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Preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride

A technology of aminocyclopentanol hydrochloride and isopropanol, applied in the field of preparation of -3-aminocyclopentanol hydrochloride, can solve the problems of restricting industrial application, high application risk factor and high operation requirements, and achieves suitable Large-scale production, good process stability, high yield and high purity

Inactive Publication Date: 2018-11-09
ANHUI TWISUN HI TECH PHARM CO LTD
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  • Abstract
  • Description
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Problems solved by technology

[0007] But the m-chloroperoxybenzoic acid used in this method is a kind of strong oxidizing agent, and it is easy to explode when heated; meanwhile, m-chloroperoxybenzoic acid usually contains a certain amount of moisture, which not only affects the yield of the oxidation reaction, but also increases the amount of impurities The generation of m-chlorobenzoic acid, the by-product of the reaction, also increases the difficulty of handling; and m-chloroperoxybenzoic acid is expensive, resulting in high production costs
Simultaneously, the hydrogen chloride gas used in this method is a kind of poisonous gas with irritating smell, has strong irritating effect to eyes and respiratory tract mucous membrane, and the application risk factor in industry is high, and operation requirement is high; And, use hydrogen chloride gas to carry out Deprotection reaction, poor process stability
These characteristics seriously restrict the industrial application of this method

Method used

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  • Preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride
  • Preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride
  • Preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride

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preparation example Construction

[0033] The invention provides a preparation method of (1R,3S)-3-aminocyclopentanol hydrochloride, comprising the following steps:

[0034] (1) In a protective atmosphere, mix compound I, carbamide peroxide and an organic solvent, add trifluoroacetic anhydride to the resulting mixture, and carry out an oxidation reaction to obtain a mixture of compound II and compound II';

[0035] The structural formula of the compound I is:

[0036]

[0037] The structural formula of the compound II is:

[0038]

[0039] The structural formula of the compound II' is:

[0040]

[0041] (2) mixing the mixture of compound II and compound II' in the step (1), alkali solution and organic solvent, and performing a hydrolysis reaction to obtain compound III;

[0042] The structural formula of the compound III is:

[0043]

[0044] (3) In a protective atmosphere, the acid chloride compound and the compound III in the step (2) are sequentially added to isopropanol for a deprotection rea...

Embodiment 1

[0081](1) Under the protection of nitrogen, put 600mL tetrahydrofuran into the reaction flask, turn on the stirring device, put in 60.1g carbamide peroxide, 60g compound I, control the temperature to 0°C, and add 138.5g trifluoroacetic anhydride dropwise to the resulting mixed material After the dropwise addition was completed, the oxidation reaction was carried out with insulation for 7 hours; after the oxidation reaction was monitored by GC, the pH value of the obtained system was adjusted to 7.5 with a sodium carbonate solution with a mass concentration of 30%, and the temperature control was <10°C. layer, the obtained aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed successively with 180 mL of 5% sodium thiosulfate solution and 180 mL of saturated brine, and the obtained organic phase was dried with anhydrous sodium sulfate. After filtration, the obtained organic phase was concentrated under reduced pressure, and the obtained concentrate...

Embodiment 2

[0086] (1) Prepare the mixture of compound II and compound II' according to the method of step (1) in Example 1, the difference is that the temperature when trifluoroacetic anhydride is added dropwise is -20°C, and the temperature of the oxidation reaction is -20°C °C, the time of the oxidation reaction was 18h; the total purity of the mixture of compound II and compound II' obtained by final GC detection was 82.0%;

[0087] (2) Compound III was prepared according to the method of step (2) in Example 1, the difference being that an aqueous solution of sodium hydroxide (prepared by dissolving 25.8g of sodium hydroxide in 180mL of water) was added dropwise at 0°C, and finally Obtained 55.8g of compound III, GC detection showed that the purity was 90.5%, and the yield was 95.3%;

[0088] (3) Prepare (1R,3S)-3-aminocyclopentanol hydrochloride according to the method of step (3) in Example 1, the difference is that 71.6g propionyl chloride is used as the acid chloride compound, and...

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Abstract

The invention provides a preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride. A urea peroxide-trifluoroacetic anhydride system is adopted as an oxidizing agent, and a compound I is subjected to oxidation reaction so as to generate a compound II and a compound II', so that the use of an oxidizing agent with high price and big risk is avoided. Hydrogen chloride obtained through esterification reaction of isopropanol and an acyl chloride compound is subjected to de-protection reaction with a compound III, so that the process stability is good compared with the way of directly feeding hydrogen chloride and carrying out de-protection reaction on the hydrogen chloride and the compound III, the condition that the (1R,3S)-3-amino cyclopentanol hydrochloride can be smoothly separatedout from a reaction solution is ensured, and the method is convenient to operate and friendly to the work environment. In addition, the preparation method provided by the invention is high in productyield and purity, low in production cost, high in safety, simple to operate, and suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of (1R,3S)-3-aminocyclopentanol hydrochloride. Background technique [0002] Biktarvy is a new anti-AIDS drug developed by Gilead Sciences of the United States, which was approved by the FDA in February 2018. Biktarvy is a combination preparation containing the novel integrase inhibitor Bictegravir, the nucleoside reverse transcriptase inhibitor tenofovir alafenamide and emtricitabine. Biktarvy has a viral suppression rate of up to 93% in treatment-naïve HIV-1 infected and virally suppressed adult patients. The industry predicts that Biktarvy’s sales will reach US$896 million in 2018, rapidly rise to US$2.282 billion in 2019, and reach US$3.716 billion in 2022. The market prospect is very broad. [0003] The integrase inhibitor Bictegravir in Biktarvy is a small organic molecule drug with a complex structure. It is obtained by constructing a bridg...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/00
CPCC07B2200/07C07C213/00C07C269/06C07C2601/08C07C271/24C07C215/44
Inventor 叶方国曾青峰
Owner ANHUI TWISUN HI TECH PHARM CO LTD
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