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Method for preparing nefopam intermediate I

An intermediate and organic solvent technology, applied in the field of preparation of Nefopam intermediate I, can solve problems such as high toxicity, and achieve the effects of increasing yield and improving post-processing methods

Inactive Publication Date: 2013-02-13
NANJING HAILING TRADITIONAL CHINESE MEDICINE RES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above process, the solvent used is dichloroethane, which is a kind of solvent with high toxicity

Method used

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  • Method for preparing nefopam intermediate I
  • Method for preparing nefopam intermediate I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Put 9L of toluene into the reaction kettle, and put in 3.6kg of o-benzoylbenzoic acid while stirring. Add 0.9kg of phosphorus trichloride dropwise, the dropwise addition is completed in about 1 hour, and stir for 16 hours at 25°C. Stand for stratification, and remove the insoluble matter in the lower layer. The upper layer acid chloride solution is transferred to a drop tank or container.

[0039] (2) Put 1.32kg of N-methylethanolamine, 7.26L of toluene, and 1.98kg of triethylamine into the reaction kettle in sequence, and cool to -5°C~0°C while stirring. Slowly add the above-mentioned acid chloride solution dropwise, and control the dropping temperature at -5°C~5°C, not exceeding 5°C. After the dropwise addition is completed, heat to 25°C±5°C and stir for 1h to prepare the reaction solution.

[0040] (3) Add 1 kg of phosphorus trichloride dropwise to the reactor again, and finish dropping within 1h~2h. Then heated to 75°C±5°C for 4h. Remove the salt in the org...

Embodiment 2

[0044] (1) Put 9L of toluene into the reaction kettle, and put in 3.6kg of o-benzoylbenzoic acid while stirring. Add 0.9kg of phosphorus trichloride dropwise, the dropwise addition is completed in about 1 hour, and stir for 16 hours at 25°C. Stand for stratification, and remove the insoluble matter in the lower layer. The upper layer acid chloride solution is transferred to a drop tank or container.

[0045] (2) Put 1.32kg of N-methylethanolamine, 7.26L of toluene, and 1.98kg of triethylamine into the reaction kettle in sequence, and cool to -5°C~0°C while stirring. Slowly add the above-mentioned acid chloride solution dropwise, and control the dropping temperature at -5°C~5°C, not exceeding 5°C. After the dropwise addition, heat to 25°C±5°C and stir for 1h for later use.

[0046] (3) Add 1 kg of phosphorus trichloride dropwise to the reactor again, and finish dropping within 1h~2h. Heat to 75°C±5°C for 4h. Filter while hot to remove the salt in the organic phase, lower t...

Embodiment example 3

[0050] (1) Put 9L of toluene into the reaction kettle, and put in 3.6kg of o-benzoylbenzoic acid while stirring. Add 0.9kg of phosphorus trichloride dropwise, the dropwise addition is completed in about 1 hour, and stir for 16 hours at 25°C. Stand for stratification, and remove the insoluble matter in the lower layer. The upper layer acid chloride solution is transferred to a drop tank or container.

[0051] (2) Put 1.32kg of N-methylethanolamine, 7.26L of toluene, and 1.98kg of triethylamine into the reaction kettle in sequence, and cool to -5°C~0°C while stirring. Slowly add the above-mentioned acid chloride solution dropwise, and control the dropping temperature at -5°C~5°C, not exceeding 5°C. After the dropwise addition, heat to 25°C±5°C and stir for 1h for later use.

[0052] (3) Add 1kg of phosphorus trichloride dropwise to the reactor again, and finish dropping within 1h~2h. Heat to 75°C±5°C for 4h. Remove the salt in the organic phase by filtration while it is hot...

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Abstract

The invention discloses a method for preparing a nefopam intermediate I. The method comprises the following steps: performing acylating chlorination on benzoylbenzoic acid by phosphorus trichloride in an organic solvent at the room temperature to obtain an acyl chloride solution; at -5 to 5 DEG C, dropwise adding the acyl chloride solution obtained in step 1 into a mixed organic solvent formed by N-methyl diethanolamine, triethylamine and toluene to obtain a reaction solution; dropwise adding phosphorus trichloride into the reaction solution and reacting at 70-80 DEG C, filtering the reaction solution after finishing the reaction, adjusting pH of filtrate to be 7-9 by organic alkali, separating out the solid, and filtering to obtain mother solution; adding organic ether into a mother solution and separating out the solid to obtain nefopam intermediate I. According to the method for preparing the nefopam intermediate, the organic solvent different from that in the past is used, and an after-treatment way of a new method is adopted to avoid accelerating the destruction of the intermediate I caused by water contact, the yield of the reaction is increased, and the intermediate I with high purity is obtained.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of Nefopam intermediate I. Background technique [0002] Nefopam intermediate Ⅰ (structural formula 1, English name is 2-Benzoyl-N-(2-chloroethyl)-N-methyl benzamide, chemical name is 2-benzoyl-N-(2-chloroethyl)-N -methylbenzamide), which is an important intermediate of a new analgesic drug Nefopam. [0003] [0004] Nefopam is a new type of analgesic, which can increase the pain threshold. It is a non-narcotic and non-morphine receptor agonist analgesic. Its effect is not blocked by naloxone, and its analgesic effect is stronger than that of morphine. , Aspirin, slow onset but longer than maintenance time, and no tolerance and addiction. In addition, it has antipyretic, local anesthetic and anti-inflammatory effects, can slow down the increase of capillary permeability in the early stage of inflammation, and has inhibitory effec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/84C07C231/12
Inventor 季世春李琴张明明
Owner NANJING HAILING TRADITIONAL CHINESE MEDICINE RES CO LTD
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