Synthetic method of fotemustine bulk drug

A synthesis method and fomustine technology, applied in the field of medicinal chemistry, can solve the problems of restricting domestic manufacturers' technological development and production, difficulty in domestic purchase of raw materials, and high production costs, and achieve simple production steps, good product quality, and simple control. Effect

Inactive Publication Date: 2012-01-11
SHANDONG RUIYING PIONEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the high price of the raw material, the production cost is high; and the domestic purchase of the raw material is difficult, which restricts the technology development and production of domestic manufacturers

Method used

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  • Synthetic method of fotemustine bulk drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The synthetic method of formustine specifically adopts the following steps:

[0029] (1) Synthesis of compound (II):

[0030] 73.2g (0.44mol) of triethyl phosphite was added to a 250mL dry reaction flask, 31.4g (0.40mol) of acetyl chloride was added dropwise, and the reaction was stirred at room temperature for 12h. Distilled under reduced pressure and collected fractions at 80-84°C / 3mmHg to obtain 58.4g of compound (II) with a yield of 81%.

[0031] (2) Synthesis of compound (Ⅲ):

[0032] In a 500mL reaction bottle, add 32g of hydroxylamine hydrochloride and 70mL of water. Add sodium hydroxide solution (18.2g sodium hydroxide dissolved in 50mL water) dropwise under stirring, control the temperature between 20~25°C, add 56g compound (II) dropwise, and stir at room temperature for 12h. The reaction mixture was extracted with 100 mL×3 dichloromethane, and the organic layer was collected and dried by adding anhydrous magnesium sulfate. After filtration, the solvent was...

Embodiment 2

[0040] The synthetic method of formustine specifically adopts the following steps:

[0041] (1) Synthesis of compound (II):

[0042] Add 73.2g (0.44mol) of triethyl phosphite to a 250mL dry reaction flask, control the temperature between 20 and 30°C, and add 31.4g (0.40mol) of acetyl chloride dropwise. The temperature was maintained and the reaction was stirred for 12h. Distilled under reduced pressure to remove the lower boiling fraction (<40°C) to obtain 78 g of colorless liquid, which is the crude product of compound (II).

[0043] (2) Synthesis of compound (Ⅲ):

[0044] In a 500mL reaction flask, add 32g of hydroxylamine hydrochloride and 125mL of water. Control the temperature between -10 and 0°C, add 37g of sodium bicarbonate in batches, and then dropwise to obtain 78g of crude compound (II) as a colorless liquid, and stir and react at room temperature for 24h. The reaction mixture was extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed ...

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Abstract

The invention belongs to the field of medical chemistry, and especially discloses a synthetic method of a fotemustine bulk drug. The synthetic method uses triethyl phosphite (I) as an initial raw material to obtain a compound (II) through an acetylation reaction; an oximation reaction is carried on the compound (II) and hydrochloric acid hydroxylamine to obtain a compound (III), which is reduced to obtain a compound (IV); the compound (IV) reacts with 2-chloroethyl isocyanate to generate a compound (V), which is directly treated with nitrosation, without separation, to obtain an objective product (VI). The invention has advantages of a mature, stable and simply controlled technology, simple production steps, good product quality, high yield, cheap and easily available raw material and mild reaction conditions.

Description

(1) Technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing a formustine bulk drug. (2) Background technology [0002] Formustine is an anti-mitotic cell inhibitor of nitrosoureas, which has alkylation and carbamylation effects, and animal experiments have shown that it has broad-spectrum anti-tumor activity. Its chemical structure contains an alanine bioisolate (1-aminoethyl phosphate) that readily penetrates cells and crosses the blood-brain barrier. After intravenous infusion in human body, its plasma clearance rate changes dynamically according to single or power of two, and its half-life is very short. Almost all of its molecules are decomposed by metabolism, and the plasma protein binding rate is low (25~30%). In the first-line chemotherapy, this product can improve the tolerance of blood. The leukocytes of patients who have not received chemotherapy before decreased by 40.4%, and those who have...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 王辉赵作正杨林青郭彩云
Owner SHANDONG RUIYING PIONEER PHARMA
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