A kind of preparation method of doxylamine succinate

A technology of doxylamine succinate and hydrochloride, which is applied in the field of medicine, can solve the problems of low purity, multiple crystallization, and large solubility of finished products, and avoid cumbersome operations, less reaction and side effects, and simple post-processing Effect

Active Publication Date: 2017-12-08
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The existing synthetic method procedure of doxylamine succinate is complicated, and patent CN201310456159 reports 2-pyridylphenylmethylcarbinol, dimethylaminochloroethane hydrochloride and sodium amide in toluene or xylene to reflux for more than 8 hours , Sodium amide is an inorganic super strong base, and it will be refluxed in high boiling point solvents such as toluene and xylene for a long time, which will cause great damage to the reaction equipment. Dimethylaminochloroethane hydrochloride is a low boiling point highly toxic organic reagent with a boiling point of only 50 °C , reflux in xylene for a long time, seriously endangering the health of operators; the post-treatment of the reaction requires column chromatography or using the difference in the pKa value of the product and impurities to adjust the pH for extraction and purification, which is costly and complicated to operate, which is not conducive to industrial scale-up Production
In the salt-forming reaction of the finished product doxylamine succinate, patents such as CN201310456159 and CN201010275180 use acetone as a solvent, and N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethyl Amine and succinic acid are salified, but the solubility of doxylamine succinate in acetone is relatively large, and the yield is low. The yield of each crystallization is only about 80%, and multiple crystallizations are required; the purity of the finished product is not high, Simplex close to 0.1%

Method used

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  • A kind of preparation method of doxylamine succinate
  • A kind of preparation method of doxylamine succinate
  • A kind of preparation method of doxylamine succinate

Examples

Experimental program
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Embodiment 1

[0044] The reaction equation is as follows:

[0045] S1: Synthesis of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine

[0046]

[0047]Dissolve 200g of 2-pyridylphenylmethylmethanol in 1L of xylene, pass through nitrogen protection, add 222g of sodium amide at 0-5°C, stir for 15-30 minutes, add 1.07kg of dimethylaminoethyl chloride salt Acid salt, stir at 0-5°C for 15-30 minutes, slowly heat up to 140°C, reflux and stir for 1 hour, cool down to 0-5°C after the reaction, add 500ml of 20-30% ammonium chloride dropwise, stir for 30 minutes, and let stand Separate the layers, discard the water layer, add 300ml of 3-5% dilute hydrochloric acid, mix thoroughly for 15 minutes, let the layers stand, discard the organic phase, add 300ml of the water phase, 20-30% sodium carbonate aqueous solution and 1L ethyl acetate, fully After mixing, let stand to separate the layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter and distill off the ethyl acetate und...

Embodiment 2

[0052] The reaction equation is as follows:

[0053] S1: Synthesis of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine

[0054] Dissolve 200g of 2-pyridylphenylmethylmethanol in 1L of xylene, pass through nitrogen protection, add 254g of sodium amide at 0-5°C, stir for 15-30 minutes, add 1.39kg of dimethylaminoethyl chloride salt Acid salt, stir at 0-5°C for 15-30 minutes, slowly heat up to 140°C, reflux and stir for 1 hour, cool down to 0-5°C after the reaction, add 500ml of 20-30% ammonium chloride dropwise, stir for 30 minutes, and let stand Separate the layers, discard the water layer, add 300ml of 3-5% dilute hydrochloric acid, mix thoroughly for 15 minutes, let stand to separate the layers, discard the organic phase, add 300ml of the water phase, 20-30% aqueous sodium bicarbonate and 1L ethyl acetate, Mix well and let stand to separate layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter and distill off the ethyl acetate under reduced pressu...

Embodiment 3

[0058] S1: Synthesis of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine

[0059] Dissolve 200g of 2-pyridylphenylmethylmethanol in 1L of xylene, pass through nitrogen protection, add 190g of sodium amide at 0-5°C, stir for 15-30 minutes, add 0.89kg of dimethylaminoethyl chloride salt Acid acid salt, stir at 0-5°C for 15-30 minutes, slowly heat up to 150°C, reflux and stir for 1 hour, cool down to 0-5°C after the reaction, add 500ml of 20-30% ammonium chloride dropwise, stir for 30 minutes, and let stand Separate layers, discard the water layer, add 300ml of 3-5% dilute hydrochloric acid, mix thoroughly for 30 minutes, let stand to separate layers, discard the organic phase, add 300ml, 20-30% aqueous sodium carbonate solution and 1L dichloromethane to the water phase, and fully After mixing, let it stand and separate layers, dry the dichloromethane layer with anhydrous sodium sulfate, filter and distill off the dichloromethane under reduced pressure to obtain N,N-dimet...

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Abstract

The invention discloses a preparation method of doxylamine succinate. The preparation method comprises following steps: step 1, 2-pyridyl phenyl methyl carbinol is dissolved in an organic solvent, and is reacted with 2-dimethylaminoethyl chloride hydrochloride at high temperature, after reaction, target product N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)oxethyl]ethylamine is obtained via quenching extracting separation; and step 2, N,N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxethyl]ethylamine obtained in the step 1 and succinic acid are subjected to salt forming in an organic solvent; and finished product N,N-dimethyl-2-(1-phenyl-1-(2-pyridine)ethoxy)ethanamine succinate (doxylamine succinate) is obtained via cooling crystallization. The preparation method is simple, safe, and reliable, is high in doxylamine succinate yield, and is suitable for industrialized enlarged production; and post-treatment is simple and convenient.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a preparation method of doxylamine succinate. Background technique [0002] Doxylamine succinate belongs to ethanol antihistamine drug, which has antihistamine effect, anticholinergic effect and significant sedative and hypnotic effect. It is suitable for various allergic skin diseases, hay fever, allergic rhinitis, asthmatic Bronchitis, etc.; because it can produce drowsiness by inhibiting the central nervous system, it is also used as a sleeping pill for short-term treatment of insomnia. [0003] In October 1978, the FDA approved the marketing of doxylamine succinate 25mg tablets of CHATTEM Company, which is used to help alleviate the difficulty of falling asleep. Became OTC (over the counter) in 1979. It was approved in September 1996, and in August 2004, LNK was officially listed as a generic drug. Doxylamine succinate, as an OTC antihistamine for adjuvant treatment of sleep, is cl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 卢翔张元元郭梦玲霍立茹赵卿周静李战
Owner NANJING GRITPHARMA CO LTD
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