Novel preparation method of intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride

A technology of piperidinylmethyl and phenol, which is applied in the field of intermediate synthesis, can solve the problems of cost increase and raw material m-hydroxybenzaldehyde supply price increase, and achieve the effect of avoiding the increase of production cost and the failure of feeding

Active Publication Date: 2018-02-16
内蒙古京东药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] In order to overcome the shortage of the raw material m-hydroxybenzaldehyde needed in the preparation method of prior art 3-(1-piperidylmethyl)phenol and the problem that the cost that its price rise brings greatly improves, the invention provides a kind of Each reactant is cheap and easy to obtain, the reaction method is simple and safe, and the yield is high, especially the preparation method of 3-(1-piperidylmethyl)phenol (ie compound 1) suitable for industrial production

Method used

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  • Novel preparation method of intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride
  • Novel preparation method of intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride
  • Novel preparation method of intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1: Preparation of 3-(1-piperidylmethyl)nitrobenzene (compound 6)

[0044] Add 1500g of toluene to the reaction flask, then add 604g (4.00mol) of m-nitrobenzaldehyde (compound 3), and then add 6.0g of tetrabutylammonium bromide; cool to about 15°C. Under stirring, an aqueous solution containing 45.5 g (1.20 mol) of sodium borohydride was added dropwise into the reaction liquid, and the temperature was controlled below 30°C. After the dropwise addition was completed, the temperature was controlled at 20-30° C. for 2 hours. Until m-nitrobenzaldehyde is completely reacted.

[0045] After confirming that compound 3 has reacted completely, add 1800g of water to the reaction solution, and then add 820g (4.31mol) of p-toluenesulfonyl chloride under stirring, control the reaction temperature below 30°C, and add dropwise a pre-prepared solution containing 200g (5.00mol) of hydrogen After the aqueous solution of sodium oxide is added dropwise, the temperature is contr...

Embodiment 2

[0049] Embodiment 2: Preparation of 3-(1-piperidylmethyl)aniline (compound 7)

[0050] All the oily matter obtained in Example 1 (calculated on a theoretical basis of 880g, 3.995mol; compound 6) was added to the hydrogenation kettle, then 7700g of methanol was added, and after stirring evenly, 176g of catalyst Raney Ni was added, and then 1100g of methanol was used to dissolve the The catalyst is rinsed clean and added to the hydrogenation kettle. Nitrogen replacement 2-3 times, hydrogen replacement 2-3 times, and then hydrogenation at a pressure of about 3 atm and a temperature of 45-50°C until the reaction is complete.

[0051] After confirming that compound 6 is completely converted into compound 7, cool to room temperature, filter the catalyst, collect the filtrate, concentrate methanol to obtain a solid, and dry to obtain 730 g of compound 7 as an off-white solid (theoretical amount: 760.26 g); yield: 96.0% .

[0052] After the sample was refined and purified with petro...

Embodiment 3

[0057] Embodiment 3: the preparation of 3-(1-piperidinylmethyl)phenol (compound 1)

[0058] Add 1750g of water into the reaction flask, cool to 10-15°C, add 500g (about 5.000mol) of concentrated sulfuric acid dropwise under stirring, and control the temperature below 30°C. After the dropwise addition, cool to 15°C, add 475g (2.50mol) of compound 7 prepared in Example 2, stir to make it completely dissolve, cool down to below 0°C, add dropwise an aqueous solution containing 181g (2.63mol) of sodium nitrite . Control the temperature below 5°C. After the dropwise addition, keep warm at below 5°C and react for 0.5 hr. After TLC confirms that all the compound 7 has reacted, it is ready for use (standby solution 1).

[0059] 1250g of water was added to another reaction flask, and 375g (about 3.75mol) of concentrated sulfuric acid was added dropwise. After the dropwise addition is complete, heat to a temperature of 75°C to 80°C. Add stock solution 1 dropwise through the dropping ...

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Abstract

The invention relates to a preparation method of an intermediate namely 3-(1-piperidine methyl)phenol of roxatidine acetate hydrochloride. M-nitrobenzaldehyde is taken as the primary raw material; under the effect of a phase transfer catalyst, m- nitrobenzaldehyde is reduced by metal borohydride to obtain corresponding benzyl alcohol; in the presence of an alkali, benzyl alcohol reacts with organic sulfonyl chloride to generate active organic sulfonate; then in the presence of an alkali, organic sulfonate carries out N-alkylation reactions with piperidine to generate N-substituted piperidine derivatives; reducing the nitro groups of N-substituted piperidine derivatives to obtain corresponding amino compounds; and subjecting the amino compounds to diazotization, hydrolysis, and alkalizationin a sulfuric acid water solution to obtain 3-(1-piperidine methyl)phenol. The problem that the supply of the conventional raw material (m-hydroxyl benzaldehyde) is not enough and the cost is greatlyincreased is solved. The method is simple and safe, the raw materials are cheap and easily available, the reaction yield is high, and the method is very suitable for industrial production of 3-(1-piperidine methyl)phenol.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing an intermediate of the medicinal compound roxatidine acetate hydrochloride. Background technique [0002] Roxatidine acetate hydrochloride (Roxatidine acetate hydrochloride) was developed by Nippon Zoki Pharmaceutical Co., Ltd. Since it was approved by the Japanese Ministry of Health and Welfare in 1986, it has been listed in 9 countries. The drug is deacetylated by hydrolysis and rapidly converted to the active metabolite Roxatidine, which selectively blocks histamine H 2 It is mainly used clinically to prevent and treat digestive system diseases caused by hypersecretion of gastric acid, such as gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, acute gastritis, and acute exacerbation of chronic gastritis; For administration before anesthesia to prevent aspiration pneumonia. [0003] Roxatidine acetate hydrochloride is a fat-solub...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 郭荣耀王晓锋
Owner 内蒙古京东药业有限公司
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