CN101531667A - Method for synthesizing prasugrel intermediate and method for synthesizing prasugrel - Google Patents
Method for synthesizing prasugrel intermediate and method for synthesizing prasugrel Download PDFInfo
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- CN101531667A CN101531667A CN200910049455A CN200910049455A CN101531667A CN 101531667 A CN101531667 A CN 101531667A CN 200910049455 A CN200910049455 A CN 200910049455A CN 200910049455 A CN200910049455 A CN 200910049455A CN 101531667 A CN101531667 A CN 101531667A
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- prasugrel
- cyclopropyl
- fluorophenyl
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Abstract
The invention belongs to the field of chemical engineering and pharmacy, and relates to a method for synthesizing a prasugrel intermediate and a method for synthesizing prasugrel. The method for synthesizing the prasugrel intermediate comprises that: 2-bromine-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2-ethylamine thiophene are condensated under the action of alkali; then, after the reactant reacts with formaldehyde, 1-cyclopropyl-2-(6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-yl)-2-(2-fluorophenyl) ketone after cycization of protonic acid. The method for synthesizing the prasugrel by the intermediate comprises that: after the intermediate 1-cyclopropyl-2-(6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-yl)-2-(2-fluorophenyl)ketone is oxidized, the reactant is esterified with acetic anhydride to obtain the prasugrel. Synthesis of the prasugrel by the method can obtain products with high yield and simple operation steps.
Description
Technical field
The invention belongs to chemical industry and pharmacy field, relate to a kind of preparation technology of compound, more specifically, the present invention relates to a kind of synthetic method of prasugrel intermediate, and the method for the synthetic prasugrel of intermediate thus.
Background technology
Prasugrel (prasugrel) is to be come and affiliate's first pharmacy three oral antiplatelet drug of the common exploitation of company altogether by gift, has obtained the preferential examination and approval authority of FDA at present.Prasugrel is a kind of oral platelet suppressant drug, belongs to anticoagulation medicine.The initial exploitation of this product need to be used to the patient of the acute coronary syndrome of percutaneous coronary intervention (pci), comprises the patient that need carry out stent endoprosthesis.If get the Green Light, this product is at the commodity of U.S. Efient by name.
The synthetic route of existing prasugrel mainly is the original synthetic route of three common companies in the prior art; 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; then with its α position bromo; with 2-thienone and piperidines generation substitution reaction, products therefrom obtains prasugrel through after the acetylize again.This route is more succinct, cause reaction efficiency to reduce greatly but crucial replacement connects two segmental productive rates low excessively (32%), thereby synthetic cost is too high.
Synthetic route 1:
Prasugrel intermediate 1-cyclopropyl-2-(6, the 7-dihydro-thiophene also structural formula of [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone is as follows:
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of prasugrel intermediate 1-cyclopropyl-2-, and (6, the 7-dihydro-thiophene is the preparation method of [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone also.
Another technical problem to be solved by this invention also is to provide the method by the synthetic prasugrel of above-mentioned prasugrel intermediate.
The present invention solves the problems of the technologies described above the technical scheme of being taked: a kind of preparation method of prasugrel intermediate, condensation under the effect of alkali gets 1-cyclopropyl-2-(2-fluorophenyl)-2-(2-(thiophene-2-yl) ethamine) ethyl ketone (compound 8) by 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone (compound 4) and 2 thiophene ethyl amine (compound 7), then with formaldehyde reaction after, with obtaining intermediate 1-cyclopropyl-2-(6 behind the ring of protonic acid pass, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone (being compound 9), reaction formula is:
On the basis of such scheme, the mol ratio of described 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is 1:1～10.
Concrete, mol ratio can be 1:1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5 or 10.
On the basis of such scheme, the condensation condition of 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is: be incubated under the alkaline condition of pH8～14 in 10～60 ℃ of reactions.
On the basis of such scheme, described alkali is trimethylamine alkali or alkaline earth metal carbonate; Described protonic acid is sulfuric acid or hydrochloric acid or phosphoric acid.
On the basis of such scheme, a kind of preparation method of concrete prasugrel intermediate is provided, with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is the condensation raw material, with methylene dichloride or N, dinethylformamide is a solvent, reacts 1～36 hour in 10 ℃～60 ℃ (preferred 30 ℃～60 ℃) under the alkaline condition of pH8～14; After reaction solution is cooled to-10 ℃～10 ℃, add formaldehyde, stirred 1～24 hour, be adjusted to pH1～4 backs with protonic acid then and continue reaction 0.5～12 hour, (6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone also to obtain intermediate 1-cyclopropyl-2-.
Further, in the preparation method of described prasugrel intermediate, the alkali described in the reaction is trimethylamine alkali or alkaline earth metal carbonate; Protonic acid described in the reaction is sulfuric acid, hydrochloric acid or phosphoric acid.
