the steps: that formula (IV) compound gets described product in 60-130 ℃ of alkaline hydrolysis in alkaline solution, under the phase-transfer catalyst effect; Described alkaline solution is the alkali aqueous solution of 20-50% and the mixed solution of organic solvent;
Wherein X represents hydrogen, fluorine, chlorine, bromine or iodine atom, is preferably 2-chlorine; M is an alkalimetal ion, is preferably sodium or potassium ion.
Phase-transfer catalyst is indispensable to reaction.Do not have phase-transfer catalyst, almost can not or can only the ground hydrolysis of very low yield obtain the formula V compound.The suitable phase-transfer catalyst of the present invention is for example: quaternary ammonium salt, season phosphonium salt and molecular weight be polyoxyethylene glycol (PEG), crown ether of 200-3000 etc., preferentially be chosen as triethyl benzyl ammonia chloride (TEBA), PEG400, PEG600 or PEG800.The 0.1%-10% that catalyst consumption is generally reaction raw materials formula (IV) compound quality preferentially selects 0.5%-5%.
Described organic solvent such as C
1-C
8Alcohol or their arbitrary combination, be preferably one of following or more than one arbitrary combination: methyl alcohol, ethanol, propyl carbinol are preferably propyl carbinol again.The consumption of organic solvent calculates by every 1g formula (IV) compound and is generally 1～5ml.
The concentration of alkali is crucial to reaction, is lower than the aqueous sodium hydroxide solution of 20% concentration or potassium hydroxide aqueous solution or their mixed solution and obtains the formula V compound with can only hanging down yield.The concentration of alkali is big more, and hydrolysis is abundant more, thorough more.Alkali aqueous solution is preferably the sodium hydroxide of 35-50% or the mixed solution of potassium hydroxide aqueous solution or their arbitrary proportions.The equivalence ratio 1-20 of described alkali and formula (IV) compound: 1, be preferably 15-20: 1.
Described alkaline hydrolysis temperature is preferably 90-120 ℃.
The formula V compound promptly obtains compound (VI) through simple acidification.
By the control synthesis material, synthetic method of the present invention can be used for synthesizing optics (chirality) isomer and the racemic modification thereof of key intermediate formula (VI) compound and salt formula V thereof.
The present invention also provides a kind of preparation method of the thienotetrahydropyriacidcetic acidcetic suc as formula (VI), comprises the steps:
(1) formula (IV) compound must be as the thienotetrahydropyriacidcetic acidcetic salt of formula V in 60-130 ℃ of alkaline hydrolysis in alkaline solution, under the phase-transfer catalyst effect; Described alkaline solution is the alkali aqueous solution of 20-50% and the mixed solution of organic solvent;
(2) thienotetrahydropyriacidcetic acidcetic salt promptly gets thienotetrahydropyriacidcetic acidcetic through being acidified to pH4-5;
Wherein X represents hydrogen, fluorine, chlorine, bromine or iodine atom, and M is an alkalimetal ion; The equivalence ratio of described alkali and formula (IV) compound is 1-20: 1, be preferably 15-20: 1.。
The present invention adopts single stage method can obtain thienotetrahydropyriacidcetic acidcetic and salt (V) thereof suc as formula (VI) with high yield, for the preparation of methyl thienotetrahydropyridinacetates such as clopidogrel provides important intermediate.
(4) embodiment
The invention will be further described below in conjunction with embodiment, but protection scope of the present invention is not limited to this.
Synthesizing of embodiment 1 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 360g with 40% and the methyl alcohol of 100ml, (±) of 60g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA 1.0g places suitable reaction flask, and the system back flow reaction is 12 hours then, stopped reaction.Cold filtration gets product 61g, yield 89%.
Synthesizing of embodiment 2 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
With the 100ml propyl carbinol is solvent, and other is with embodiment 1.Obtain formula V compound 63g, yield 92%.
Synthesizing of embodiment 3 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 320g with 50% and the methyl alcohol of 100ml, (±) of 60g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA, 1.0g place suitable reaction flask, the system back flow reaction is 15 hours then, stopped reaction.Cold filtration obtains target product 61g, yield 89%.
Synthesizing of embodiment 4 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 360g with 35% and the methyl alcohol of 100ml, (±) of 60g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA, 1.0g place suitable reaction flask, the system back flow reaction is 12 hours then, stopped reaction.Cold filtration obtains target product 61g, yield 89%.
