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Industrialization production process of entecavir-monohydrate

A technology of entecavir and production process, applied in the field of organic synthetic drugs, can solve problems such as being unsuitable for industrial production, the method is not simple enough, and achieve the effects of reduced synthesis cost, low cost and easy preparation

Active Publication Date: 2009-09-16
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In order to overcome the technical problems existing in the existing entecavir-hydrate industrial production process, the products in the production process must be separated, it is not suitable for industrial production, and the method is not simple enough. The present invention discloses a simple production process. , an industrialized production process that does not require process separation for each production process product

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1, the preparation of methyl diphenylchlorosilane:

[0045] In a 500ml four-necked bottle, add 50ml of THF dried with sodium in advance, 16.7g (0.687mol) of magnesium chips, 5ml of chlorobenzene, one grain of iodine is added to trigger, the temperature rises to 70°C, and 200ml of THF solution of 65ml of chlorobenzene is added dropwise , keep slightly boiling, after addition, reflux reaction for 6 hours, after completion of reaction, seal and store for later use.

[0046] Add 400ml of THF, 3g of cuprous cyanide, 133g (0.695mol) of methylphenyldichlorosilane into another 1000ml four-necked bottle, raise the temperature to 50°C, add the above-mentioned Grignard solution dropwise at this temperature, and complete the addition. Insulate and react for 3 hours, add 200ml of n-hexane, stir for 30 minutes, filter, concentrate the filtrate under reduced pressure, collect about 112g of 128-133°C / 670pa fraction, and the yield is about 70%.

Embodiment 2

[0047] The preparation of embodiment 2, ent-1A:

[0048] In a 500ml four-necked bottle, add 100ml of THF dried with sodium in advance, 20.5g (0.088mol) of methyldiphenylchlorosilane, blow nitrogen, cool to -40°C, and dissolve 44ml (0.088mol) of cyclopentadiene sodium solution (2M inTHF) was fully dissolved with 60ml THF, and 1ml of catalyst was added, and stirred evenly.

[0049] Under the protection of nitrogen, add cyclopentadiene sodium solution dropwise for about two hours, keep warm for 2 hours, stop refrigeration, let the reaction solution gradually warm up to 0°C, carefully add 80ml of water, stir for 30 minutes, separate layers, and use 50ml× Wash twice with 2 water, dry over anhydrous sodium sulfate for 2 hours, filter, and concentrate to dryness under reduced pressure at 50°C to obtain about 22.5 g of dark red oil ent-1A

Embodiment 3

[0050] Embodiment 3, the preparation of ent-1B:

[0051]In a 500ml dry four-neck flask, add 22.5g (0.0857mol) of ent-1A, 200ml of n-hexane, lower the temperature to -10°C under the protection of nitrogen, add 25.3g (0.171mol) of dichloroacetyl chloride dropwise, after the addition is complete, stir In 30 minutes, 17.3 g (0.171 mol) of triethylamine was added dropwise, and the addition was completed in 90 minutes. The reaction solution was slowly raised to room temperature, and stirred at room temperature for 12 hours. Wash once with 50ml of sodium solution, wash twice with 50ml×2 water, dry over anhydrous sodium sulfate for 2 hours, filter, and concentrate to dryness at 50°C to obtain about 32g of dark red oil ent-1B

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Abstract

The invention provides an industrialization production process of entecavir-monohydrate. The special features of the process different from the other process are that: methyldiphenylchlorosilane is used as the silanization protector and special catalyst, thus the reaction temperature is -40 DEG C and the object product is smoothly produced (the reaction temperature is -78 DEG C in the prior process). Thus the production process is more suitable for industry production and because the silanization protector is cheaper and easily obtained, the production cost is greatly reduced. The invention comprises the preparation of methyldiphenylchlorosilane as the silanization protector which is obtained by directly synthesizing the methylphenyldichlorosilane and Grignard reagent of chlorobenzene under the action of special catalyst.

Description

Technical field: [0001] The invention belongs to the field of organic synthetic medicines, in particular to a synthesis process of entecavir monohydrate. technical background: [0002] Entecavir monohydrate is an anti-hepatitis B virus drug developed by Bristol Myers Squibb Company of the United States. It was first launched in the United States in 2005. It is clinically used to treat adult patients with active virus replication, continuous elevation of serum transaminase (ALT or AST) or liver tissue Chronic hepatitis B with active disease. This product is a 2'-deoxyguanine carbocyclic analog, which can inhibit the initiation and elongation steps in the viral DNA replication process by inhibiting the hepatitis B virus DNA polymerase. [0003] Its molecular formula: C 12 h 15 N 5 o 3 ·H 2 O Its chemical name is: 2-amino-9-[(1S,3R,4S)4-hydroxyl-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purine 1-6-ketone monohydrate. English name: [0004] 2-Amino-1, 9-dihy...

Claims

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Application Information

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IPC IPC(8): C07D473/18B01J31/02C07F7/12B01J27/122B01J27/26
Inventor 曾运才王志邦高达孙徐志全
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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