CN102532161A - Prasugrel phenyl sulfonate and preparation method thereof - Google Patents
Prasugrel phenyl sulfonate and preparation method thereof Download PDFInfo
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- CN102532161A CN102532161A CN2012100462228A CN201210046222A CN102532161A CN 102532161 A CN102532161 A CN 102532161A CN 2012100462228 A CN2012100462228 A CN 2012100462228A CN 201210046222 A CN201210046222 A CN 201210046222A CN 102532161 A CN102532161 A CN 102532161A
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Abstract
The invention mainly relates to Prasugrel phenyl sulfonate and a preparation method thereof and belongs to the field of chemical medicament synthesis.
Description
Technical field
The present invention is a kind of hydrogenated pyridine verivate Phenylsulfonic acid pula lattice and preparation method thereof, belongs to medical technical field.
Background technology
Prasugrel (Prasugrel) is a kind of novel thienopyridine analog derivative; It is the P2Y12 purinoceptor antagonist that is total to the oral property of the common exploitation of company by Lilly Co., Eli. and Japan three; As platelet aggregation inhibitor, with prevention and treatment thrombosis.Its chemical name is 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, and the 7-THTP is [3,2-C] pyridine also, and structural formula is as shown in the formula (I):
Research shows that prasugrel has the prevention thrombus effect stronger than clopidogrel, and onset is faster.Usually the addition hydrochlorate that uses prasugrel is as its medicinal compound, and patent US2003134872 discloses hydrochloride and PHENRAMINE MALEATE of prasugrel and preparation method thereof, but does not relate to the Phenylsulfonic acid prasugrel shown in the formula (II).
Patent CN101456864 discloses prasugrel hydrosulfate and preparation method thereof.Patent CN101899056 discloses the preparation method of prasugrel hydrobromide and different crystal forms thereof.Patent 101633662 discloses the multiple organic and inorganic acid addition salt of multiple prasugrel, but does not also relate to Phenylsulfonic acid prasugrel and compound method thereof.
Summary of the invention
The inventor provides the compound method of Phenylsulfonic acid prasugrel of formula (II) expression following:
With 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-THTP also [3,2-C] pyridine is dissolved in the organic solvent, stirs the solution that adds Phenylsulfonic acid solid or its organic solvent down, adds afterreaction liquid and continues to be stirred to and react completely.
After reaction is accomplished, separate out and directly to obtain product through filtering, or reaction removes solvent under reduced pressure after accomplishing and obtains title product if any crystal.
In above-mentioned preparation feedback:
A) temperature of reaction changes with the variation of solvent etc., but normally 0～60 ℃ of temperature of reaction, preferred 25～45 ℃.The variation of reaction times with solvent or temperature of reaction changes, and needs 15 minutes to 24 hours usually, preferred 1 hour to 6 hours.
B) Phenylsulfonic acid is normally excessive with respect to prasugrel in the salt-forming reaction, and its preferred molar ratio is a prasugrel: Phenylsulfonic acid=1: 1～1: 1.2.
C) the Phenylsulfonic acid solid can directly join in the reaction solution of quick stirring, also can be dissolved in earlier in the organic solvent slowly to drip again.In addition, can also the organic solution of prasugrel be dropped in the organic solution or suspension of Phenylsulfonic acid.
D) solvent that reacts used needs only ability solubilizing reaction thing and does not hinder the carrying out of reaction; Can for aromatic hydrocarbon, aliphatic hydrocarbon, halohydrocarbon, ester class, ketone, alcohols, nitrile organic solvent one or more; Like benzene,toluene,xylene, ethane, hexanaphthene, methylene dichloride, ETHYLE ACETATE, ether, THF, sherwood oil, acetone, butanone, methyl alcohol, ethanol, acetonitrile, DMF etc.; Ethyl acetate, ether, acetone, butanone, methyl alcohol, ethanol, further ethyl acetate, ether, acetone, methyl alcohol.Though the difference of quantity of solvent solvent and changing make material dissolution.