Synthesizing of embodiment 5 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 360g with 45% and the methyl alcohol of 100ml, (±) of 60g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA, 1.0g place suitable reaction flask, the system back flow reaction is 14 hours then, stopped reaction.Cold filtration obtains target product 61g, yield 89%.
Synthesizing of embodiment 6 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 320g with 50% and the methyl alcohol of 100ml, (S) of 60g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst 18 hats 6,1.0g place suitable reaction flask, the system back flow reaction is 12 hours then, stopped reaction.Cold filtration obtains target product 61g, yield 89%.
Synthesizing of embodiment 7 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) potassium salt
Potassium hydroxide solution 360g with 40% is an alkali, and propyl carbinol is a solvent, and other is with embodiment 1.Obtain target product 70g, yield 97%.
Synthesizing of embodiment 8 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
With phase-transfer catalyst 18 hats 6,0.20g replaces TEBA, and other obtains target product 62g with embodiment 4, yield 90.5%.
Synthesizing of embodiment 9 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Replace TEBA with phase-transfer catalyst tributyl benzyl chlorination microcosmic salt 0.50g, other gets target product 60g, yield 87.6% with embodiment 1.
Synthesizing of embodiment 10 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Replace TEBA with phase-transfer catalyst PEG4001.5g, other gets target product 60g, yield 87.6% with embodiment 1.
Synthesizing of embodiment 11 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
With phase-transfer catalyst 18 hats 6,0.20g substitutes TEBA, and other gets target product 63g, yield 92% with embodiment 2.
Synthesizing of embodiment 12 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Sodium hydroxide solution 360g with 30% and the propyl carbinol of 100ml, (R) of 64g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA, 1.0g place suitable reaction flask, the system back flow reaction is 16 hours then, stopped reaction.Cold filtration obtains target product 64g, yield 87.6%.
Synthesizing of embodiment 13 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) potassium salt
Potassium hydroxide solution 360g with 35% and the propyl carbinol of 100ml, (S) of 64g-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetonitrile, phase-transfer catalyst TEBA, 1.0g place suitable reaction flask, the system back flow reaction is 10 hours then, stopped reaction.Cold filtration obtains target product 64g, yield 83.5%.
Synthesizing of embodiment 14 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
With phase-transfer catalyst 18 hats 6,0.20g replaces TEBA, and ethanol is made solvent, and other obtains target product 62g with embodiment 1, yield 90.5%.
Synthesizing of embodiment 15 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetic acid sodium salt
Replace TEBA with phase-transfer catalyst PEG6001.8g, ethanol is made solvent, and other obtains target product 61g with embodiment 3, yield 89%.
Synthesizing of embodiment 16 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) potassium salt
Make solvent with ethanol, other obtains target product 70g with embodiment 13, yield 97%.
Synthesizing of embodiment 17 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) potassium salt
Potassium hydroxide solution 360g with 40% is an alkali, replaces TEBA with phase-transfer catalyst PEG6001.8g, and other obtains target product 68g with embodiment 1, yield 94.6%.
Synthesizing of embodiment 18 (±)-(2-chloro-phenyl-)-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetate
Get the reaction solution that obtains by embodiment 1 method, add acetic acid and regulate pH to 4-5, cold filtration gets product 60g, yield 93.8%.
Claims (12)
1. preparation method as the thienotetrahydropyriacidcetic acidcetic salt of formula V comprises the steps: that formula (IV) compound gets described product in 60-130 ℃ of alkaline hydrolysis in alkaline solution, under the phase-transfer catalyst effect; Described alkaline solution is the alkali aqueous solution of 20-50% and the mixed solution of organic solvent;
Wherein X represents hydrogen, fluorine, chlorine, bromine or iodine atom, and M is an alkalimetal ion; The equivalence ratio of described alkali and formula (IV) compound is 1-20: 1.
2. preparation method as claimed in claim 1, it is characterized in that described phase-transfer catalyst is one of following: quaternary ammonium salt, season phosphonium salt, molecular weight be polyoxyethylene glycol, the crown ether of 200-3000, catalyst levels is the 0.1-10% of reaction raw materials formula (IV) compound quality.
3. preparation method as claimed in claim 2, it is characterized in that described phase-transfer catalyst is one of following: triethyl benzyl ammonia chloride, PEG400, PEG600, PEG800, catalyst levels are the 0.5-5% of reaction raw materials formula (IV) compound quality.
4. preparation method as claimed in claim 1 is characterized in that described organic solvent is C
1-C
8Alcohol or their arbitrary combination, the consumption of organic solvent is calculated as 1～5ml by every 1g formula (IV) compound.
