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Medicine midbody and preparation method thereof

An intermediate and pharmaceutical technology, applied in the field of pharmaceutical intermediates and their preparation, can solve the problems of large-scale production danger, harsh reaction conditions, flammability and explosion of n-butyllithium, etc. Excellent yield and mild reaction conditions

Inactive Publication Date: 2008-08-20
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction conditions are relatively harsh, requiring a low temperature of -40°C. At the same time, n-butyllithium is flammable and explosive, which will bring danger to large-scale production.

Method used

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  • Medicine midbody and preparation method thereof
  • Medicine midbody and preparation method thereof
  • Medicine midbody and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～2

[0033] Preparation of 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula III):

[0034] 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%.

[0035] 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

[0037] Preparation of 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula IV):

[0038] 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

[0040] Preparation of 2-methoxy-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (formula V):

[0041] 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%.

[0042] 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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PUM

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Abstract

The invention discloses a new intermediate of Prasugrel, the structural formula of which is shown as the Fig; wherein, R represents alkyl. The invention can succinctly prepare a new intermediate of Prasugrel by utilizing existing industrial raw materials; the preparation of the Prasugrel by adopting the intermediate has mild reaction condition and prominent yield, but does not need low temperature and the adoption of flammable and combustible raw materials, thus being suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of a pharmaceutical intermediate and a preparation method thereof. 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 aspirin, clopidogrel, 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. The chemical name of prasugrel is: 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 吴雪松岑均达郭珩邓韧
Owner SHANGHAI INST OF PHARMA IND
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