Method at the synthetic prasugrel of above-mentioned prasugrel intermediate, (6, the 7-dihydro-thiophene is also after [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone oxidation with described intermediate 1-cyclopropyl-2-, obtain prasugrel with the diacetyl oxide esterification again, reaction formula is:
In the method for described synthetic prasugrel, with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is the condensation raw material, with methylene dichloride or N, dinethylformamide is a solvent, reacts 1～36 hour in 10 ℃～60 ℃ (preferred 30 ℃～60 ℃) under the alkaline condition of pH8～14; After reaction solution is cooled to-10 ℃～10 ℃, add formaldehyde, stirred 1～24 hour, be adjusted to pH1～4 backs with protonic acid then and continue reaction 0.5～12 hour, (6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone also to obtain intermediate 1-cyclopropyl-2-.
Further, in the method for synthetic prasugrel, the alkali described in the reaction is trimethylamine alkali or alkaline earth metal carbonate; Protonic acid described in the reaction is sulfuric acid, hydrochloric acid or phosphoric acid.
The invention has the beneficial effects as follows:
The present invention innovates on the basis of original synthetic route 1, described alkali can be trimethylamine alkali or alkaline earth metal carbonate, reduce the two-step reaction that to go up protecting group and deprotection base when preparing compound 5 in the former route 1, simplified step, improved yield;
Intermediate of the present invention is the core intermediate of synthetic prasugrel, by being carried out oxidizing reaction, this intermediate obtains compound 6, further just can obtain prasugrel after the esterification again, and easy to operate, carry out oxidizing reaction with intermediate of the present invention, can obtain 5-[2-cyclopropyl-1-(2-fluoro-phenyl)-2-oxo-ethyl more easily]-5,6,7,7a-tetrahydrochysene-4H-thieno-[3,2-c] pyridin-2-ones (6), the alkali described in the reaction is trimethylamine alkali or alkaline earth metal carbonate.
Embodiment:
Now further specify the present invention by following examples, but and non-limiting scope of the present invention.
The first step: 1-cyclopropyl-2-(2-fluorophenyl)-2-(2-(thiophene-2-yl) ethamine) ethyl ketone synthetic, reaction formula is:
With 2 thiophene ethyl amine (2.3g 18.1mmol) is dissolved in the 80ml methylene dichloride, add salt of wormwood (2.5g, 18.1mmol), at N
2Protection slowly drips 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone (3.82g down; 14.8mmol) dichloromethane solution; dropwise; back flow reaction 6h, after the cooling, water (50ml * 3) washing; tell organic layer; with anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure solvent, obtain the 3.14g light yellow liquid after the column chromatography for separation, productive rate 73%.
1H?NMR(400MHz，CDCl
3)δ：0.72-1.08(4H，m)，1.87(1H，m)，2.75(1H，m)，2.85(1H，m)，3.00(2H，m)，4.95(1H，s)，6.79-7.30(7H，m).ESI(m/z)：304(M+H)
+
Second step: 1-cyclopropyl-2-(6, the 7-dihydro-thiophene is synthesizing of [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone also, and reaction formula is:
(6.0g 19.8mmol) is dissolved in the 50ml methyl alcohol, is chilled to-4 ℃ under stirring with 1-cyclopropyl-2-(2-fluorophenyl)-2-(2-(thiophene-2-yl) ethamine) ethyl ketone.At the uniform velocity slow 38% formaldehyde solution 40.6g.Dropwise stirring reaction 4h under the room temperature of back.TLC tracks to raw material and disappears.Revolve to steam and remove methyl alcohol, residuum dissolves with methylene dichloride, washing, anhydrous sodium sulfate drying, suction filtration, removal of solvent under reduced pressure, a pale brown look oily matter, use DMF (60ml) dissolving then after, add the concentrated hydrochloric acid of 2ml, TLC tracks to raw material and disappears.Stopped reaction, about concentrating under reduced pressure solvent to 1/4, cooling, suction filtration, filter cake are dried after with washed with dichloromethane, the 4.7g light yellow solid, productive rate 75%.
1H?NMR(400MHz，CDCl
3)δ：0.86(2H，m)，1.00-1.08(2H，m)，2.29(1H，m)，2.77，2.90(2H，m)，2.92(2H，s)，3.57-3.68(2H，m)，4.84(1H，s)，6.67(1H，d)，7.05(1H，d)，7.09-7.51(4H，m)。
The 3rd step: 5-[2-cyclopropyl-1-(2-fluoro-phenyl)-2-oxo-ethyl]-5,6,7,7a-tetrahydrochysene-4H-thieno-[3,2-c] pyridin-2-ones synthetic, reaction formula is:
With 1-cyclopropyl-2-(6, the 7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone (0.1g 0.32mmol) is dissolved in the methyl alcohol of 20ml, adds CuSO
45H
2O (0.12g, 0.48mmol), the sulfuric acid of 1N (0.8ml 0.8mmol), is cooled to 0 ℃, drip 30% hydrogen peroxide (0.22g, 6.4mmol), rise to room temperature after, stirring reaction 24h, TLC follows the tracks of reaction process.Raw material reaction finishes behind the 24h, stopped reaction, and the evaporated under reduced pressure solvent obtains the 80mg light yellow liquid after the column chromatography for separation, productive rate 75%.
