Preparation method of benzodiazothioketone serving as intermediate of alprazolam

A technology of alprazolam and heterothione, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of unfavorable industrial production product quality, large dosage, expensive sodium iodide, etc. The effect of production costs

Active Publication Date: 2014-11-05
河南豫辰药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In "Synthesis of the sedative and hypnotic drug methyltriazolam", p-chloronitrobenzene was used as the main raw material, and benzodiazepinethione was synthesized in five steps, and alprazolam was synthesized in six steps, but the cyclization reaction used Expensive sodium iodide is used in a large amount, and the reaction condition is reflux; benzodiazepinethione is obtained as a crude product in the vulcanization reaction, which is not refined, and only the melting point is detected, which will have a certain impact on the next step of synthesis.
These are not conducive to industrial production and improve product quality

Method used

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  • Preparation method of benzodiazothioketone serving as intermediate of alprazolam
  • Preparation method of benzodiazothioketone serving as intermediate of alprazolam
  • Preparation method of benzodiazothioketone serving as intermediate of alprazolam

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] A kind of preparation method of alprazolam intermediate benzodiazepine thione,

[0019]

[0020] Specific steps are as follows:

[0021] 1. Acylation reaction

[0022] In the reaction flask, add 2-amino-5-chloro-benzophenone (M 2 ) 250g (1.08mol), cyclohexane 1750g, stirred and heated to 60°C, 160g (1.36mol) of chloroacetyl chloride was added dropwise, then heated to 81°C, refluxed for 4h (hydrogen chloride was released during the reaction). After the reaction was completed, it was cooled to 10°C, and light yellow crystals were precipitated. Filter and dry to obtain light yellow crystal M 3 320g, yield 95%, HPLC content>98%, mp117~119℃.

[0023] 2. Cyclization reaction

[0024] Add M to the reaction vial 3 320g (1.03mol), 3200g absolute ethanol, 260g urotropine (that is, hexamethylenetetramine), heat and stir to 50°C, add 142g (1.80mol) of ammonium bicarbonate, ammonium bicarbonate in 3 hours Average added. Reacted at 40°C for 6 hours, followed by HPLC until ...

Embodiment 2

[0030] A kind of preparation method of alprazolam intermediate benzodiazepine thione, comprises the steps:

[0031] 1. Acylation reaction

[0032] In the reaction flask, add 2-amino-5-chloro-benzophenone (M 2 ) 250g (1.08mol), cyclohexane 1750g, stirred and heated to 59°C, 160g (1.36mol) of chloroacetyl chloride was added dropwise, then heated to 70°C, and reacted for 6h (hydrogen chloride was released during the reaction). After the reaction was completed, the material was discharged while it was hot, cooled to 10°C, and light yellow crystals were precipitated. Filter and dry to obtain light yellow crystal M 3 305g, yield 91%, HPLC content > 98%. mp117~119℃.

[0033] 2. Cyclization reaction

[0034] Add M to the reaction vial 3 305g (0.98mol), 3050g absolute ethanol, 190g urotropine, heated and stirred to 60°C, added 237g (3mol) of ammonium bicarbonate, and the ammonium bicarbonate was added evenly within 3 hours. React at 60°C for 5 hours, and track and detect by HPLC...

Embodiment 3

[0040] A kind of preparation method of alprazolam intermediate benzodiazepine thione, comprises the steps:

[0041] 1. Acylation reaction

[0042] In the reaction flask, add 2-amino-5-chloro-benzophenone (M 2 ) 250g (1.08mol), cyclohexane 1750g, stirred and heated to 61°C, 160g (1.36mol) of chloroacetyl chloride was added dropwise, then heated to 70°C, and reacted for 6h (hydrogen chloride was released during the reaction). After the reaction was completed, the material was discharged while it was hot, cooled to 10°C, and light yellow crystals were precipitated. Filter and dry to obtain light yellow crystal M 3 320g, yield 91%, HPLC content>98%, mp117~119℃.

[0043] 2. Cyclization reaction

[0044] Add M to the reaction vial 3320g (1.03mol), 3200g absolute ethanol, 260g urotropine, heated and stirred to 60°C, and 166g (2.1mol) of ammonium bicarbonate was added several times. Reacted at 80°C for 4 hours, followed by HPLC detection until the reaction of the raw materials w...

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Abstract

The invention relates to a preparation method of benzodiazothioketone serving as an intermediate of alprazolam. The preparation method comprises the following steps: performing a typical acylation reaction, a cyclization reaction and a vulcanization reaction on 2-amino-5-chloro-benzophenone (M2) serving as a raw material to obtain a benzodiazothioketone crude product (the HPLC (High Performance Liquid Chromatography) content is about 94 percent); and recrystallizing the crude product in a mixed solvent at the normal temperature to obtain a fine product of which the HPLC content is over 98.5 percent, wherein the melting point of the fine product is 238-242 DEG C (the melting range is below 3 DEG C). The preparation method has the advantages of small number of synthesis steps, mild process condition, easiness in controlling a refining method, high yield, high fine product content, controllable low production cost, reduction in environmental pollution, and contribution to industrialization.

Description

Technical field [0001] The present invention is a preparation technology field for pharmaceutical intermediates, and it involves a preparation method of Aprzolehon intermediate benzene and dietary aldosterone. Background technique [0002] Apzolun, commonly known as methyltamazole, is a central nervous system drug listed in the United States in 1981. This drug is often used to treat psychiatric neurosis such as insomnia, anxiety, and depression.Due to a metabolic and stable triazole ring, its physiological activity is stronger than that of normal benzene and two nitrogen-oriented drugs. The sedative and hypnotic effects are stable 25-30 times and 3.5-11 times, respectively.It also has obvious anti -epilepsy and antidepressants. [0003] Azhenyl two nitrogen ketones, chemical names 7-chloro-5-benzene-1, 4-benzene and two nitrogen-2-sulberry, which is a key intermediate to prepare Aprzoleon.Regarding the synthesis of benzene combined nitrogen, "Chemical World" 1999 Issue 2 "Synthet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/22
CPCC07D243/22
Inventor 路明郭学超石艳彩叶继东岳晓凯
Owner 河南豫辰药业股份有限公司
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