5. preparation method as claimed in claim 4 is characterized in that described organic solvent is one of following or more than one arbitrary combination: methyl alcohol, ethanol, propyl carbinol.
6. preparation method as claimed in claim 5 is characterized in that described organic solvent is a propyl carbinol.
7. as the described preparation method of one of claim 1～6, it is characterized in that X is a 2-chlorine in the described formula V, M is sodium or potassium ion.
8. preparation method as claimed in claim 7 is characterized in that described alkaline hydrolysis temperature is 90-120 ℃.
9. preparation method as claimed in claim 8 is characterized in that described alkali aqueous solution is the sodium hydroxide of 35-50% or the mixed solution of potassium hydroxide aqueous solution or their arbitrary proportions.
10. preparation method as claimed in claim 9 is characterized in that the equivalence ratio of described alkali and formula (IV) compound is 15-20: 1.
11. the preparation method suc as formula the thienotetrahydropyriacidcetic acidcetic of (VI) comprises the steps:
(1) formula (IV) compound must be as the thienotetrahydropyriacidcetic acidcetic salt of formula V in 60-130 ℃ of alkaline hydrolysis in alkaline solution, under the phase-transfer catalyst effect; Described alkaline solution is the alkali aqueous solution of 20-50% and the mixed solution of organic solvent;
(2) thienotetrahydropyriacidcetic acidcetic salt promptly gets thienotetrahydropyriacidcetic acidcetic through being acidified to pH4-5;
Wherein X represents hydrogen, fluorine, chlorine, bromine or iodine atom, and M is an alkalimetal ion; The equivalence ratio of described alkali and formula (IV) compound is 1-20: 1.
12. the preparation method as thienotetrahydropyriacidcetic acidcetic as described in the claim 11 is characterized in that the equivalence ratio of described alkali and formula (IV) compound is 15-20: 1.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100607208A CN100417653C (en) | 2005-09-08 | 2005-09-08 | Preparation method of thienotetrahydropyridinacetic acid and salt thereof |
| US12/066,187 US7932391B2 (en) | 2005-09-08 | 2006-09-07 | Method for the preparation of clopidogrel and its analogues of methyl-tetrahydrothieno[3,2-C]pyridine acetate |
| EP20060775625 EP1942110A4 (en) | 2005-09-08 | 2006-09-07 | Preparation of clopidogrel and its analogues methyl tetrahydrothienopyridine acetate compounds |
| PCT/CN2006/002316 WO2007028337A1 (en) | 2005-09-08 | 2006-09-07 | Preparation of clopidogrel and its analogues methyl tetrahydrothienopyridine acetate compounds |
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| CNB2005100607208A CN100417653C (en) | 2005-09-08 | 2005-09-08 | Preparation method of thienotetrahydropyridinacetic acid and salt thereof |
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| CN1927864A CN1927864A (en) | 2007-03-14 |
| CN100417653C true CN100417653C (en) | 2008-09-10 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1487943A (en) * | 2001-01-24 | 2004-04-07 | Process for preparing clopidogrel | |
| WO2005026174A1 (en) * | 2003-09-11 | 2005-03-24 | Generics [Uk] Limited | Novel crystalline polymorphs of clopidogrel |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1487943A (en) * | 2001-01-24 | 2004-04-07 | Process for preparing clopidogrel | |
| WO2005026174A1 (en) * | 2003-09-11 | 2005-03-24 | Generics [Uk] Limited | Novel crystalline polymorphs of clopidogrel |
Non-Patent Citations (4)
| Title |
|---|
| ortho-Metalation/ChlorinationofBenzoicAcidDerivatives:Preparationof[benzene-U-13C]-rac-Clopidogrel([benzene-U-13C]-rac-SR25990C). Alain Burgos,et al.Journal of Labelled Compounds and Radiopharmaceuticals,Vol.43 . 2000 |
| ortho-Metalation/ChlorinationofBenzoicAcidDerivatives:Preparationof[benzene-U-13C]-rac-Clopidogrel([benzene-U-13C]-rac-SR25990C). Alain Burgos,et al.Journal of Labelled Compounds and Radiopharmaceuticals,Vol.43 . 2000 * |
| 氯吡格雷合成路线图解. 陈子明等.中国医药工业杂志，第33卷第4期. 2002 |
| 氯吡格雷合成路线图解. 陈子明等.中国医药工业杂志，第33卷第4期. 2002 * |
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