Preparation method for continuous flow synthesis of clonazepam

A technology for clonazepam and flow synthesis is applied in the field of preparation of continuous flow synthesis of clonazepam, can solve problems such as unfavorable production capacity, and achieve the effects of improving purity, safe and efficient mass transfer and heat transfer, and no amplification effect.

Active Publication Date: 2021-06-04
济南同路医药科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, there are few reports on the synthesis of clonazepam raw materials. In 1997, the article published by Organic Process Research & Development (Development of a Commercially Viable Clonazepam Process Organic Process Research & Development 1997, 1, 268-272) reported that clonazepam Synthetic preparation method, which belongs to the traditional batch reaction, requires multi-step separation, which is not conducive to improving production capacity, and will inevitably produce high content of dimer impurities in the process of synthesizing intermediates

Method used

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  • Preparation method for continuous flow synthesis of clonazepam
  • Preparation method for continuous flow synthesis of clonazepam
  • Preparation method for continuous flow synthesis of clonazepam

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Effect test

Embodiment 1

[0040] The preparation method of clonazepam comprises the following steps:

[0041] (1) Pump the acetone solution of 2 mol / L starting material chloride into the heat exchanger, stay for 0.5s, then flow into the fixed bed of potassium iodide, and react to obtain the intermediate iodide;

[0042] (2) The iodide flows into the tubular reactor again, the flow rate is 30ml / min, and the residence time is maintained at 20s. At the same time, ammonia gas is introduced into the reactor, and the internal pressure of the reactor is controlled to be 0.5Mpa. The reaction liquid is continuously collected, and the organic phase Concentrate under reduced pressure, reclaim acetone, obtain crude product clonazepam;

[0043] (3) Further recrystallization using methanol to obtain clonazepam.

[0044] After testing, the yield of the obtained product was 78%, HPLC detection showed that the purity of the product was 99.8%, and the content of impurity dimer was about 0.074%.

Embodiment 2

[0046] The preparation method of clonazepam comprises the following steps:

[0047] (1) Pump the acetone solution of 2 mol / L starting material chloride into the heat exchanger, stay for 0.5s, then flow into the fixed bed of potassium iodide, and react to obtain the intermediate iodide;

[0048] (2) The iodide flows into the tubular reactor again, the flow rate is 30ml / min, and the residence time is maintained at 20s. At the same time, ammonia gas is introduced into the reactor to control the internal pressure of the reactor to 0.1Mpa, and the reaction liquid is collected continuously. The organic phase Concentrate under reduced pressure, reclaim acetone, obtain crude product clonazepam;

[0049] (3) Further recrystallization with ethanol to obtain clonazepam.

[0050] After testing, the yield of the obtained product was 85%, HPLC detection showed that the purity of the product was 92%, and the content of impurity dimers was about 0.092%.

Embodiment 3

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

[0053] (1) Pump the acetone solution of 2 mol / L starting material chloride into the heat exchanger, stay for 0.5s, then flow into the fixed bed of potassium iodide, and react to obtain the intermediate iodide;

[0054] (2) The iodide flows into the tubular reactor again, the flow rate is 40ml / min, and the residence time of 20s is maintained. At the same time, ammonia gas is introduced into the reactor, and the internal pressure of the reactor is controlled to 1Mpa. The reaction liquid is continuously collected, and the organic phase is subtracted. Concentrate under pressure, reclaim acetone, obtain crude product clonazepam;

[0055] (3) Further recrystallization with ethanol to obtain clonazepam.

[0056] After testing, the yield of the product obtained was 79%, HPLC detection showed that the purity of the product was 99%, and the content of impurity dimers was about 0.085%.

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Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method for continuous flow synthesis of clonazepam. The method comprises the following steps: (1) pumping an acetone solution of a starting material chloride into a heat exchanger, then flowing into a potassium iodide fixed bed, and reacting to obtain an intermediate iodide; and (2) enabling the iodide to flow into a reactor, introducing ammonia gas into the reactor at the same time, continuously collecting the reaction liquid, carrying out vacuum concentration on an organic phase, and thus obtaining a crude product clonazepam. The preparation method has the beneficial effects that (1) compared with a traditional method in the prior art, the clonazepam prepared by the method disclosed by the invention has the advantages that the generation of impurity dimers is greatly reduced, and the purity of the product is remarkably improved; (2) the method disclosed by the invention is short in reaction time and time-saving; and (3) the yield of the product is high, the highest yield of the product can reach 88% or above, and the highest purity can reach about 99.8%.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method for continuous flow synthesis of clonazepam. Background technique [0002] Clonazepam is a benzodiazepine antiepileptic and anticonvulsant drug that acts on the benzodiazepine receptor (BZR) in the central nervous system. It is mainly used to control various types of epilepsy, especially for absence seizures, infants Spasticity, myoclonic, akinetic seizures, and Lennox-Gastaut syndrome. Clonazepam was first approved by the U.S. FDA in 1975, and its global marketed dosage forms mainly include tablets and injections. [0003] At present, there are few reports on the synthesis of clonazepam raw materials. In 1997, the article published by Organic Process Research & Development (Development of a Commercially Viable Clonazepam Process Organic Process Research & Development 1997, 1, 268-272) reported that clonazepam Synthetic preparation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 刘鸽王海波刘学森
Owner 济南同路医药科技发展有限公司
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