CN101812070B - Prasugrel compound and new preparation method thereof - Google Patents
Prasugrel compound and new preparation method thereof Download PDFInfo
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- CN101812070B CN101812070B CN2010101483824A CN201010148382A CN101812070B CN 101812070 B CN101812070 B CN 101812070B CN 2010101483824 A CN2010101483824 A CN 2010101483824A CN 201010148382 A CN201010148382 A CN 201010148382A CN 101812070 B CN101812070 B CN 101812070B
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- prasugrel
- catalyzer
- organic solvent
- anhydrous
- midbody
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- 0 CCCC(C)=*(C=C=C)C(C(C1CC1)=O)=NCCC Chemical compound CCCC(C)=*(C=C=C)C(C(C1CC1)=O)=NCCC 0.000 description 2
- AGOUCQBHFLXQAB-DKSNIGFESA-N CCN(CC1=C(C)CC(OC(C)=O)=C1)C(C(C1CC1)=O)/C(/C=C\C=C)=C(/C)\I Chemical compound CCN(CC1=C(C)CC(OC(C)=O)=C1)C(C(C1CC1)=O)/C(/C=C\C=C)=C(/C)\I AGOUCQBHFLXQAB-DKSNIGFESA-N 0.000 description 1
Abstract
The invention provides a prasugrel compound and a new preparation method thereof. The new preparation method comprises the following steps: carrying out hydrolysis reaction on a prasugrel crude product to obtain a prasugrel precursor intermediate, adding activated carbon for adsorbing and purifying, and then, carrying out esterification reaction under the catalysis of strong acid salt catalysts to obtain the high-purity prasugrel. The invention has the advantages of simple reaction steps, high yield, low cost and high product purity.
Description
Technical field
The present invention relates to a kind of prasugrel compound and new preparation method thereof, belong to medical technical field.
Background technology
Cardiovascular disorder becomes ascendant trend year by year, is to cause one of human disabled with dead serious disease at present.The appearance of ADP acceptor inhibitor is an important milestone of Antiplatelet therapy; It can reduce high-risk patient generation cardiovascular event risk; Control is blocked through the skin coronary artery PCI person distal vessels that happens suddenly, and significantly reduces myocardial infarction, apoplexy, lung or venothrombotic incidence and mortality ratio.
After a thiophene chlorine amine and clopidogrel; Platelet adp receptor blocker prasugrel of new generation by Japanese Sankyo company and the joint development of U.S. Eli Lilly company; Anticoagulant more quickly and efficiently; Be a kind of Thienopyridines medicine, combine, become the best therapy of treatment acute coronary syndrome probably with it with through skin coronary artery interventional procedure.
Prasugrel, chemistry 2-[2-(acetoxyl group)-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl also] by name-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, molecular formula C
20H
20FNO
3S, molecular weight 373.44, structural formula is:
Prasugrel has obtained the preferential examination and approval authority of U.S. FDA at present, and with obtained European Union's approval listing on February 23rd, 2009.U.S. Pat 5288726 discloses prasugrel and its purposes in the treatment cardiovascular disorder relevant with thrombus; Chinese patent ZL98109220.9 discloses the oral preparation composition that prasugrel is used to treat the cardiovascular disorder relevant with thrombus; Chinese patent ZL200780021085.x discloses high purity prasugrel or its acid salt preparation method.
Mainly the original synthetic route of Japanese Sankyo company in the synthetic route prior art of prasugrel; With adjacent fluorine bromobenzyl is starting raw material; Obtain 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone with the cyclopropylniitrile condensation after being made into grignard reagent; With its α position bromo, again with 2-thienone and piperidines generation substitution reaction, products therefrom obtains prasugrel through after the acetylize then.This route is more succinct, and productive rate is low excessively, and cost is too high, and the product purity that obtains is relatively poor.
Summary of the invention
The object of the present invention is to provide a kind of prasugrel compound and new preparation method thereof; The prasugrel bullion is obtained prasugrel precursor midbody through hydrolysis reaction, add the charcoal absorption purifying, carry out esterification again and obtain highly purified prasugrel; Reactions step is simple; Productive rate is high, and cost is low, and product purity is high.
