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Preparation method of clonazepam related substance B

A related substance, clonazepam technology, applied in the field of preparation of clonazepam related substance B, can solve the problems such as less amount of impurity A, complicated separation, easy overreaction, etc. Simple steps and high yield

Pending Publication Date: 2022-04-19
济南同路医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The disadvantage of the above method is: it is easy to over-react, and the amount of impurity A produced by over-reaction is too small, the separation is complicated, and the efficiency is too low, which cannot meet the requirements of the amount and purity of the impurity reference substance

Method used

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  • Preparation method of clonazepam related substance B
  • Preparation method of clonazepam related substance B
  • Preparation method of clonazepam related substance B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation method of clonazepam related substance B comprises the following steps:

[0045] Add chloride (10.00g, 28.32mmol) to the reaction flask, add 110ml of methanol and stir to dissolve, the system is off-white turbid, add ammonia water (30ml, 212.40mmol) dropwise at 25°C, after the addition is complete, the system becomes light yellow turbid system, continue stirring at room temperature for 1 h.

[0046] TLC showed that the reaction was complete, 70ml of water was added dropwise to the reaction system, filtered, and dried at 40°C to obtain a light yellow powder weighing 7.47g with a yield of 65.3%. The HPLC test results showed that the purity was 98.55%.

Embodiment 2

[0048] The preparation method of clonazepam related substance B comprises the following steps:

[0049] Add chloride (10.00g, 28.32mmol) to the reaction bottle, add methanol 110ml and stir to dissolve, the system is off-white turbidity, 7M ammonia methanol solution (20ml, 141.60mmol) is added dropwise at 25°C, after the addition is complete, the system is pale Yellow turbidity, continue to stir at room temperature for 1h, the system dissolves and becomes clear, and it is a light yellow solution.

[0050] TLC showed that the reaction was complete, methanol was concentrated to obtain a light yellow solid, and air-dried to obtain a light yellow powder weighing 10.06 g with a yield of 88.0%. The HPLC test results showed that the purity was 99.67%.

Embodiment 3

[0052] The preparation method of clonazepam related substance B comprises the following steps:

[0053] Add chloride (10.00g, 28.32mmol) to the reaction flask, add methanol 110ml and stir to dissolve, the system is off-white turbidity, 7M ammonia methanol solution (20ml, 141.60mmol) is added dropwise at 20°C, after the addition is complete, the system is pale Yellow turbidity, continue to stir at room temperature for 1h, the system dissolves and becomes clear, and it is a light yellow solution.

[0054] TLC showed that the reaction was complete, 90ml of water was added dropwise to the reaction system, filtered, and dried at 40°C to obtain a light yellow powder weighing 7.50g with a yield of 66.0%. The HPLC test results showed that the purity was 99.28%.

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Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a preparation method of a clonazepam related substance B. The preparation method of the clonazepam related substance B provided by the invention comprises the following steps: dissolving chloride into a protonic solvent, adding an acid-binding agent, reacting at room temperature until the reaction is finished, and filtering to obtain a target compound. The protonic solvent is any one of methanol, ethanol and isopropanol; the acid-binding agent is any one of ammonia water and an ammonia methanol solution. According to the method, commercially available chlorides are used as starting materials, and a high-yield and high-purity clonazepam related substance B can be obtained through cascade reaction. The method provided by the invention is simple in operation steps, and after a crude product is obtained through filtration, the related substance B which is high in purity and meets the requirements of pharmacopoeia can be obtained without post-treatment purification such as recrystallization and the like. According to the clonazepam related substance B obtained by the method disclosed by the invention, the quality of a clonazepam product and the production safety and effectiveness are ensured.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a preparation method of clonazepam-related substance B. Background technique [0002] Clonazepam is an anticonvulsant drug that is about 5 times more potent than diazepam or nitrazepam. The drug is especially suitable for controlling epilepsy. It has a better effect on absence seizures, infantile spasms, myoclonic and akinetic seizures. It has a broad-spectrum antiepileptic effect, and most of it is metabolized in the body. Epilepsy is also effective for chorea. It also has a certain effect on drug-induced ADHD, chronic multiple convulsions, stiff-man syndrome, and various types of neuralgia. Its structural formula is shown in the figure below: [0003] [0004] The relevant standards of the European Pharmacopoeia are as follows: [0005] [0006] [0007] The quality standards of clonazepam are recorded in the European Pharmacopoeia and the United State...

Claims

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Application Information

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IPC IPC(8): C07D215/38
CPCC07D215/38
Inventor 陈日星李正强王海波俞仑王建
Owner 济南同路医药科技发展有限公司
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