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Method for preparing prasugrel intermediate

A technology for intermediates and compounds, applied in the field of organic chemistry, can solve problems such as being unsuitable for industrial production requirements, difficult to obtain raw materials, and expensive, and achieve the effects of significant industrial application value, easy large-scale production, and low production costs.

Inactive Publication Date: 2016-01-27
重庆瑞泊莱制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because trimethylsilylnitrile and 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one are used in this method, not only raw materials are difficult to obtain, but also expensive, so that The cost is high, so it is not suitable for industrial production requirements

Method used

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  • Method for preparing prasugrel intermediate
  • Method for preparing prasugrel intermediate
  • Method for preparing prasugrel intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of compound 3

[0042]

[0043] Dissolve 35.7g (0.189mol) of compound 1 and 20g (0.157mol) of compound 2 in 100mL of tetrahydrofuran, add 20g (0.189mol) of sodium carbonate, and stir at room temperature for 2 hours; the reaction is complete, filter, and wash the filtrate with saturated saline , liquid separation, extract the aqueous phase with 20mL ethyl acetate, separate the liquid, combine the organic phases, dry with 10g of anhydrous sodium sulfate, filter, and distill under reduced pressure at 40°C. After the distillation is completed, 33.2g of yellow oily compound 3 is obtained, with a purity of 98.4 %, yield 89.7%.

[0044] 1 H-NMR (CDCl 3 ; TMS): δ: 2.33 ~ 2.67 (m, 4H, CH 2 CH 2 ), 3.81~3.93 (m, 2H, CH 2 ), 6.68~7.22 (m, 7H).

[0045] MS (ESI, m / z): 236 [M+H] + .

Embodiment 2

[0046] Embodiment 2: the synthesis of compound 4

[0047]

[0048] Dissolve 30g (0.121mol) of compound 3 in 150mL of methanol, add 4g (0.133mol) of paraformaldehyde, stir at room temperature until the reaction is complete (about 5 hours), add 10mL of concentrated hydrochloric acid, when TLC traces that the starting point disappears, stop Reaction, remove methanol by rotary evaporation, dissolve the residue with 150mL dichloromethane, wash with water, separate liquids, dry the organic phase with anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure, evaporate, stir with 90mL methyl tert-butyl ether, filter , air-dried at 40° C. to constant weight to obtain 22.5 g of off-white solid compound 4 with a purity of 98.6% and a yield of 71.4%.

[0049] 1 HNMR (CDCl 3 ; TMS): δ: 2.58 ~ 2.64 (m, 4H, CH 2 CH 2 ), 3.52~3.59 (m, 2H, CH 2 ), 3.61~3.72 (m, 2H, CH 2 ), 6.33(s, 1H, CH), 6.46(s, 1H, CH), 7.12~7.52(m, 4H, ArH);

[0050] MS (ESI, m / z): 248 [M+H] ...

Embodiment 3

[0051] Embodiment 3: the synthesis of compound 5

[0052]

[0053]Dissolve 20g (0.081mol) of compound 4 in 100mL of methanol, add 9.8g (0.097mol) of triethylamine at the same time, cool down to 0-10°C, add dropwise a mixed solution of 12.9g (0.081mol) of bromine and 20mL of methanol, After dropping, react at room temperature for 2 hours. When TLC traces no raw material point, add 10% sodium thiosulfate aqueous solution dropwise, extract with 3×50mL dichloromethane, combine the organic phases, wash with 50mL water, separate the layers, and use Dry over sodium sulfate, filter, and distill the filtrate under reduced pressure to obtain a yellow oil, which is crystallized by stirring with 60 mL of methyl tert-butyl ether, filter, and air-dried at 40°C to obtain 19.3 g of compound 5 as a yellow solid, with a purity of 96.3%, yield 73.1%.

[0054] 1 HNMR (CDCl 3 ; TMS): δ: 2.42~2.61 (m, 4H, CH 2 CH 2 ), 3.58 (m, 2H, CH 2 ) 5.72 (s, 1H, CH), 6.19 (s, H, CH), 6.24 (s, H, CH), ...

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PUM

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Abstract

The invention discloses a method for preparing a prasugrel intermediate 5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-1,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. The method comprises a following reaction route. As a result of experiments, the method provided by the invention has the advantages of simple operation, mild reaction conditions, low requirement on equipment, inexpensive and easy-to-obtain raw materials, high yield, and low production cost. An adopted solvent can synchronously recovered. The method can be easily applied in large-scale productions. The method meets the requirements of prasugrel industrialized production, and has industrial application value.

Description

technical field [0001] The present invention relates to a method for preparing prasugrel intermediates, specifically, the key intermediate for preparing prasugrel: 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-1, A preparation method of 4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine belongs to the technical field of organic chemistry. Background technique [0002] Antiplatelet medicines are used to prevent platelets from clumping together, or sticking together, as platelets clog up in the arteries and can lead to heart attack or stroke. Prasugrel is an oral antiplatelet drug jointly developed by Eli Lilly and Daiichi Pharmaceutical Sankyo. The mechanism of action is to inhibit platelet activation and concurrent aggregation by blocking the P2Y12 adenosine diphosphate receptor on the platelet surface. It was released in 2009 It was approved for marketing in the European Union on February 27 and started selling in the UK. Due to its good tolerance and safety, it is expected to be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 高河勇陈琳钟齐昌
Owner 重庆瑞泊莱制药有限公司
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