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Novel process for preparing prucalopride intermediate

A technology of reaction time and compound, applied in the direction of organic chemistry, etc., can solve the problems of stability and safety restriction of hypervalent iodine compounds, not meeting the quality requirements of prucalopride raw materials, low chemical purity, etc. The effect of heavy metal residues and high chemical purity of products

Inactive Publication Date: 2016-11-23
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prices of the two raw materials are very high, and the stability and safety problems of hypervalent iodine compounds have always restricted their large-scale use in industrial production (Ref: US6479487)
When the inventor repeated the work, some of the obtained products had darker colors and low chemical purity, which did not meet the quality requirements for the production of prucalopride raw materials. Therefore, it is necessary to develop new synthetic methods to reduce costs and further improve product quality.

Method used

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  • Novel process for preparing prucalopride intermediate
  • Novel process for preparing prucalopride intermediate
  • Novel process for preparing prucalopride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Synthesis of Methyl 4-piperidinecarboxylate Hydrochloride

[0042]

[0043] 4-piperidinecarboxylic acid (500g, 3.87mol) and methanol (2.5L) were added to the reaction flask, and thionyl chloride (460.4g, 3.87mol) was added dropwise. The temperature was raised to 80°C and the reaction was refluxed for 3h. The reaction solution was concentrated under reduced pressure at 50°C to obtain 687 g of white solid with a yield of 98.8%, which could be directly used in the next reaction. 1 H NMR (300MHz, CDCl 3 ) δ9.63 (m, 2H), 3.70 (s, 3H), 3.36 (m, 2H), 3.05 (m, 2H), 2.59 (m, 1H), 2.16 (m, 4H).

Embodiment 2

[0045] Synthesis of ethyl 4-piperidinecarboxylate hydrochloride

[0046]

[0047] The specific embodiment is the same as Example 1, and the yield is 97%.

Embodiment 3

[0049] Synthesis of 4-methylformate-1-(3-methoxypropyl)-piperidine (II-1)

[0050]

[0051]Methyl 4-piperidinecarboxylate hydrochloride (681.5g, 3.79mol), methanol (3.4L), potassium carbonate (1.3Kg, 9.48mol) and 3-bromopropyl methyl ether (638.4g, 4.17mol) They were added to the reaction flask in turn, and the external temperature was raised to 75°C and refluxed overnight. The reaction solution was filtered with suction, the filtrate was concentrated under reduced pressure at 60°C, the residue was added to 1.5 L of water, extracted with DCM, the organic layers were combined and dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure at 60°C to obtain 590 g of a light yellow solid, with a yield of 72.2 %, can be directly used in the next reaction. 1 H NMR (300MHz, CDCl 3 )δ: 3.68(s, 3H), 3.39(t, J=6.3Hz, 2H), 3.31(s, 3H), 2.86(m, 2H), 2.24~2.42(m, 3H), 1.70~2.03(m , 8H).

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Abstract

The invention discloses a preparation method of 1-(3-methoxypropyl)-4-piperidinamine shown as formula (I). The preparation method includes (1), allowing a compound of the formula (II) to react in an ammoniac solution to obtain a compound of the formula (III); (2), allowing the compound of the formula (III) to react with 1,3-dibromo-5,5-dimethylhydantoin under an alkaline condition to obtain the compound of the formula (I). The preparation method has the advantages that special reaction equipment is not needed, and the method is simple and convenient to operate and suitable for industrial production; yield is high, three wastes are few, and cost is low; chemical purity of products is high, and heavy metal residues are avoided.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new process for preparing prucalopride intermediates. Background technique [0002] Constipation is a gastrointestinal motility disorder and is the most common gastrointestinal disease syndrome. With the aging trend of the social population, changes in diet structure and the influence of mental, psychological and social factors, constipation, especially intractable constipation, has become a social problem. The problem, its high incidence rate and complex etiology, often brings a lot of pain and troubles to patients, seriously affecting the quality of life of patients. Constipation is a serious health problem especially in the elderly. Constipation is related to the occurrence of colon cancer, heart and cerebrovascular diseases, and senile dementia. However, the elderly population in China is increasing year by year, and the proportion of the population is increa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
Inventor 周西朋浦益清龚彦春吕伏生袁方刘永强
Owner JIANGSU VCARE PHARMATECH
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