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Preparation method of lorazepam intermediate

A technology of intermediates and compounds, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of increasing sewage treatment costs, increasing the difficulty of temperature control, increasing organic impurities, etc., reducing raw material costs and sewage treatment costs, and improving production safety performance, emission reduction effect

Pending Publication Date: 2021-12-21
HUAZHONG PHARMA
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  • Description
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Problems solved by technology

[0016] Technical personnel 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, and the prior art has the following defects: the material system 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 inevitably adds new organic impurities, thereby affecting the purity of the target compound; in addition, the mother liquor produced at the end of the reaction Unable to recycle, increasing the cost of sewage treatment for enterprises

Method used

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  • Preparation method of lorazepam intermediate
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  • Preparation method of lorazepam intermediate

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preparation example Construction

[0034] Above-mentioned preparation method comprises the following steps:

[0035] S1. To 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide (hereinafter referred to as formula II compound), acetic anhydride, aprotic Add 4-dimethylaminopyridine to the polar solvent, stir and raise the temperature to 85°C-90°C, then keep it warm for 2-3 hours, then cool down to -5°C-5°C, more preferably 0°C, add water and filter 1. Obtain the crude product of the target product after washing with water; the aprotic polar solvent is dimethylformamide and / or dimethylacetamide, and the proportion of the compound of formula II and the aprotic polar solvent is 1g: (0.6~1.0)ml; The proportioning ratio of formula II compound and acetic anhydride is 1g: (0.6~1.0) ml; the mass ratio of formula II compound and 4-dimethylaminopyridine is 1: (0.08~0.12); The mass ratio of compound II is (0.3-0.5):1.

[0036] S2. The target product crude product described in step S1 is beaten and refined in a mix...

Embodiment 1

[0042] Add 50g of the compound of formula II, 50ml of acetic anhydride, 30ml of dimethylformamide and 4g of 4-dimethylaminopyridine to the reaction flask in sequence, stir and raise the temperature to 85-90°C, and then keep the reaction for 3 hours. Cool down to 0°C, add 20g 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 lorazepam intermediate. The crude product was added into a mixed solvent of 100 ml of acetone and 50 ml of water for beating and refining to obtain 52.6 g of a lorazepam intermediate, with an HPLC purity of 99.3% and a yield of 93.03%.

Embodiment 2

[0044] Add 50g of the compound of formula II, 30ml of acetic anhydride, 50ml of dimethylacetamide and 6g of 4-dimethylaminopyridine to the reaction flask in sequence, stir and raise the temperature to 85-90°C, and then keep the reaction for 2 hours. Cool down to -5°C, add 25g 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 product of lorazepam intermediate. The crude product was added into a mixed solvent of 80 ml of acetone and 20 ml of water for beating and refining to obtain 52.9 g of a lorazepam intermediate, with an HPLC purity of 99.1% and a yield of 93.56%.

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Abstract

The invention discloses a preparation method of a lorazepam intermediate, which comprises the following steps: adding 4-dimethylaminopyridine into a mixed solution of 7-chloro-2-oxo-5-(2-chlorphenyl)-1, 4-benzodiazepin-4-oxide, acetic anhydride and an aprotic polar solvent, stirring, heating, carrying out heat preservation reaction, cooling after the reaction is finished, adding water to separate out materials, filtering, washing with water, refining to obtain a target product. According to the invention, under the condition of greatly reducing the dosage of acetic anhydride, the yield of acylation and rearrangement reactions of lorazepam is ensured, and the discharge of acid-containing wastewater is greatly reduced; in addition, in the reaction process, the temperature is stable, the phenomenon of violent rising does not occur, and the production safety is greatly improved.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of a lorazepam intermediate. Background technique [0002] Lorazepam (Lorazepam) belongs to benzodiazepine sedative-hypnotics, and is a benzodiazepine psychotropic drug developed by Wyeth Company of the United States. The drug of choice for anti-status epilepticus is a national essential drug. [0003] Lorazepam intermediate 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepine -2-ketone, CAS number: 2848-96-6, its structural formula is: [0004] [0005] 7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepine -2-ketone is the key intermediate for preparing lorazepam, and it is also the lorazepam impurity B specified in the European Pharmacopoeia EP9.0 and the lorazepam impurity A specified in the United States Pharmacopoeia USP40. [0006] Lorazepam intermediate 7-chloro-5-(2-chlo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/26
CPCC07D243/26
Inventor 罗浩廖俊王定军曾建华邬德琦邹谨霜
Owner HUAZHONG PHARMA
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