The technical scheme that the present invention solves comprises:
The preparation method of the prasugrel compound shown in a kind of formula (I),
Step comprises:
(1) the prasugrel bullion is scattered in the water, adds sodium hydroxide solution as catalyzer, heating, stirring reaction is separated out solid, filters, and drying gets midbody (II);
(2) midbody (II) is dissolved in the organic solvent, adds the gac whip attachment, filter decarburization, must filtrate;
(3) in filtrating, add glacial acetic acid and mix stirring, add strong acid salt again as catalyzer, cyclohexane give is the band aqua; Stirring reaction, the filtering insolubles, filtrating uses solid drier dry again; Organic solvent is removed in underpressure distillation, and vacuum-drying obtains highly purified prasugrel;
Further; As preferably; Organic solvent is selected from chloroform, methylene dichloride, ethanol, methyl alcohol, acetonitrile, the trimethyl carbinol, propyl carbinol, Virahol, acetone, ether, phenylcarbinol, N in the aforesaid method, one or more in dinethylformamide, the DMAC N,N; Be preferably N, dinethylformamide.
Further, as preferably, the strong acid salt catalyzer is selected from iron(ic)chloride (FeCl in the aforesaid method
36H
2O), cupric chloride (CuCl
22H
2O), ferric sulfate (Fe
2(SO4)
39H
2O), copper sulfate (CuSO45H
2O) a kind of in is preferably iron(ic)chloride (FeCl
36H
2O).
Further, as preferably, solid drier is selected from a kind of in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate or the activated alumina in the aforesaid method, is preferably activated alumina.
The prasugrel compound purity of method preparation of the present invention is all greater than 99.8%.
As the present invention's one preferred embodiment, the preparation process of described prasugrel compound comprises:
(1) the prasugrel bullion is scattered in the water, adds 10% sodium hydroxide solution, be heated to 70-80 ℃ as catalyzer, stirring reaction 1-2 hour, separate out solid, to filter, drying gets midbody (II);
(2) midbody (II) is dissolved in the organic solvent, adds the gac of total liquid volume 0.1-0.5% (g/ml), be incubated 70-80 ℃ of whip attachment 30min, filter decarburization, must filtrate;
(3) in filtrating, add glacial acetic acid and mix stirring, add strong acid salt again as catalyzer, cyclohexane give is the band aqua; 40-50 ℃ of stirring reaction 40-60min; Filtering insolubles, filtrating use solid drier dry again, and organic solvent is removed in underpressure distillation; 50-60 ℃ of vacuum-drying obtains highly purified prasugrel;
Advantage of the present invention shows: the present invention makes highly purified prasugrel compound through hydrolysis reaction and esterification, and reactions step is simple, and productive rate is high, and cost is low.In addition, the present invention selects the strong acid salt catalyzer for use, and the reaction times is short, and yield is high, and cost is low, is the good catalyzer of a kind of ideal.
Embodiment
The preparation of embodiment 1 prasugrel
(1) 100g prasugrel bullion is scattered in the 500ml water, adds 10% sodium hydroxide solution 20ml as catalyzer, be heated to 70 ℃, stirring reaction 2 hours is separated out solid, filters, and 50 ℃ of vacuum-dryings get 82.17g midbody (II), yield 92.6%;
(2) 82.17g midbody (II) is dissolved in N, among the dinethylformamide 500ml, adds the 0.5g gac, be incubated 80 ℃ of whip attachment 30min, filter decarburization, must filtrate;
(3) in filtrating, add the 16.1g glacial acetic acid and mix stirring, add 3.5g iron(ic)chloride (FeCl again
36H
2O) as catalyzer, the 20ml cyclohexane give is band aqua, 40 ℃ of stirring reaction 60min; Filtering insolubles, filtrating use activated alumina dry again, and N is removed in underpressure distillation; Dinethylformamide, 60 ℃ of vacuum-dryings obtain highly purified prasugrel 91.5g; Yield 91.5%, purity 99.92%, mp122 ℃.
The preparation of embodiment 2 prasugrels
(1) 100g prasugrel bullion is scattered in the 500ml water, adds 10% sodium hydroxide solution 20ml as catalyzer, be heated to 80 ℃, stirring reaction 1 hour is separated out solid, filters, and 50 ℃ of vacuum-dryings get 83.05g midbody (II), yield 93.5%;
(2) 83.05g midbody (II) is dissolved in N, among the dinethylformamide 500ml, adds the 2.5g gac, be incubated 70 ℃ of whip attachment 30min, filter decarburization, must filtrate;
(3) in filtrating, add the 16.2g glacial acetic acid and mix stirring, add 3.5g iron(ic)chloride (FeCl again
36H
2O) as catalyzer, the 20ml cyclohexane give is band aqua, 50 ℃ of stirring reaction 40min; Filtering insolubles, filtrating use activated alumina dry again, and N is removed in underpressure distillation; Dinethylformamide, 50 ℃ of vacuum-dryings obtain highly purified prasugrel 90.6g; Yield 90.6%, purity 99.89%, mp122 ℃.
