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A method for the preparation of 3-amino-n-cyclopropyl-2-hydroxyl-hexanamide

A technology of cyclopropyl and hexamide, applied in the field of preparing pharmaceutical intermediates, can solve the problems of difficult handling, strict reaction conditions, expensive reaction conditions and the like, and achieves the effects of low equipment requirements, simple operation and high yield

Inactive Publication Date: 2015-07-29
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In this pathway, the starting material L-norvaline is expensive
The second step employs lithium aluminum hydride as reducing agent, which is expensive and difficult to handle under industrial production
The third step employs cyclopropylisocyanide, which is difficult to obtain and therefore not suitable for industrial production
However, the most important drawbacks of this method are: the need for some expensive reagents, such as HOBT and EDC; and the use of sodium azide as a ring-opening reagent, which is highly flammable and explosive, thus making These reaction conditions are harsh and not suitable for large-scale industrial production
[0011] Due to reasons such as expensive materials, harsh reaction conditions, or toxic reagents, the above preparation methods are not suitable for large-scale production

Method used

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  • A method for the preparation of 3-amino-n-cyclopropyl-2-hydroxyl-hexanamide

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0128] Example 1. To a 1 L reaction flask was added 400 g of water, then trans-2-hexenoic acid (45.7 g, 0.4 mol) and cetylpyridinium chloride (13.6 g, 0.04 mol) were added with stirring. The pH of the solution was adjusted to 6 with 30% sodium hydroxide solution. 30% aqueous hydrogen peroxide (91 g, 0.8 mol) was added at room temperature. The reaction mixture was then heated to 50°C and allowed to react for 6 hours until completion. The reaction mixture was collected to room temperature and the pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted twice with 400 g of dichloromethane. The extract was concentrated until dry. 48.6 g of 3-propyloxirane-2-carboxylic acid were obtained in a yield of 92%. The molecular weight of this compound was confirmed by GC-MS.

[0129] In the above examples, if the sodium hydroxide solution is replaced by ammonia water, sodium carbonate solution, potassium carbonate solution, potassium hydroxide solution, sodi...

example 2

[0130] Example 2. To a 1 L reaction flask was added 130 g of water and then trans-2-hexenoic acid (45.7 g, 0.4 mol) and sodium tungstate (26.4 g, 0.08 mol) were added under stirring. The pH of the mixture was adjusted to about 5 with sodium carbonate solution. 30% aqueous hydrogen peroxide (91 g, 0.8 mol) was added to the reaction mixture at room temperature. The reaction mixture was then heated to 60°C and allowed to react for a further approximately 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the pH was adjusted to about 1 with concentrated hydrochloric acid. The mixture was extracted twice with 400 g of dichloromethane. The extract was concentrated until dry. 47.5 g of 3-propyloxirane-2-carboxylic acid were obtained in a yield of 90%. The molecular weight of this compound was confirmed by GC-MS.

example 3

[0131] Example 3. To a 1 L reaction flask was added 400 g of water and trans-2-hexenoic acid (45.7 g, 0.4 mol) and cetylpyridinium chloride (20.4 g, 0.06 mol) were added with stirring. The pH of the mixture was adjusted to about 6 with 30% sodium hydroxide solution and then 30% hydrogen peroxide (102.3 g, 0.9 mol) was added to the mixture. Then, the reaction mixture was heated to 50 °C and allowed to react for a further 5.5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the pH was adjusted to about 2 with concentrated hydrochloric acid. The mixture was extracted twice with 400 g of dichloromethane. The extract was concentrated until dry. 49.4 g of product were obtained in a yield of 93.5%.

[0132] Preparation of Methyl 3-Propyloxirane-2-carboxylate (III)

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Abstract

The present invention discloses a method for preparing 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide. The invention relates to the technical field of the preparation of pharmaceutical intermediates. The method uses trans-2-hexenoic acid as the starting material, through the steps of epoxidation, ring-opening by nitrile, amidation, etc., to obtain the final product 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide. The method uses easily-obtainable materials, requires mild reactive conditions, and adopts stable processes. Therefore it is suitable for large scale industrial production.

Description

technical field [0001] The invention relates to the technical field of preparing pharmaceutical intermediates, in particular to a method for preparing 3-amino-N-cyclopropyl-2-hydroxyl-hexanamide. technical background [0002] The compound involved in the present invention is 3-amino-N-cyclopropyl-2-hydroxy-hexanamide, which is an intermediate for the preparation of pharmaceutical products, such as antiviral drugs. For example, the compound can be used to synthesize telaprevir, a drug used to treat hepatitis C. [0003] Patent application WO 2005058821 A discloses a preparation method as follows: [0004] [0005] In this route, the starting material L-norvaline is expensive. The second step employs lithium aluminum hydride as reducing agent, which is expensive and difficult to handle under industrial production. The third step employs cyclopropylisocyanide, which is difficult to obtain and therefore not suitable for industrial production. [0006] Patent application W...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02
CPCC07C231/02C07C237/38
Inventor 林邦平王忠美郭斌
Owner JANSSEN PHARMA NV
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