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Method for preparing 2-methoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothiophene [3,2-c] pyridine

A technology of cyclopropylcarbonyl and tetrahydrothiophene, which is applied in the direction of organic chemistry, can solve the problems of unsuitability for large-scale industrial production, and achieve the effects of being suitable for large-scale industrial production, mild reaction conditions, and outstanding yield

Inactive Publication Date: 2008-08-27
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the existing method for preparing 2-methoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Not suitable for large-scale industrial production, it is prepared by the above-mentioned compound (3), and the preparation method of compound (3) is also the target product obtained by the reaction of compound (1) and compound (2)

Method used

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  • Method for preparing 2-methoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothiophene [3,2-c] pyridine
  • Method for preparing 2-methoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothiophene [3,2-c] pyridine
  • Method for preparing 2-methoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothiophene [3,2-c] pyridine

Examples

Experimental program
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Effect test

Embodiment 1～2

[0035] Preparation of 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula III):

[0036] 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (7.0g), potassium carbonate (7.2g) and acetonitrile (50ml) were mixed, benzyl chloride (6.1g) was added, stirred for 0.5 After 3 hours it was refluxed for 3 hours. Cool, filter, concentrate the filtrate to dryness, add ethyl acetate (30ml) and water (50ml), separate the layers, extract the aqueous layer with ethyl acetate (30ml×2), combine the organic layers, wash with water, dry, and concentrate to dryness to obtain 8.3 g of the title compound 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, yield 90.8%.

[0037] 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (18.0g), potassium carbonate (18.6g), benzyl chloride (15.0g), sodium iodide (0.8g) in DMF ( 100ml) was stirred for 0.5 hours, then reacted at 80°C for 3 hours, cooled, added water (150ml) and ethyl acetate (100ml), separated, and the aqueous layer was extracted with ethyl acetate (50ml×2). ...

Embodiment 3

[0039] Preparation of 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula IV):

[0040] The compound (23.2g) obtained in Example 2 was dissolved in acetic acid (100.0ml), 40% hydrobromic acid (75.0ml), methanol (100ml), and the methanol of 30% hydrogen peroxide (33.0ml) was added dropwise under ice-water bath cooling (100ml) solution, stirred at room temperature for 3 hours. Sodium thiosulfate solution (150ml) was added dropwise, then saturated sodium carbonate solution was added dropwise until the pH was 9, extracted with dichloromethane (100ml×3), the organic layers were combined, washed with water, dried, and concentrated to dryness to obtain 30.5g of light yellow solid , yield 97.8%.

Embodiment 4～6

[0042] Preparation of 2-methoxy-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula V):

[0043]Dissolve sodium (0.43g) in methanol (20ml), add 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.88g), bromide Cuprous (0.17g), stirred and refluxed for 12 hours. Cool, filter, concentrate the filtrate to dryness, add ethyl acetate (30ml) and water (50ml), separate the layers, extract the aqueous layer with ethyl acetate (30ml×2), combine the organic layers, wash with water, dry, and concentrate to dryness to obtain 3.3 g of oily matter was separated by column to obtain 1.3 g of the title compound, with a yield of 39.8%.

[0044] Dissolve sodium (5.6g) in methanol (120ml), concentrate to dryness, add tetrahydrofuran (100ml), 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c ] Pyridine (7.5g), cuprous bromide (0.34g) and sodium iodide (0.15g), stirred and refluxed for 24 hours. Cool, filter and wash with ethyl acetate, concentrate the filtrate to dryness, add ethyl ...

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Abstract

The invention discloses a new preparation method of 2-methoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4, 5, 6, 7-tetrahydrothiophene [3, 2-c] pyridine, which only needs to one step that condenses 2-methoxy-4, 5, 6, 7-tetrahydrothiophene [3, 2-c] pyridine and alpha-halogenated p-fluorine benzyl cyclopropyl ketone to obtain targe product, with mild reaction conditions, non low temperature demand, non explosive material, high yield, low cost and high efficiency. The invention is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method technology of 2-methoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine field. Background technique [0002] Thrombosis can cause ischemia and infarction of major organs, and can also cause edema and venous insufficiency, thereby causing various dysfunctions. Representative antithrombotic drugs currently in clinical use are clopidogrel, aspirin, and asimumab. The effect of clopidogrel is stronger than that of aspirin and has less side effects. It is clinically used to treat atherosclerosis, acute coronary syndrome, and prevent in-stent restenosis and thrombotic complications after coronary stent implantation. Prasugrel is a tetrahydrothienopyridine compound similar to clopidogrel. It has shown better activity, tolerance and safety than clopidogrel in the third phase of clinical trials, and it is expected to become a good antithrombotic drug. [0003] Chinese patent 921115...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 吴雪松岑均达郭珩
Owner SHANGHAI INST OF PHARMA IND CO LTD
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