The preparation of embodiment 3 prasugrels
(1) 100g prasugrel bullion is scattered in the 500ml water, adds 10% sodium hydroxide solution 20ml as catalyzer, be heated to 75 ℃, stirring reaction 1.5 hours is separated out solid, filters, and 50 ℃ of vacuum-dryings get 81.15g midbody (II), yield 91.4%;
(2) 81.15g midbody (II) is dissolved in N, among the dinethylformamide 500ml, adds the 1.5g gac, be incubated 75 ℃ of whip attachment 30min, filter decarburization, must filtrate;
(3) in filtrating, add the 16.15g glacial acetic acid and mix stirring, add 3.5g iron(ic)chloride (FeCl again
36H
2O) as catalyzer, the 20ml cyclohexane give is band aqua, 45 ℃ of stirring reaction 50min; Filtering insolubles, filtrating use activated alumina dry again, and N is removed in underpressure distillation; Dinethylformamide, 55 ℃ of vacuum-dryings obtain highly purified prasugrel 91.1g; Yield 91.1%, purity 99.90%, mp121 ℃.
Embodiment 4 structural identifications
1, ultimate analysis C
20H
20FNO
3S
Theoretical value: C:64.32%; H:5.39%; F:5.08%; N:3.75%; O:12.85%; S:8.58%.
Measured value: C:64.55%; H:5.41%; F:5.03%; N:3.77%; O:12.81%; S:8.62%.
2, nuclear-magnetism POP data
1HNMR(CDCl
3)δ：7.05-7.44(m，4H)，6.26(s，1H)，4.82(s，1H)，3.47-3.59(m，2H)，2.77-2.94(m，4H)，2.27-2.29(m，1H)，2.27(s，3H)，1.01-1.06(m，2H)，0.82-0.88(m，2H)。
MS-ESI(m/z)：374[M+H]
+。
Claims (5)
1. the preparation method of the prasugrel compound shown in the formula (I),
Step comprises:
(1) the prasugrel bullion is scattered in the water, adds 10% sodium hydroxide solution, be heated to 70-80 ℃ as catalyzer, stirring reaction 1-2 hour, separate out solid, to filter, drying gets midbody (II);
(2) midbody (II) is dissolved in the organic solvent, adds the gac of total liquid volume 0.1-0.5% (g/ml), be incubated 70-80 ℃ of whip attachment 30min; Filter decarburization, must filtrate, wherein said organic solvent is selected from N; Dinethylformamide or DMAC N,N;
(3) in filtrating, add glacial acetic acid and mix stirring, add strong acid salt again as catalyzer, cyclohexane give is the band aqua; 40-50 ℃ of stirring reaction 40-60min, the filtering insolubles, filtrating uses solid drier dry again; Organic solvent is removed in underpressure distillation; 50-60 ℃ of vacuum-drying obtains highly purified prasugrel, and wherein said strong acid salt catalyzer is selected from FeCl
36H
2O;
2. method according to claim 1 is characterized in that organic solvent is N, dinethylformamide.
3. method according to claim 1 is characterized in that solid drier is selected from a kind of in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate or the activated alumina.
4. method according to claim 3 is characterized in that solid drier is an activated alumina.
5. according to each described method of claim 1-4, the prasugrel compound purity that it is characterized in that preparing is all greater than 99.8%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| CN101245073A (en) * | 2008-03-21 | 2008-08-20 | 上海医药工业研究院 | Medicine midbody and preparation method thereof |
| CN101402642A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Novel environment friendly preparation method for prasugrel |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
-
2010
- 2010-04-16 CN CN2010101483824A patent/CN101812070B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| CN101245073A (en) * | 2008-03-21 | 2008-08-20 | 上海医药工业研究院 | Medicine midbody and preparation method thereof |
| CN101402642A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Novel environment friendly preparation method for prasugrel |
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