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Preparation method of 5-flucytosine

A technology of flucytosine and cytosine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of highly toxic fluorine gas production operations and production equipment, environmental and operator injuries, unfavorable industrial production, etc., to achieve low cost and avoid Corrosiveness, the effect of product quality stability

Active Publication Date: 2014-05-28
ZHEJIANG XIANFENG TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In view of the above-mentioned problems existing in the prior art, the object of the present invention is to provide a chemical preparation method of 5-fluorocytosine to solve the problem of high product cost, unstable quality or the use of highly corrosive and highly toxic fluorine in the prior art. Gas has extremely high requirements on production operations and production equipment, which may cause great harm to the environment and operators, poor production safety, and is not conducive to industrial production.

Method used

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  • Preparation method of 5-flucytosine
  • Preparation method of 5-flucytosine

Examples

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Embodiment 1

[0023] Embodiment 1: Preparation of 5-bromocytosine

[0024] Suspend cytosine (55.6g, 0.5mol) in 120mL of acetic acid, slowly add a mixed solution of liquid bromine (87.9g, 0.55mol) and 80mL of acetic acid dropwise at room temperature, track by TLC until the reaction of cytosine is complete, and cool in an ice-water bath to 10 ℃, filtered, and the filter cake was washed successively with 20 mL of acetic acid and 20 mL of water, and dried to obtain 5-bromocytosine (89.7 g, 94.3%).

[0025] In this embodiment, the halogenating reagent uses chlorine gas, iodine, N - Chlorosuccinimide, N -Bromosuccinimide, N -Iodosuccinimide, tetrabutylammonium tribromide, tetrabromocyclic ketone, copper bromide or a mixture of several of them instead of liquid bromine; organic solvents use carbon tetrachloride, chloroform, dichloromethane , 1,2-dichloroethane, toluene, xylene, DMF, DMSO, acetonitrile, ethyl acetate, ethanol or a mixture of several of them instead of acetic acid can achieve sim...

Embodiment 2

[0026] Example 2: N - Preparation of acetyl-5-bromocytosine

[0027] Add 5-bromocytosine (95g, 0.5 mol) and acetic anhydride (306.3g, 3mol) into the reaction flask, raise the temperature to 70°C for 4 hours, distill off the solvent under reduced pressure, add 200mL of methanol, raise the temperature to reflux for 30min, and cool to room temperature , filtered, the filter cake was washed with 30mL of methanol, and dried to obtain N - Acetyl-5-bromocytosine (114.3 g, 98.5%).

Embodiment 3

[0028] Example 3: Preparation of 5-fluorocytosine

[0029] Will N -Acetyl-5-bromocytosine (69.6g, 0.3 mol) was put into a dry reaction flask, anhydrous potassium fluoride (23.2g, 0.4mol), acetamide (29.5g, 0.5mol), DMF150mL, heat up to 130°C to react for 5h, evaporate the solvent under reduced pressure, add 150 mL of ammonia methanol after cooling to 40°C and keep the reaction for 12h, trace by TLC until the reaction of intermediate (Ⅲ) is complete, evaporate methanol under reduced pressure, add 400 mL of water Heated until dissolved, cooled to 10°C, filtered, and dried to obtain 5-fluorocytosine (36 g, 93%) as a white crystalline solid, with an HPLC content of 99.5%.

[0030] In this embodiment, sodium fluoride, cesium fluoride, lithium fluoride, antimony trifluoride, antimony pentafluoride, mercury fluoride, silver fluoride, copper fluoride, cobalt fluoride, cerium fluoride , pyridinium hydrogen fluoride, tetrabutylammonium fluoride, tetramethylammonium fluoride or carrier...

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Abstract

The invention discloses a preparation method of 5-flucytosine. The method comprises the following steps of: 1) cytosine and a halogenating reagent perform halogenating reaction in an organic solvent at 0-80 DEG C to prepare an intermediate (I), 2) the intermediate (I) reacts with an amino protecting agent at 0-120 DEG C to prepare an intermediate (II), and 3) the intermediate (II) and a fluoro reagent perform fluoro reaction in a polar aprotic solvent or hydrogen fluoride at 70-200 DEG C to prepare an intermediate (III), and the intermediate (III) directly performs amino deprotecting reaction, and is separated and purified to prepare 5-flucytosine. According to the method, a process route is reasonable, the product yield is high, the quality is good, the production safety of the fluoro reagent is high, and the method is simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of an antifungal drug or a pharmaceutical intermediate 5-fluorocytosine, which is used to prepare the antitumor drug capecitabine and the antiviral drug emtricitabine coast. Background technique [0002] 5-Fluorocytosine is a chemically synthesized antifungal drug, which has high antifungal activity against Cryptococcus and Candida, and is used as the first choice drug for the treatment of severe systemic Candida albicans and cryptococcal infections in foreign countries "United States Pharmacopoeia" (Nineteenth Edition), for the treatment of fungal meningitis, fungal respiratory tract infection and black mycosis. At the same time, 5-fluorocytosine is also an important intermediate for the preparation of antitumor drug capecitabine and antiviral drug emtricitabine. [0003] In the prior art, the preparation method of 5-fl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47Y02P20/55
Inventor 陈小平姚福友卢娓肖木杰高飞飞
Owner ZHEJIANG XIANFENG TECH
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