Synthesis method of bictegravir intermediate

A synthesis method and intermediate technology, applied in the field of medicinal chemistry, can solve the problems of high equipment and personnel operation requirements, no large synthetic route, large amount of waste residue, etc., to avoid chemical splitting, short reaction route and less by-products Effect

Active Publication Date: 2019-08-06
INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic method has the following disadvantages: (1) chiral (-)-venslides are prepared by chemical resolution of venslides, which is expensive; (2) the reaction needs to use palladium carbon catalytic hydrogenation and Grignard reagent , high requirements for equipment and personnel operation, high production cost; (3) long reaction route, low yield, large amount of waste water and waste residue
[0008] Chinese patent document CN201810503486 discloses a preparation method of (1R,3S)-3

Method used

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  • Synthesis method of bictegravir intermediate
  • Synthesis method of bictegravir intermediate
  • Synthesis method of bictegravir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: the preparation of (3R)-3-hydroxycyclopentane carboxylic acid (formula II)

[0039]

[0040] Add 500ml of 0.1mol / L phosphate buffer (pH=6.7), 50g of 3-oxocyclopentacarboxylic acid into a 1L reaction flask, and stir to dissolve completely. Then add 10 g of carbonyl reductase, 5 g of coenzyme NAD+, 25 g of glucose, and 5 g of glucose dehydrogenase. The system was reacted at 25°C and stirred for 24 hours. The system was filtered with 20 g of diatomaceous earth, and the aqueous phase was extracted three times with ethyl acetate, each time with 200 ml. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to obtain 52.2 g of a pale yellow oil. ee value ≥ 98.5%, yield 102.8%.

[0041] ESI-MS 129.1(M-1).

Embodiment 2

[0042] Example 2: Preparation of (1R,5S)-2-oxo-4-azabicyclo[3.2.1]octan-3-one

[0043]

[0044] Add 400ml of toluene, 50g of (3R)-3-hydroxycyclopentanecarboxylic acid, and 116.2g of diphenylphosphoryl azide into a 1L reaction flask, and heat up to 70-80°C for 10 hours. Cool the reaction system to below 30°C, add 300ml 10% sodium carbonate aqueous solution and stir for 30 minutes, separate the liquids, add 300ml 10% sodium carbonate aqueous solution and stir for 30 minutes, separate the liquids again and combine the water phases, and use 400ml toluene for the water phases After extraction, the toluene phases were combined, dried over anhydrous sodium sulfate, and the toluene was dried under reduced pressure to obtain 48.3 g of a tan solid. 48.3 g of tan solid was recrystallized from 150 ml of acetonitrile to obtain 31.6 g of pale yellow solid. ee value ≥ 97%, yield 64.8%. ESI-MS 128.1 (M+1).

[0045]1H-NMR

[0046] (500MHz, DMSO) δ5.00(m, 1H), 4.10(p, 1H), 3.41(hept, 1H)...

Embodiment 3

[0048] Embodiment 3: Preparation of (1R,3S)-3-aminocyclopentanol hydrochloride

[0049]

[0050] Add 200ml of 4mol / L hydrochloride and 20g of (1R,5S)-2-oxo-4-azabicyclo[3.2.1]octan-3-one into a 500ml reaction bottle, heat up to reflux reaction, and react for 5 hours . After cooling down, concentrate under reduced pressure, add 200ml of pure water after basically shrinking to dryness, then add 3g of activated carbon and stir at room temperature for 2 hours to decolorize. Filter, evaporate the filtrate to dryness under reduced pressure, add 200ml of toluene to concentrate under reduced pressure, and take away the remaining water in the product. Add 100ml of acetonitrile to the finally obtained solid, stir well, filter and dry the solid to obtain 20.7g of white solid. ee value ≥ 97%, yield 95.4%. The overall yield of the synthetic route is 63.5%. ESI-MS 102.1 (M+1).

[0051] 1H-NMR (500MHz, D2O)

[0052] δ4.29 (m, 1H), 3.64 (tt, 1H), 2.17 (m, 1H), 2.07 (m, 1H), 1.77 (m, ...

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Abstract

The invention discloses a synthesis method of a bictegravir intermediate. Starting material 3-carbonyl cyclopentacarboxylic acid (formula I) undergoes asymmetric reduction reaction under the conditionof an enzyme to generate (3R)-3-hydroxycyclopentane carboxylic acid (formula II); the (3R)-3-hydroxycyclopentane carboxylic acid (formula II) and diphenylphosphoryl azide (DPPA) undergoe rearrangement cyclization reaction to generate (1R, 5S)-2-oxy-4-azabicyclo [3.2.1] octane-3-one (formula III); the (1R, 5S)-2-oxy-4-azabicyclo [3.2.1] octane-3-one (formula III) is hydrolyzed in hydrochloric acidto directly obtain the bictegravir intermediate (1R, 3S)-3-aminocyclopentanol hydrochloride. The raw materials used in the method are cheap and easily available, and the cost is low; the reaction selectivity is high, by-products are few, the yield is high, and the total yield reaches 63.5%; the synthesis method has the advantages of short reaction route, shortened production period, reduced discharge of three wastes, avoidance of hydrogen pressure reduction and Grignard reagent reaction, safety and environmental protection, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of a Bictegravir intermediate (1R, 3S)-3-aminocyclopentanol hydrochloride. Background technique [0002] Bictegravir is a new anti-AIDS drug developed by Gilead Sciences, which belongs to HIV integrase inhibitors. In February 2018, the new AIDS cocktail therapy drug Biktarvy (Bictegravir50mg+Emtricitabine200mg+Tenofovir Alafenamide 25mg) was launched. EvaluatePharma expects Biktarvy sales to reach $4.3 billion in 2022. [0003] The chemical structural formula of Bictegravir is as follows: [0004] [0005] The synthesis process of Bictegravir bulk drug involves the synthesis of intermediate (1R,3S)-3-aminocyclopentanol hydrochloride. Gilead's patent WO2015195656 discloses a synthesis method of (1R,3S)-3-aminocyclopentanol hydrochloride, the chemical reaction route is as follows: [0006] [0007] The method uses (-)-venslide as the initi...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/44
CPCC07C213/00C07D265/12C07C51/367C07C62/02C07C215/44
Inventor 路文娟王延风张平平石秀娟孙倩李文艺韩林妗王鑫怡
Owner INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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