Embodiment
Embodiment 1: compound (II) 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is the preparation of [3,2-C] pyridine benzene sulfonate also
With 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6; 7-THTP also [3,2-C] pyridine 1.3g is dissolved in the 15mL acetone, stirs to add 0.65g Phenylsulfonic acid solid; Behind 35 ℃ of stirring reaction 4h of control reaction temperature, cool to 0～5 ℃ and stir 24h.The solid that filtration is separated out is washed with a spot of acetone, decompression, and 45 ℃ of dry 5h obtain the 1.7g (92%) of white crystals
HPLC purity: 99.3%
Embodiment 2: compound (II) 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is the preparation of [3,2-C] pyridine benzene sulfonate also
With 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6; 7-THTP also [3; 2-C] pyridine 5.9g is dissolved in the 48mL acetone, and room temperature (25 ℃) stirs, and slowly drips the diethyl ether solution (42mL) of 2.75g Phenylsulfonic acid; Behind 30 ℃ of stirring reaction 4h of control reaction temperature, cool to room temperature (25 ℃) and stir 24h.The solid that filtration is separated out is washed with a spot of acetone mixed solution, and the 45 ℃ of dry 5h that reduce pressure obtain the 7.8g (92%) of white crystals
HPLC purity: 99.6%
Embodiment 3: compound (II) 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is the preparation of [3,2-C] pyridine benzene sulfonate also
With 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6; 7-THTP also [3,2-C] pyridine 1.2g is dissolved in the 18mL ETHYLE ACETATE, stirs to add 0.49g Phenylsulfonic acid solid; Behind 45 ℃ of stirring reaction 4h of control reaction temperature, cool to 0～5 ℃ and stir 24h.The solid that filtration is separated out is washed with a spot of ETHYLE ACETATE, and the 50 ℃ of dry 5h that reduce pressure obtain white crystals 1.4g (82%)
HPLC purity: 99.6%
Embodiment 4: compound (II) 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is the preparation of [3,2-C] pyridine benzene sulfonate also
With 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6; 7-THTP also [3,2-C] pyridine 2.5g is dissolved in the 50mL methyl alcohol stirring at room; The methanol solution that adds the 1.1g Phenylsulfonic acid; Behind the stirring at room reaction 2h, remove solvent under reduced pressure, obtain white solid 3.3g (92.7%) after the drying
HPLC purity: 99.6%.
Claims (6)
1.2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-THTP also [3; 2-C] preparation method of benzene sulfonate of pyridine, its step is with 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5; 6,7-THTP also [3,2-C] pyridine is dissolved in the organic solvent; The organic solvent solution that adds Phenylsulfonic acid solid or Phenylsulfonic acid in the whipping process adds the back insulated and stirred to reacting completely, and temperature of reaction is 0 ℃ to 60 ℃.
2. the method for claim 1 is characterized in that, the mol ratio of reactant prasugrel and Phenylsulfonic acid is 1: 1～1.2.
3. the method for claim 1 is characterized in that, said solvent is one or more of aromatic hydrocarbon, aliphatic hydrocarbon, halohydrocarbon, ester class, ethers, ketone, alcohols, nitrile organic reagent.
4. the method for claim 1; It is characterized in that said solvent is one or more of benzene,toluene,xylene, ethane, hexanaphthene, methylene dichloride, trichloromethane, ETHYLE ACETATE, ether, THF, sherwood oil, acetone, butanone, methyl alcohol, ethanol, acetonitrile, DMF.
5. the method for claim 1 is characterized in that, said solvent is ETHYLE ACETATE, ether, acetone, butanone, methyl alcohol, ethanol.
6. the method for claim 1 is characterized in that, said solvent is ETHYLE ACETATE, ether, acetone, methyl alcohol.
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| CN201210046222.8A CN102532161B (en) | 2012-02-27 | 2012-02-27 | Prasugrel phenyl sulfonate and preparation method thereof |
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| CN201210046222.8A CN102532161B (en) | 2012-02-27 | 2012-02-27 | Prasugrel phenyl sulfonate and preparation method thereof |
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| CN102532161A true CN102532161A (en) | 2012-07-04 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848844A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Prasugrel salt-forming compound and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009098142A1 (en) * | 2008-02-06 | 2009-08-13 | Helm Ag | Prasugrel salts with improved properties |
| WO2009129983A1 (en) * | 2008-04-21 | 2009-10-29 | Ratiopharm Gmbh | Acid addition salts of prasugrel and pharmaceutical compositions comprising the same |
| WO2011057593A2 (en) * | 2009-11-16 | 2011-05-19 | Zentiva, K.S. | New salts of prasugrel and a method of their production |
| WO2011057592A1 (en) * | 2009-11-16 | 2011-05-19 | Zentiva, K.S. | Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof |
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2012
- 2012-02-27 CN CN201210046222.8A patent/CN102532161B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009098142A1 (en) * | 2008-02-06 | 2009-08-13 | Helm Ag | Prasugrel salts with improved properties |
| WO2009129983A1 (en) * | 2008-04-21 | 2009-10-29 | Ratiopharm Gmbh | Acid addition salts of prasugrel and pharmaceutical compositions comprising the same |
| WO2011057593A2 (en) * | 2009-11-16 | 2011-05-19 | Zentiva, K.S. | New salts of prasugrel and a method of their production |
| WO2011057592A1 (en) * | 2009-11-16 | 2011-05-19 | Zentiva, K.S. | Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848844A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Prasugrel salt-forming compound and preparation method thereof |
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Address after: 225107 Jiangsu city of Yangzhou Province Li Dian Zhen Wuqiao Xin Ba Patentee after: Yangzhou Addie Pharmaceutical Co., Ltd. Address before: 225107 Jiangsu city of Yangzhou Province Li Dian Zhen Wuqiao Xin Ba Patentee before: Yangzhou Xingdou Pharmaceutical Co., Ltd. |