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Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection

A kind of compound and solvate technology, used in the field of preparation of therapeutic compounds and intermediates that can be used for the treatment of retroviral infection

Active Publication Date: 2020-12-08
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science 2010, 327:697-701 )

Method used

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  • Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection
  • Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection
  • Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[1136] Example 1a: Preparation of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII-02) or its co- Crystals, solvates, salts or combinations, and starting materials and / or intermediates therein

[1137]

[1138] Synthesis of 3,6-Dibromopyridinecarbaldehyde (1a)

[1139]

[1140] 2,5-Dibromopyridine (1.0 g) was added to a dry reaction vial with a magnetic stir bar. The flask was inertized under nitrogen, THF (4.2 mL) was added, and the slurry was stirred. Separately, 2,2,6,6-tetramethylpiperidinylmagnesium chloride, lithium chloride complex (TMPMgCl·LiCl) (5.8ml, 6.3mmol) was added in a dry glass reactor. The TMPMgCl·LiCl solution was stirred and cooled to about -20°C. The 2,5-dibromopyridine solution was added to the TMPMgCl·LiCl solution over about 30 minutes, keeping the temperature below about -18°C. After the addition was complete, the flask was rinsed into the reactor with three additional portions of THF (1 mL x 2) and aged at about -2...

Embodiment 1b

[1168] Example 1b: For the formation of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII) or its co- Preparation of Alternative Starting Materials and Intermediates for Crystals, Solvates, Salts or Combinations

[1169] Synthesis of (R)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-ol (XII)

[1170]

[1171] Compound XI (1.00 g) and (R)-RuCY-XylBINAP (16 mg, 0.05 equiv) were charged into a stainless steel autoclave fitted with a glass inner tube. EtOH (1.0 mL) and IPA (1.0 mL) were added to the autoclave, followed by tert-BuOK (1.0 M solution in THF, 0.51 mL, 0.2 equiv). with H 2 After purging, add 3MPa to the autoclave H 2 . The mixture was stirred at about 20°C for about 10 hours. Concentrated aqueous HCl was added to the mixture, and the pH was adjusted to 2. 1H NMR (400MHz, CDCl3): δ7.72(d, J=8.2Hz, 1H), 7.33(d, J=8.2Hz, 1H), 6.80–6.72(m, 2H), 6.68(tt, J=9.2 ,2.4 Hz,1H),5.16(dd,J=8.2,3.4Hz,1H),3.60(br,1H),3.12(dd,J=13.8,3....

Embodiment 1c

[1196] Example 1c: Racemization via (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII) Preparation of 1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (X)

[1197]

[1198] A vial was charged with zinc acetate (25M%), enantiomerically enriched VIII (1.0 g, enantiomeric ratio 92:8), toluene (10 ml) and 2-formylpyridine (5 mol%). The vial was warmed to about 60°C and stirred for about 4 hours.

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Abstract

The present disclosure relates to methods and intermediates useful for preparing a compound of formula (I); or a co-crystal, solvate, salt or combination thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application 62 / 710,575, filed February 16, 2018, the entire contents of which are hereby incorporated by reference. technical field [0003] The present disclosure relates to methods and intermediates for the synthesis of novel compounds useful in the treatment of retroviridae viral infections, including infections caused by the HIV virus. Background technique [0004] The present disclosure generally relates to the field of organic synthesis methodologies for the preparation of antiviral compounds and their synthetic intermediates. [0005] Positive single-stranded RNA viruses that make up the family Retroviridae include those of the subfamily Orthoretrovirinae, and the alpha, beta, and gamma retroviruses that cause many human and animal diseases. Viruses, delta retroviruses, epsilon retroviruses, lentiviruses, and those of the spumaretrovirus genus. Among len...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D231/54C07D231/56C07D339/06C07D401/12C07C45/61C07D495/10C07D213/61
CPCC07D213/61C07D401/12C07D401/14C07D231/56C07D231/54C07D495/10C07D339/06C07C45/65A61P31/14C07B2200/07C07C2602/18C07C49/427C07C45/673C07C59/50A61K31/4439A61P31/18
Inventor K·M·艾伦A·L·范德海G·布里吉斯S·达尔I·J·多克斯塞A·戈尔德贝格L·V·休曼黄子林N·T·卡敦克S·卡策拉尼W·卢V·X·恩格B·M·奥克菲T·J·雷尼B·J·罗伯茨石兵D·P·斯坦休贝尔W·C·特斯A·M·瓦格纳王翔宏S·A·沃尔肯豪尔C·Y·王J·R·张
Owner GILEAD SCI INC
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