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Method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride

A technology of aminocyclopentanol hydrochloride and carbamic acid, which is applied in the field of organic chemical synthesis, can solve the problems of difficult chiral control and high price, and achieve the effects of low cost, novel and short route, and high optical purity

Pending Publication Date: 2021-03-30
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In order to improve the shortcomings of (1R,3S)-3-aminocyclopentanol hydrochloride starting materials such as expensive starting materials and difficult chiral control, the present invention has developed a new process route, and the synthesis route is as follows

Method used

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  • Method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride
  • Method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride
  • Method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031]

[0032] (1) Synthesis of tert-butyl cis-2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0033] In a 3L reaction flask, tert-butyl carbonate-protected hydroxylamine (280 g, 2.1 mol) and 2-methyltetrahydrofuran (1 L) were sequentially added. Then start stirring, then add cyclopentadiene (208g, 3.2mol), 2-ethyl-2-oxazoline (17g, 0.20mol) and copper chloride (14g, 0.10mol) and copper chloride (14g, 0.10mol) successively in the reaction flask, and maintain The inner temperature of the reaction bottle was stirred for 10 minutes at 20-30°C. Then air (286 g, 2.5 mol) was slowly bubbled into the reaction flask, and the whole system was stirred and reacted under this condition for 12 hours. Afterwards, add water to dilute the system, and separate the liquids to obtain an organic phase, and then extract the aqueous phase with ethyl acetate. The combined organic phases were washed with saturated brine and dried, and the organic solvent was removed by rotary evaporation un...

Embodiment 2

[0050] Steps 1-2 and steps 4-6 in this implementation are the same as in Example 1.

[0051]

[0052] (3) Synthesis of cis-(+)-N-[4-hydroxyacetyl ester cyclopent-2-en-1-yl] tert-butyl carbamate

[0053]Intermediate (+ / -)-3 obtained in the third step was added to a 3L reaction flask, and then methylene chloride (830 mL), vinyl acetate (680 g, 8.0 mol, 5 equiv.) and Lipozyme40086 ( 22g). The whole reaction system was stirred and reacted at room temperature (25° C.) for 48 hours. Pad celite was filtered to remove the enzyme catalyst, and then the filtrate was concentrated by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (elution machine: n-hexane / ethyl acetate mixed system) to obtain about 158 ​​g of optically pure intermediate III, with a yield of 41% and an ee value >99%.

Embodiment 3

[0055] Steps 1-5 in this implementation are the same as in Example 1.

[0056]

[0057] (6) Synthesis of (1R,3S)-3-aminocyclopentanol hydrochloride

[0058] Add 250mL methanol to the dry reaction flask, then add acetyl chloride (70g, 0.89mol, 1.5equiv.) dropwise to the reaction flask under the condition of nitrogen protection, and keep the temperature of the system not exceeding 25 ℃, methanol solution of hydrogen chloride is generated in situ. After the methanol solution of hydrogen chloride was prepared, the intermediate was dissolved in 250 mL of methanol and added dropwise to the methanol solution of hydrogen chloride. After the dropwise addition, the whole system was reacted at room temperature (25° C.) for 12 hours. After the reaction is complete, distill and concentrate under reduced pressure to obtain a brown oily crude product, which is then recrystallized with isopropanol to obtain the target product (1R,3S)-3-amino-cyclopentanol hydrochloride as a white solid ...

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Abstract

The invention discloses a method for preparing (1R, 3S) 3-aminocyclopentanol hydrochloride, belongs to the field of organic chemical synthesis, and provides a process route to overcome the defects ofhigh price, difficulty in chiral control and the like in the prior art. The process route comprises the following steps: 1) oxidizing tert-butyl carbonate hydroxylamine into tert-butyl carbonate nitrosyl under the catalysis of copper chloride and 2-ethyl-2-oxazoline, then carrying out a hetero Diels-Alder reaction with cyclopentadiene in situ; 2) selectively reducing nitrogen-oxygen bonds in a zinc powder-acetic acid reaction system; 3) under the catalysis of lipase, reacting with vinyl acetate to optically and selectively realize chiral resolution; 4) reducing double bonds through palladium carbon hydrogenation; 5) under the alkaline condition of lithium hydroxide-methanol, performing deacetylation protection; and 6) removing tert-butyl carbonate protection in a hydrogen chloride isopropanol acid solution prepared from acetyl chloride and isopropanol in situ, and forming hydrochloride in situ to obtain a target product. The synthetic method has the beneficial effects that the synthetic method has the characteristics of novel and short route, high optical purity, low cost and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a method for (1R,3S)-3-aminocyclopentanol hydrochloride. Background technique [0002] The method of (1R,3S)-3-aminocyclopentanol hydrochloride is the key chiral intermediate of anti-AIDS drug Bictegravir. [0003] [0004] (1R,3S)-3-Aminocyclopentanol hydrochloride structure [0005] At present, there are three main synthetic routes for this intermediate. Among them, as shown in the synthetic route 1, the target product is obtained by using an expensive chiral source (-)-Vince, and then undergoes a five-step reaction. Chiral control has advantages, but the cost control of this route is difficult due to the high price of starting materials. In addition, the use of format reagents in the process of scale-up production will have certain safety risks. [0006] [0007] Synthetic Route 2 uses CbzCl to protect hydroxylamine hydrochloride, and then mixes i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C215/44C07C269/06C07C271/24C07D261/20
CPCC07C213/02C07C215/44C07C269/06C07D261/20C07C2601/10C07C2601/08C07B2200/07C07C271/24
Inventor 费安杰叶伟平周章涛王杨程冰心
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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