Preparation method of cisapride key intermediate

An intermediate and key technology, applied in the field of medicinal chemistry, can solve the problems of long synthetic route, low yield, and expensive starting materials, and achieve the effect of low equipment requirements, low reaction temperature, and easy access

Inactive Publication Date: 2018-11-27
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting material of this synthetic scheme is expensive, the synthetic route is long, and the yield is low

Method used

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  • Preparation method of cisapride key intermediate
  • Preparation method of cisapride key intermediate
  • Preparation method of cisapride key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Step 1, the preparation of 3-methoxypyridine: under ice-bath conditions, add 113g 3-chloropyridine to 200mLN,N-dimethylformamide (DMF) solvent, add 75g potassium methylate in batches and stir until Completely dissolved. After the addition, the temperature was slowly raised to room temperature, and then heated to 70° C. to continue the reaction for 8 hours. After the reaction was completed, the DMF solvent was recovered by conventional operation to obtain 99 g of a light yellow liquid.

[0028] Step 2, preparation of 4-nitro-3-methoxypyridine: under ice-bath conditions, dissolve 55g of 3-methoxypyridine in 150mL of glacial acetic acid, add 120g of concentrated nitric acid dropwise for nitration reaction, after the dropwise addition , the reaction system was warmed up to room temperature and reacted for 5 hours. After the reaction, the reaction system was slowly poured into ice water, and the glacial acetic acid was recovered by conventional operation, and dried to obtain ...

Embodiment 2

[0033] Step 1, preparation of 3-methoxypyridine: under ice-bath conditions, add 75g of 3-chloropyridine to 200mLN,N-dimethylformamide (DMF) solvent, add 75g of potassium methylate in batches and stir until Completely dissolved. After the addition, the temperature was slowly raised to room temperature, and then heated to 60° C. to continue the reaction for 9 hours. After the reaction was completed, the DMF solvent was recovered by conventional operation to obtain 40 g of a light yellow liquid.

[0034] Step 2, preparation of 4-nitro-3-methoxypyridine: under ice-bath conditions, dissolve 36g of 3-methoxypyridine in 150mL of glacial acetic acid, add 120g of concentrated nitric acid dropwise for nitration reaction, after the addition is complete , the reaction system was warmed up to room temperature and reacted for 4 hours. After the reaction, the reaction system was slowly poured into ice water, and the glacial acetic acid was recovered by conventional operation, and dried to obt...

Embodiment 3

[0039] Step 1, preparation of 3-methoxypyridine: under ice-bath conditions, add 150g 3-chloropyridine to 200mL N,N-dimethylformamide (DMF) solvent, add 75g potassium methylate in batches and stir until Completely dissolved. After the addition, slowly warm up to room temperature, and then heated to 80°C to continue the reaction for 7h. After the reaction, the DMF solvent was recovered by conventional operation to obtain 107g of light yellow liquid.

[0040]Step 2, the preparation of 4-nitro-3-methoxypyridine: under ice-bath conditions, dissolve 72g of 3-methoxypyridine in 150mL of glacial acetic acid, add 120g of concentrated nitric acid dropwise for nitration reaction, after the dropwise addition , the reaction system was warmed up to room temperature and reacted for 6 hours. After the reaction, the reaction system was slowly poured into ice water, and the glacial acetic acid was recovered by conventional operation, and dried to obtain 86 g of a yellow solid.

[0041] Step 3, ...

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Abstract

The invention provides a preparation method of a cisapride key intermediate. The preparation method includes the steps of adopting 3-pyridine as an initial raw material, 3-methoxypyridine is synthesized through nucleophilic substitution, 4-nitryl-3-methoxypyridine is prepared through a nitration reaction, a 4-nitryl-3-methoxyl-N-(3-(4-fluorophenoxy)propyl) quaternized pyridinium is prepared through quaternization, and the cisapride key intermediate, namely (cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxy piperidine, is prepared through catalytic hydrogenation at last. The preparation method has the advantages of being low in cost, easy to operate and the like.

Description

technical field [0001] The invention relates to a preparation method of a cisapride intermediate, belonging to the field of medicinal chemistry. Background technique [0002] Cisapride (I) is a third-generation gastrointestinal motility drug developed by Janssen Pharmaceuticals, which can selectively stimulate the release of acetylcholine in the enteromyous plexus and activate 5-HT 4 Receptors, acting through the cholinergic nervous system, promote motility of the esophagus, stomach, and intestines. [0003] The synthesis of intermediate (cis)-N-(3-(4-fluorophenoxy) propyl group)-4-amino-3-methoxypiperidine is a key step in the preparation of cisapride, common in industry ( cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxypiperidine is synthesized using 4-piperidone as the starting material, protected by carbonyl, oxidized , Methylation, deprotection by hydrolysis, N-alkylation, oximation, and reduction. The starting materials of this synthetic scheme are expensive, th...

Claims

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Application Information

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IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor严宾冯成亮张民
OwnerIANGSU COLLEGE OF ENG & TECH