Intermediate for preparing bictegravir and preparation method thereof

A technology for intermediates and compounds, which is applied in the preparation of intermediates for bictegravir and the preparation field thereof, can solve the problems of low yield, low epoxidation yield and high cost, achieve high yield, mild route reaction conditions, and improve stereo selective effect

Active Publication Date: 2018-12-18
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this route is cheap and easy to get raw materials, the first step epoxidation yield is lower; the second step reaction needs to use non-recoverable homogeneous palladium catalyst, and the yield is lower; the product obtained is a racemate, The cost of later chiral resolution is high

Method used

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  • Intermediate for preparing bictegravir and preparation method thereof
  • Intermediate for preparing bictegravir and preparation method thereof
  • Intermediate for preparing bictegravir and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] The compound of formula I is condensed with hydroxylamine to obtain the compound of formula II; wherein RCOOH is D-alanine.

[0072]

[0073] Dissolve 147.8g of the compound of formula I in 450mL of tetrahydrofuran, add 79.5g of triethylamine, lower the temperature to 0-5°C, add 106.5g of isobutyl chloroformate dropwise, a large amount of solids precipitate out, and keep warm for 2 hours; dissolve 81.75g ​​of hydroxylamine hydrochloride in In 750mL of methanol, cool down to 0-5°C, add sodium hydroxide in batches, a large amount of solids precipitate, keep warm for 2h, add the filtrate from step 1, and continue stirring for 2h. Suction filtration, the filtrate was concentrated under reduced pressure, 1L ethyl acetate was added, a white solid precipitated, suction filtration, the filter cake was washed with 200mL ethyl acetate, and concentrated to dryness. 750mL of dichloromethane was beaten, suction filtered, and air-dried at 45°C to obtain 137.2g of white solid with ...

Embodiment 2

[0075] The compound of formula II is oxidized and asymmetric Diels-Alder reaction to obtain the compound of formula III; wherein RCOOH is D-alanine.

[0076]

[0077] 12.5 g of the compound of formula II was dissolved in 300 mL of methanol and 100 mL of water, and the temperature was lowered to 0-5°C. Add 12.6g of sodium periodate and 14mL of cyclopentadiene, the color of the solution becomes dark rapidly, a large amount of light yellow solid precipitates, the temperature rises slightly, and the temperature is controlled not to exceed 5°C. After stirring for 30min, add 10mL of cyclopentadiene and 7.6 g sodium periodate, heat preservation reaction 1h. Spin-dried, column chromatography gave 11.9 g of white solid, yield 73%.

[0078] 1 H NMR (500MHz, DMSO-d 6 )δ6.97(s,1H),6.55–6.50(m,1H),6.43(s,1H),5.45(s,1H),5.28(s,1H),4.15(s,1H),1.85(d ,J=9.1Hz,1H),1.78(d,J=8.9Hz,1H),1.36(s,9H),0.91(s,3H).

Embodiment 3

[0080] The compound of formula III obtains the compound of formula IVa through cleavage of the amide bond, and the compound of formula IVa undergoes catalytic hydrogenation and Boc protection to obtain the compound of formula V; wherein RCOOH in the compound of formula III is D-alanine;

[0081]

[0082]

[0083] Dissolve 10g of the compound of formula III in 60mL of methanol and 20mL of water, add 2.5g of lithium hydroxide at room temperature, stir for 2h, add 8.1g of Boc anhydride, and stir for 1h at room temperature. Spin dry, add 20mL water, extract twice with 30mL dichloromethane, and dry over anhydrous sodium sulfate. Spinning to dryness and column chromatography gave 3.6 g of the compound of formula V as an oil, with a yield of 48%.

[0084] 1 H NMR (500MHz, DMSO-d6) δ6.63 (d, J = 7.7Hz, 1H), 4.54 (d, J = 4.5Hz, 1H), 4.06-3.97 (m, 1H), 3.70 (h, J = 7.3Hz, 1H), 2.01(dt, J=13.5, 6.9Hz, 1H), 1.79-1.66(m, 1H), 1.63(ddt, J=13.8, 10.0, 6.5Hz, 1H), 1.50(pd, J =8.5,4.6...

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PUM

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Abstract

The invention relates to the technical field of a drug, and concretely relates to an intermediate for preparing bictegravir and a preparation method thereof. The present invention provides two novel types of compounds and three routes for preparation of a compound (VI). Through substrate induction, chiral catalysis or synergistic effect of substrate induction and chiral catalysis, the stereoselectivity of a Diels-Alder reaction can be greatly improved, and a high chiral purity of a common intermediate (III) can be obtained; cut-out of N-O bond and reduction the double bond use catalytic hydrogenation, which can be environmentally friendly; the reaction conditions are mild, the yield is higher than the existing preparation method, the method is economic and effective, and is adapted to large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an intermediate for preparing bictegravir and a preparation method thereof. Background technique [0002] Bictegravir (GS-9883) is a new class of integrase inhibitors developed by Gilead. Unlike the previously developed integrase inhibitors, Bictegravir only needs to be used once a day and does not require the synergist cobicistat. It is currently in the first phase of clinical trials. Phase 3, namely the study of the TAF / FTC / BIC program. Previous studies have shown that Bictegravir is well tolerated in healthy people, can inhibit renal tubular transport proteins, reduce creatinine levels, and lead to a decrease in glomerular filtration rate, but does not damage renal function. In addition, Bictegravir has a higher resistance barrier than other integrase inhibitors and has fewer interactions with other drugs. [0003] At the 2017 CROI Conference in Boston, the results of an on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20C07C213/08C07C215/44C07C259/06C07C269/06C07C271/24
CPCC07C213/08C07C215/44C07C259/06C07C269/06C07C271/24C07D261/20C07C2601/08C07B2200/07
Inventor 孙光祥张云然孙海江王敏峰陶维洁付军马旭伟李新刚
Owner CHANGZHOU PHARMA FACTORY
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