1H?NMR(400MHz，CDCl
3)δ：0.82-0.90(2H，m)，1.04-1.06(2H，m)，1.87-1.96(1H，m)，2.09-2.11(1H，m)，2.32-2.53(2H，m)，2.84-3.09(2H，m)，3.90-4.11(2H，m)，4.85-4.89(1H，m)，5.30(1H，s)，6.03-6.05(1H，m)，7.14-7.38(4H，m).
The 4th step: obtain prasugrel through the diacetyl oxide esterification.
Claims (9)
1, a kind of synthetic method of prasugrel intermediate, by 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine condensation under the effect of alkali, then with formaldehyde reaction after, with obtaining intermediate 1-cyclopropyl-2-(6 behind the ring of protonic acid pass, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone, reaction formula is:
2, the preparation method of prasugrel intermediate according to claim 1 is characterized in that: the mol ratio of described 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is 1:1～10.
3, the preparation method of prasugrel intermediate according to claim 1 and 2 is characterized in that: the condensation condition of 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is: be incubated under the alkaline condition of pH8～14 in 10～60 ℃ of reactions.
4, the preparation method of prasugrel intermediate according to claim 3 is characterized in that: described alkali is trimethylamine alkali or alkaline earth metal carbonate.
5, the preparation method of prasugrel intermediate according to claim 1 and 2 is characterized in that: described protonic acid is sulfuric acid or hydrochloric acid or phosphoric acid.
6, the preparation method of prasugrel intermediate according to claim 1 and 2, it is characterized in that: with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and 2 thiophene ethyl amine is the condensation raw material, with methylene dichloride or N, dinethylformamide is a solvent, reacts 1～36 hour in 10 ℃～60 ℃ under the alkaline condition of pH8～14; After reaction solution is cooled to-10 ℃～10 ℃, add formaldehyde, stirred 1～24 hour, be adjusted to pH1～4 backs with protonic acid then and continue reaction 0.5～12 hour, (6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone also to obtain intermediate 1-cyclopropyl-2-.
7, the preparation method of prasugrel intermediate according to claim 6 is characterized in that: described alkali is trimethylamine alkali or alkaline earth metal carbonate.
8, the preparation method of prasugrel intermediate according to claim 6 is characterized in that: described protonic acid is sulfuric acid or hydrochloric acid or phosphoric acid.
9, utilize the method for the synthetic prasugrel of the described prasugrel intermediate of one of claim 1 to 8, with described intermediate 1-cyclopropyl-2-(6, the 7-dihydro-thiophene also after [3,2-c] pyridines-5 (4H)-yl)-2-(2-fluorophenyl) ethyl ketone oxidation, obtains prasugrel with the diacetyl oxide esterification again.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042918A3 (en) * | 2009-10-07 | 2011-06-03 | Msn Laboratories Limited | Improved processes for preparing prasugrel and pharmaceutically acceptable salts thereof |
| WO2012052788A1 (en) | 2010-10-22 | 2012-04-26 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Method for preparing pharmaceutically active ingredient and intermediates thereof |
| CN102731574A (en) * | 2011-03-30 | 2012-10-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof |
| CN103923101A (en) * | 2014-04-29 | 2014-07-16 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
| WO2014114964A2 (en) | 2013-01-24 | 2014-07-31 | Egis Pharmaceuticals Public Limited Company | Improved process for the preparation of prasugrel and intermediate thereof |
-
2009
- 2009-04-16 CN CN200910049455A patent/CN101531667A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042918A3 (en) * | 2009-10-07 | 2011-06-03 | Msn Laboratories Limited | Improved processes for preparing prasugrel and pharmaceutically acceptable salts thereof |
| WO2012052788A1 (en) | 2010-10-22 | 2012-04-26 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Method for preparing pharmaceutically active ingredient and intermediates thereof |
| CN102731574A (en) * | 2011-03-30 | 2012-10-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof |
| CN102731574B (en) * | 2011-03-30 | 2016-03-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Thienopyridines α-amido benzyl phosphonic acid ester, Preparation Method And The Use |
| WO2014114964A2 (en) | 2013-01-24 | 2014-07-31 | Egis Pharmaceuticals Public Limited Company | Improved process for the preparation of prasugrel and intermediate thereof |
| CN103923101A (en) * | 2014-04-29 | 2014-07-16 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
| CN103923101B (en) * | 2014-04-29 | 2017-05-03 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
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Open date: 20090916 |