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ChemicalBook CAS DataBase List 5-Fluorocytosine
2022-85-7

5-Fluorocytosine synthesis

6synthesis methods
Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino- 2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine.

An alternative way of synthesis consists of making flucytosine from a precursor of fluorouracil—5-fluoro-2-methylthiouracil (30.1.3.2) using a somewhat analogous scheme. Treating 5-fluoro-2-methylthiouracil (30.1.3.2) with phosphorous pentachloride gives 4-chloro-5-fluoro-2-methylthiopyrimidine (35.4.5), which upon being reacted with ammonium is transformed into 4-amino-5-fluoro-2-methylthiopyrimidine (35.4.6). Hydrolysis of the methylthiovinyl fragment using concentrated hydrobromic acid gives the desired flucytosine.
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Yield:2022-85-7 98.1%

Reaction Conditions:

with ammonia in hydrogenchloride;ethanol;water;

Steps:

4 Preparation of 5-fluorocytosine from 2,5-difluoro-4-chloropyrimidine

EXAMPLE 4 Preparation of 5-fluorocytosine from 2,5-difluoro-4-chloropyrimidine 15.05 g (0.1 mole) of 2,5-difluoro-4-chloropyrimidine were stirred in 30 ml of 37% strength aqueous hydrochloric acid at 50° C. for 2 hours. After the mixture had cooled, it was neutralized with 33% strength aqueous ammonia solution. The mixture was then diluted with 100 ml of ethanol and a further 20 ml of aqueous 33% strength ammonia solution were added. The mixture was subsequently stirred at room temperature for 2 hours. Thereafter, it was concentrated in vacuo, the residue was taken up in 60 ml of water and the solid obtained was filtered off with suction, washed with water and dried. 11.5 g of product with a melting point of 294° to 296° C. were obtained, corresponding to a yield of 98.1% of theory.

References:

US4703121,1987,A

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