The preparation method of tetracaine hydrochloride

A technology of tetracaine hydrochloride and n-butyraldehyde, which is applied in the field of preparation of tetracaine hydrochloride, can solve the problems of increasing production cost, incomplete concentration, and affecting the content of tetracaine hydrochloride, so as to achieve the possibility of increasing the content and eliminating impurities Effect

Active Publication Date: 2021-10-15
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Yet the main problem that existing tetracaine hydrochloride synthetic method exists is: (1) synthetic steps are many, and yield is low; Such solvents will not only increase the production cost, but also are not friendly to the environment, especially the use of alcohol solvents must be concentrated first, otherwise it will affect the subsequent esterification reaction, and it is easy to cause incomplete concentration for large-scale industrial production, which will Impurities that are difficult to separate are produced in the subsequent esterification reaction, which affects the content of tetracaine hydrochloride

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0027] The preparation method of the tetracaine hydrochloride of the present embodiment is specifically as follows:

[0028] ①Add 58kg of p-aminobenzoic acid (0.42kmol), 260kg of N,N-dimethylethanolamine, 3kg of 3wt% palladium carbon catalyst into the autoclave, replace nitrogen three times, fill with hydrogen, and adjust the temperature to 45 ~50°C, adjust the pressure to 0.4±0.1MPa, then slowly add 30.5kg of n-butyraldehyde (0.42kmol) dropwise to the autoclave, and keep the temperature and pressure until complete (about 3h).

[0029] ②After the reaction, filter and recover the palladium-carbon catalyst, add the filtrate directly into the esterification reaction kettle, then add 258.3g of 4-dimethylaminopyridine (2.12mol), heat up to reflux (about 135±2°C), and react to Completely (about 6h). The N,N-dimethylethanolamine distilled out during the reaction is cooled by a cooling tower, dried by a 4A molecular sieve drying tower, and then returned to the esterification reaction...

Embodiment 2～ Embodiment 3）

[0032] The preparation method of each embodiment is basically the same as that of Example 1, and the differences are shown in Table 1.

[0033] Table 1

[0034] Example 1 Example 2 Example 3 p-aminobenzoic acid 58kg (0.42kmol) 66kg (0.48kmol) 100kg (0.73kmol) N,N-Dimethylethanolamine 260kg 300kg 450kg hydrogenation catalyst 3kg of 3wt% palladium carbon 5wt% palladium carbon 3.2kg 5kg of 5wt% palladium carbon Step ① Reaction temperature 45～50℃ 40～45℃ 40～45℃ Step ①Response pressure 0.4±0.1MPa 0.7±0.1MPa 0.3±0.1MPa n-Butyraldehyde 30.5kg (0.42kmol) 34.7kg (0.48kmol) 52.6kg (0.73kmol) Step ① Response complete time about 3h about 2h about 4h 4-Dimethylaminopyridine 258.3g (2.1mol) 610.9g (5mol) 5kg (41mol) Step ② Complete reaction time about 6h about 6h about 6h crystallization solvent Ethanol 80L+ ethyl acetate 80L Methanol 90L+ ethyl acetate 90L Ethanol 120L+ et...

Embodiment 4）

[0036] The preparation method of the tetracaine hydrochloride of the present embodiment is specifically as follows:

[0037] ①Add 58kg of p-aminobenzoic acid (0.42kmol), 500kg of N,N-dimethylethanolamine, 3kg of 3wt% palladium carbon catalyst into the autoclave, replace nitrogen three times, fill with hydrogen, and adjust the temperature to 40 ~45°C, adjust the pressure to 0.3±0.1MPa, then slowly add 30.5kg of n-butyraldehyde (0.42kmol) dropwise to the autoclave, and keep the temperature and pressure until complete (about 3h).

[0038] ② After the reaction, filter and recover the palladium carbon catalyst, put the filtrate directly into the esterification reaction kettle, then add 1kg of 4-dimethylaminopyridine (8.2mol) and 50L of toluene, heat up to reflux, and react until complete (about 8h) .

[0039] ③After the reaction is over, concentrate under reduced pressure to recover N,N-dimethylethanolamine and toluene, add 78L ethanol and 78L ethyl acetate to the concentrated res...

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Abstract

The invention discloses a method for preparing tetracaine hydrochloride, which comprises the first step reaction of p-aminobenzoic acid and n-butyraldehyde, the second step reaction of the reaction product of the first step and N,N-dimethylethanolamine, and The third step is the salt-forming reaction; the first step reaction is carried out in the presence of N,N-dimethylethanolamine, and the system after the first step reaction is directly subjected to the second step reaction without being concentrated. In the present invention, N,N-dimethylethanolamine is used to replace the alcohol solvent in the aldehyde-amine reaction, which not only saves the solvent switching before the second step of the esterification reaction, but also eliminates the possibility of impurities caused by incomplete removal of the alcohol solvent. Effectively improve the content of the final product.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of tetracaine hydrochloride. Background technique [0002] Tetracaine hydrochloride is a high-efficiency local anesthetic that reversibly blocks nerve function. It is clinically used in infiltration anesthesia, nerve block anesthesia, epidural anesthesia, etc. It is recognized as one of the clinically powerful anesthetics with stable Physical and chemical properties, rapid action, long maintenance time and other advantages. [0003] At present, the most commonly used synthetic method of tetracaine hydrochloride is to use p-aminobenzoic acid as a starting material, and obtain a butyl group at one end of its amino group and a dimethylaminoethyl group at one end of its carboxyl group respectively. [0004] For the dimethylaminoethyl group on one end of the carboxyl group, there are currently two main methods: one is to perform esterific...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/60C07C227/04C07C227/18C07C227/42C07C251/08C07C249/02
Inventor 胡国宜胡锦平吴建华张培锋
Owner CHANGZHOU SUNLIGHT PHARMA
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