Preparation method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride

A technology of hydroxycaproamide and methyl hydroxycaproate, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of being unsuitable for large-scale production, unsuitable for industrial production, and unsuitable for large-scale production, and achieves low toxicity and low equipment requirements , the effect of convenient operation

Inactive Publication Date: 2012-10-03
ZHEJIANG LANGHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The raw material L-norvaline used in this route is very expensive, and the second step reaction needs to use Lithium Aluminum Hydride for reduction reaction. The price of this reagent is Very expensive and difficult to operate industrially
The cyclopropyl isocyanate raw material used in the third step reaction is not easy to buy and is not suitable for industrial production
[0011] The raw material trans-2-hexenoic acid used in this route is cheap and easy to get. However, the biggest disadvantage of this route is that it needs to use very expensive Reagents such as HOBT and EDC, and flammable and explosive sodium azide must be used as the ring-opening reagent, the reaction conditions are very harsh, and it is not suitable for large-scale industrial production
[0012] The above synthetic methods are not suitable for large-scale production because of the high price of raw materials, harsh reaction conditions, or the use of highly toxic substances

Method used

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  • Preparation method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride
  • Preparation method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride
  • Preparation method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Add 457g H to a 1L reaction flask 20, and start stirring, while adding trans-2-hexenoic acid (45.7g, 0.4 mol), cetylpyridinium chloride (13.6g, 0.04 mol), adjust the pH to 6 with 30% aqueous sodium hydroxide solution, at room temperature 30% hydrogen peroxide (91 g, 0.8 mol) was added. Then heated to 50°C for 6 hours until the reaction of the raw materials was complete, cooled to room temperature, adjusted the pH to 2 with concentrated hydrochloric acid, extracted twice with 400g of dichloromethane, and concentrated to dryness to obtain 48.6g of 3-propyl oxirane -2-Formic acid (formula II), yield 92%.

[0044] In the above examples, the catalyst uses sodium tungstate or 12-phosphotungstic acid instead of cetylpyridinium chloride, and the lye is ammonia water, sodium carbonate solution, potassium carbonate solution, potassium hydroxide solution, sodium phosphate solution, One of potassium phosphate solution, sodium bicarbonate solution or potassium bicarbonate solution...

Embodiment 2

[0046] Add 140g H to a 1L reaction flask 2 O, and start stirring, while adding trans-2-hexenoic acid (45.7g, 0.4 mol), sodium tungstate (26.4g, 0.08mol), adjust the pH to 5 with aqueous sodium carbonate solution, add 30% hydrogen peroxide at room temperature (113.7g, 1.0 mol), then heated to 60°C for 5 hours until the reaction of the raw materials was complete, cooled to room temperature, adjusted the pH to 1 with concentrated hydrochloric acid, extracted twice with 400g dichloromethane, concentrated to dryness, and obtained 47.5g 3- Propyloxirane-2-carboxylic acid (formula II), yield 90%.

Embodiment 3

[0048] Add 320g H to a 1L reaction flask 2 O, and start stirring, while adding trans-2-hexenoic acid (45.7g, 0.4 mol), cetylpyridinium chloride (20.4g, 0.06 mol), adjust pH to 5.5 with aqueous sodium carbonate solution, add 30% Hydrogen peroxide (102.4g, 0.9mol), then heated to 55°C and reacted for 5.5 hours until the reaction of the raw materials was complete, cooled to room temperature, adjusted the pH to 1.5 with concentrated hydrochloric acid, extracted twice with 400g of dichloromethane, concentrated to dryness, and obtained 49.6g of 3 -Propyloxirane-2-carboxylic acid (formula II), yield 94%.

[0049] Preparation of Propyloxirane-2-carboxylic acid (Formula III)

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Abstract

The invention discloses a preparation method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride, and belongs to the technical field of preparation of a medical intermediate. The chiral product of the (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride is obtained by performing the five reaction steps, including epoxidation, resolution, ring opening, esterification and amination, on trans-2-hexenoic acid serving as an initial raw material, wherein water is used as a reaction solvent in the first step of epoxidation. By adoption of the technology, the preparation method has the advantages of convenience in operation, mild reaction conditions, cheap and readily available used raw materials, low toxicity, high product purity reaching over 99.4 percent, high e.e. (Enantionmeric Excess) value reaching over 99.5 percent, low equipment requirement and suitability for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride. Background technique [0002] The (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride involved in the present invention is an important intermediate for the preparation of antiviral drugs and other pharmaceutical products. For example, the compound can be used to synthesize antiviral The hepatitis C drug Telaprevir. [0003] The synthesis method reported in the patent WO2005058821A is as follows: [0004] [0005] The raw material L-norvaline used in this route is very expensive, and the second step reaction needs to use lithium aluminum hydride to carry out the reduction reaction. This reagent is very expensive and difficult to operate industrially. The cyclopropyl isocyanate raw material that the third step reaction uses, this reagent ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/04C07C231/02C07B53/00
Inventor 林邦平王忠美黄明孙
Owner ZHEJIANG LANGHUA PHARMA
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