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Method for preparing 1-( 3-methoxy propyl )- 4-piperidine amine and salt thereof

A technology of methoxypropyl and piperidinamine, which is applied in the field of preparation of 1--4-piperidinamine and its salts, can solve the problems of unseen synthesis, achieve cheap raw materials, easy access to raw materials, and convenient operation Effect

Inactive Publication Date: 2013-01-30
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 1-(3-methoxypropyl)-4-piperidinamine (formula I) is an important intermediate for the preparation of prucalopride, which is combined with 4-amino-5-chloro-dihydro- The condensation of 7-benzofuran carboxylic acid promptly obtains prucalopride, and the retrieval of existing literature shows that the synthesis of 1-(3-methoxypropyl)-4-piperidinamine has not been reported in the literature

Method used

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  • Method for preparing 1-( 3-methoxy propyl )- 4-piperidine amine and salt thereof
  • Method for preparing 1-( 3-methoxy propyl )- 4-piperidine amine and salt thereof
  • Method for preparing 1-( 3-methoxy propyl )- 4-piperidine amine and salt thereof

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Embodiment 1

[0022] The synthesis of embodiment 1 prucalopride

[0023] Add 4-amino-5-chloro-dihydro-7-benzofuran carboxylic acid (1.0g, 4.68mmol) and 10ml tetrahydrofuran into a 50ml three-necked flask, stir for 15 minutes and add carbonyldiimidazole (0.98g, 6.08mmol) , under nitrogen protection, stirred at room temperature for 30 minutes. A solution of 1-(3-methoxypropyl)-4-piperidinamine (1.04 g, 6.08 mmol) in 10 ml of tetrahydrofuran was added dropwise, and the temperature was raised to 50° C. after the drop, and reacted for 5 hours. Cool, evaporate the solvent to dryness under reduced pressure, add 20ml of water to the residue, stir for 2 hours, filter, and dry the filter cake to obtain 1.4g of off-white solid, yield 81.5%, mp.98-102°C, and its structural identification data are as follows:

[0024] MS(m / z): 368[M+H] + ;

[0025] 1 HNMR (CDCl 3 )δ1.95~2.02(m, 4H), 2.17~2.20(d, 2H), 2.72(t, 2H), 2.99(t, 2H), 3.07(t, 2H), 3.33(s, 3H), 3.45 (t, 4H), 4.15-4.19 (m, 1H), 4.27 (s, 2H),...

Embodiment 2

[0026] Example 2 Synthesis of 1-(3-methoxypropyl)-4-piperidone

[0027] Add 4-piperidone hydrochloride monohydrate (10g, 0.065mol), potassium carbonate (11.04g, 0.08mol), 3-bromopropyl methyl ether (12.85g, 0.084mol) successively in a 250ml single-necked bottle ) and 100ml of acetonitrile were reacted at 50°C for 17 hours. Cool, filter with suction, remove potassium carbonate, evaporate the filtrate to dryness under reduced pressure, and obtain 13 g of a dark red oily substance, which is directly used in the next reaction.

Embodiment 3

[0028] Example 3 Synthesis of 1-(3-methoxypropyl)-4-piperidinamine and its hydrochloride

[0029] In the high-pressure hydrogenation kettle, add the obtained 1-(3-methoxypropyl)-4-piperidone (5g, 0.029mol), saturated methanol solution (60ml) of ammonia gas and 10% Pd / C (0.5g), hydrogenated to 1.5MPa, stirred at 40°C for 7 hours. Cool, filter with suction, evaporate the filtrate to dryness under reduced pressure to obtain a yellow oil, dissolve it in 20ml of ethanol, add 5mol / L ethyl hydrogen chloride solution dropwise, adjust the pH to 1-2, stir for 2 hours, filter, The filter cake was washed with an appropriate amount of ethanol to obtain 4.34 g of white solid 1-(3-methoxypropyl)-4-piperidinamine hydrochloride, mp>220°C, and the total yield of the two-step reaction was 70.8%.

[0030] Dissolve 1-(3-methoxypropyl)-4-piperidinamine hydrochloride (4g, 0.016mol) in 40ml of methanol, add potassium carbonate (4.5g, 0.032mol), stir at room temperature for 2 hours, pump After filt...

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Abstract

The invention discloses a method for preparing 1-(3-methoxy propyl)-4-piperidine amine shown as a formula I. The method comprises the following steps: carrying out the following reactions on a compound shown as a formula II in an organic solution of ammonia, under the effects of hydrogen and a hydrogenation catalyst. The invention also discloses a method for preparing a salt of the 1-( 3-methoxy propyl )-4-piperidine amine shown as the formula I. The method has advantages of cheap and easily available raw materials and convenient operation, is suitable for industrial mass production, and provides a novel path for Prucalopride synthesis.

Description

technical field [0001] The invention relates to a preparation method of 1-(3-methoxypropyl)-4-piperidinamine and salts thereof. Background technique [0002] Prucalopride, 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide , a selective 5-HT4 receptor agonist developed for Belgian movetis NV company, its monosuccinate was approved by the European Medicines Agency on October 15, 2009, for the treatment of female constipation that cannot be relieved by laxatives . [0003] 1-(3-methoxypropyl)-4-piperidinamine (formula I) is an important intermediate for the preparation of prucalopride, which is combined with 4-amino-5-chloro-dihydro- Prucalopride is obtained by condensation of 7-benzofuran carboxylic acid. Searching the existing literature shows that the synthesis of 1-(3-methoxypropyl)-4-piperidinamine has not been reported in the literature. [0004] Contents of the invention [0005] The technical problem to be solved by the p...

Claims

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Application Information

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IPC IPC(8): C07D211/58
Inventor 岑均达原友志唐家邓
Owner SHANGHAI INST OF PHARMA IND
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