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Preparation method of high-purity medicinal roxatidine acetate hydrochloride

A high-purity technology for roxatidine hydrochloride acetate, applied in the field of synthesis and production of roxatidine acetate hydrochloride, can solve the problems of no impurity content, affecting the quality and yield of intermediates, etc.

Pending Publication Date: 2021-02-05
HARBIN PHARMA GROUP TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the process of patent CN107857743, when synthesizing 3-[3-(1-piperidylmethyl)phenoxy]alanamine, the mixed solution of toluene and dimethyl sulfoxide is used to reflux and divide water for reaction, and the mixed boiling point of the two solvents Above 110°C, and at high temperature, dimethyl sulfoxide will be decomposed into dimethyl sulfide, which will affect the quality and yield of intermediates in this step
Because the impurity problem is the most important problem in this process, this patent only reflects the yield, and there is no report on the impurity content

Method used

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  • Preparation method of high-purity medicinal roxatidine acetate hydrochloride
  • Preparation method of high-purity medicinal roxatidine acetate hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0039] A kind of preparation method of high-purity medicinal roxatidine hydrochloride acetate of the present embodiment is carried out according to the following steps:

[0040] Step 1: Preparation of 3-(1-piperidinylmethyl)phenol

[0041]Add m-hydroxybenzaldehyde (60 g) and DMF (80 mL) into the reaction kettle, and stir. Control the temperature below 30°C, add piperidine (100mL) dropwise to the high level tank, after dropping, raise the temperature to 50°C, stir for 30min, cool down the system below 40°C, add formic acid (50mL) dropwise, add water (4mL) after dropping, and heat up to 110°C , Monitor the reaction until it stops, about 2h. Cool down to 40°C, add water and stir, add 0.25N sodium hydroxide to adjust the pH to 9.4, naturally crystallize, filter, wash with water, and dry in a vacuum oven to obtain 86.4 g of 3-(1-piperidylmethyl)phenol with a yield of 92 %, purity 99.98% (see figure 1 ).

[0042] Step 2: Preparation of 3-[3-(1-piperidinylmethyl)phenoxy]alanine ...

Embodiment 2

[0047] Step 2: 3-[3-(1-piperidinylmethyl)phenoxy]alanine

[0048] Add DMF (100mL), 3-(1-piperidinylmethyl)phenol, (48g), 3-chloropropylamine hydrochloride (40g) in the reaction kettle, stir, add sodium hydroxide (140g), be warming up to 90 °C, monitor the reaction until it stops. Filtrate, add water to the filtrate, stir for 15 min, extract twice with dichloromethane, wash the organic layer with saturated brine, add anhydrous sodium sulfate to dry, filter and evaporate the filtrate to give a light yellow oil 3-[3-(1-piperone Pyridylmethyl)phenoxy]alanamine (48.6g), about 78% yield, 97.89% purity. (See Figure 5 )

Embodiment 3

[0050] Step 2: 3-[3-(1-piperidinylmethyl)phenoxy]alanine

[0051] Add DMSO (100L), 3-(1-piperidinylmethyl)phenol (48kg), 3-chloropropylamine hydrochloride (40kg) into the reaction kettle, stir, add sodium hydroxide (140kg), and heat up to 90°C , and monitor the reaction until it stops. Filtrate, add water to the filtrate, stir for 15 min, extract twice with dichloromethane, wash the organic layer with saturated brine, add anhydrous sodium sulfate to dry, filter and evaporate the filtrate to give a light yellow oil 3-[3-(1-piperone Pyridylmethyl) phenoxyl group] alanine (54.2kg), about 87% yield, 99.45% purity (see Image 6 ).

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Abstract

The invention discloses a preparation method of high-purity medicinal roxatidine acetate hydrochloride, and relates to the field of medicine synthesis. The invention provides the preparation method ofthe medicinal roxatidine acetate hydrochloride which is simple in production process, high in safety coefficient, low in cost, high in yield and extremely low in impurity content. The method comprises the following steps: 1) preparing 3-piperidine methylphenol; (2) preparing N-[3-(3-aminopropoxy)-benzyl] piperidine from the 3-piperidine methylphenol obtained in the step (1); and (3) preparing theroxatidine acetate hydrochloride by adopting the N-[3-(3-aminopropoxy)-benzyl] piperidine in the step (2). The yield of the roxatidine acetate hydrochloride prepared by the method disclosed by the invention can reach 87%, and the purity can reach 99.45%. The method is applied to the field of medicine synthesis.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthetic production method of roxatidine hydrochloride acetate. Background technique [0002] Roxatidine acetate hydrochloride is a gastric ulcer treatment drug developed by Imperial Organ Corporation of Japan. It was first approved by the Ministry of Health and Welfare of Japan in 1986 and has been marketed in nine countries including Germany so far. Roxatidine acetate hydrochloride is a histamine H2 receptor antagonist. The H2 effect of histamine is to increase the level of CAMP in the cell through the adenylyl cyclase binding to the receptor, thereby activating the proton pump and promoting the secretion of gastric acid. The two main H2 effects of histamine are: ①promoting gastric acid secretion; ②immunosuppressive effect; and H2 receptor antagonists competitively antagonize these effects. [0003] Roxatidine hydrochloride acetate is enzymatically transformed into an attract...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 于海涛杨新春张道旭王巍赵乐刘宇夏琳琳潘睿张玉华崔琳王晓颖
Owner HARBIN PHARMA GROUP TECH CENT
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