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Preparation method of oxazepam intermediate

A kind of intermediate, compound technology

Pending Publication Date: 2021-12-21
HUAZHONG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Technologists generally believe that the acylation and rearrangement reactions of benzodiazepine psychotropic drugs only need to carry out the reaction substrate in the presence of a single, large excess of acetic anhydride. The prior art has the following defects: the material system is A homogeneous state can only be present in a high temperature environment, but the intense heat release of the system under high temperature conditions increases the difficulty of temperature control and easily generates organic impurities, thereby affecting the purity of the target compound; the mother liquor produced after the reaction cannot be recycled, which increases the sewage of the enterprise processing cost

Method used

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  • Preparation method of oxazepam intermediate
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  • Preparation method of oxazepam intermediate

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preparation example Construction

[0032] Above-mentioned preparation method comprises the following steps:

[0033] S1. To 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1-H-1,4-benzodiazepine-4-oxide (hereinafter referred to as formula II compound) , acetic anhydride, and aprotic polar solvents, add anhydrous acetate, stir and heat up to 95°C to 100°C, then keep the temperature for 1.5-2.5h, then cool down to -5°C to 5°C after the reaction, more preferably 0°C , add water to precipitate, filter, and wash to obtain the crude product of the target product; the aprotic polar solvent is dimethylformamide and / or dimethylacetamide, and the proportioning of the formula II compound and the aprotic polar solvent is 1g: ( 0.6~1.0)ml; the ratio of formula II compound and acetic anhydride is 1g:(0.6~1.0)ml; the mass ratio of formula II compound and anhydrous acetate is 1:(0.1~0.2); The mass ratio of added water to the compound of formula II is (0.2-0.8):1, preferably (0.4-0.6):1.

[0034] S2. The target product crude product desc...

Embodiment 1

[0037] Add 30g 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1-H-1,4-benzodiazepine-4-oxide, 24ml vinegar anhydride, 24ml of dimethylformamide and 3g of anhydrous sodium acetate, stirred and heated up to 95°C to 100°C, and then kept warm for 2 hours. Cool down to 0°C, add 12g of water dropwise, continue to stir at -5°C to 0°C for 0.5 hours, let stand for more than 2 hours, filter, and wash with water to obtain the crude oxazepam intermediate. The crude product was added into a mixed solvent of 90 ml of ethanol and 30 ml of water for beating and refining to obtain 31.8 g of an oxazepam intermediate with an HPLC purity of 99.4% and a yield of 92.4%.

Embodiment 2

[0039] Add 30g 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1-H-1,4-benzodiazepine-4-oxide, 18ml vinegar anhydride, 20ml of dimethylformamide, 10ml of dimethylacetamide and 4.5g of anhydrous potassium acetate, stirred and heated to 95°C-100°C, and then kept at 95°C-100°C for 2.5 hours. Cool down to -5°C, add 18g of water dropwise, continue to stir at -5°C to 0°C for 0.5 hours, let stand for more than 2 hours, filter and wash with water to obtain the crude oxazepam intermediate. The crude product was added into a mixed solvent of 40 ml of ethanol and 20 ml of water for beating and refining to obtain 31.6 g of an oxazepam intermediate with an HPLC purity of 99.1% and a yield of 91.9%.

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Abstract

The invention discloses a preparation method of an oxazepam intermediate, which comprises the following steps: adding acetic anhydride and anhydrous acetate into 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide in an aprotic polar solvent, stirring and heating to carry out heat preservation reaction, and then cooling, separating and refining to obtain the oxazepam intermediate as shown in a formula I. according to the method, acylation and rearrangement are carried out under a formed homogeneous system, so that the reaction yield is increased, the acetic anhydride consumption is greatly reduced, and the raw material cost and the sewage treatment cost are reduced; in addition, the reaction is stable in a homogeneous system, the safety is obviously improved, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of an oxazepam intermediate. Background technique [0002] Oxazepam is a benzodiazepine Sedative-hypnotics, clinically mainly used for the treatment of anxiety, insomnia, and alcohol withdrawal. The advantages of oxazepam are mainly reflected in the simple metabolic process, which is less affected by age and liver function; the half-life is short, and it is not easy to accumulate in the body; it is less addictive, especially suitable for patients with mild liver damage and elderly patients . [0003] Oxazepam intermediate 7-chloro-5-phenyl-3-acetoxy-2,3-dihydro-1-H-1,4-benzodiazepine-2-one, CAS number: 1824-74-4, its structural formula is: [0004] [0005] 7-Chloro-5-phenyl-3-acetoxy-2,3-dihydro-1-H-1,4-benzodiazepin-2-one is a key intermediate in the preparation of oxazepam , which is also the oxazepam impurity B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/26
CPCC07D243/26
Inventor 廖俊罗浩曾建华邬德琦胡惠珊
Owner HUAZHONG PHARMA
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