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Asymmetric synthesis of benzoxazinones via new intermediates

A compound, aniline technology, applied in the field of human immunodeficiency virus reverse transcriptase inhibitors, can solve problems such as expensive and unstable

Inactive Publication Date: 2000-04-26
DU PONT PHARMA CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] To this end, the present invention provides a novel benzylation method using acid-catalyzed benzyl alcohols instead of the corresponding benzyl chloride analogues, which are relatively more expensive and unstable

Method used

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  • Asymmetric synthesis of benzoxazinones via new intermediates

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Experimental program
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Effect test

Embodiment 1

[0216] Preparation of N-(4-chlorophenyl)-2,2-dimethylpropanamide. 4-Chloroaniline (52.7kg, 413mol) was dissolved in a mixture of tert-butyl methyl ether (180kg), 30% aqueous sodium hydroxide solution (61.6kg, 463mol) and water (24.2kg), then cooled to 15°C. To the resulting slurry was added trimethylacetyl chloride (52.2 kg, 448 mol) over 1 hour keeping the temperature below 40°C. After stirring at 30°C for 30 minutes, the slurry was cooled to -10°C and held for 2 hours. The product was collected by filtration, washed with a 90 / 10 water / methanol solution (175 kg), and dried in vacuo to afford 85 kg (97% yield) of the title compound as a crystalline solid.

[0217] mp152-153°C; 1 H NMR (300MHz, CDCl 3 )δ7.48(d, J=9Hz, 2H)7.28(d, J=9Hz, 2H); 13 C NMR (75MHz, CDCl 3 )d176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.

[0218] Preparation of N-(4-fluorophenyl)-2,2-dimethylpropanamide. Those skilled in the art of organic synthesis should know that this compound can be e...

Embodiment 2

[0220] Preparation of the hydrochloride hydrate of 4-chloro-2-trifluoroacetylaniline. N-(4-chlorophenyl)-2,2-dimethylpropanamide (36.7kg, 173mol) was added to TMEDA (20.2kg, 174mol) in anhydrous tert-butyl methyl ether (271.5kg) solution, and then Cool to -20°C. To this cold slurry was added 2.7N n-butyllithium in hexane (101.9 kg, 393 mol) while maintaining the temperature below 5°C. After aging at 0-5°C for 2 hours, the solution was cooled to below -15°C and reacted rapidly with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 minutes, the resulting solution was poured into 3N HCl (196 L, 589 mol) maintaining the temperature below 25 °C. After removing the aqueous phase, the organic solution was concentrated by distilling off approximately 200 L of solvent. Acetic acid (352 kg) was added while 325 kg of solvent was distilled off under 100 mm vacuum. After the solution was cooled to 30°C, 12N HCl (43.4kg, 434mol) was added, and the mixture was heated to 65-70°C for 4 h...

Embodiment 3-a

[0223] Preparation of 4-chloro-2-trifluoroacetylaniline. 4-Chloro-2-trifluoroacetylaniline hydrochloride hydrate (17.1 g, 62 mmol) was stirred in a mixture of toluene (100 ml) and water (50 ml). with saturated NaHCO 3 The solution neutralized the mixture to pH7. The organic phase was then concentrated in vacuo and the residue was recrystallized from heptane to afford 12.5 g (91%) of the title compound as yellow needles: mp 98-99°C.

[0224] 1 H NMR (300MHz, CDCl 3 )δ7.70(t, J=2Hz, 1H), 7.32(dd, J=2, 9Hz, 1H), 6.7(d, J=9Hz, 1H), 6.44(brs, 2H); 13 C NMR (75MHz CDCl 3 )δ180.0, 151.6, 136.9, 130.1, 120.9, 119.0, 116.8, 111.4; 19 F NMR (282 MHz, CDCl 3 )δ-70.3.

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Abstract

The present invention provides novel methods for the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of formula (VI-i) which is useful as a human immunodeficiency virus (HIV) reverse transcriptase inhibitor. In an embodiment, the present invention provides a process for the preparation of an amino alcohol compound of formula (V-i) comprising adding a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a toluene solution of a compound of formula (III-i), via a compound of formula (IV-i).

Description

field of invention [0001] The present invention provides the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazine-2- A new approach to ketones, compounds that can be used as human immunodeficiency virus (HIV) reverse transcriptase inhibitors. Background of the invention [0002] Reverse transcription is a common feature of retroviral replication. Viral replication requires a virally encoded reverse transcriptase to generate a DNA replica with viral sequences by retroviral RNA genome. Since inhibition of virally encoded reverse transcriptase interrupts viral replication, reverse transcriptase is clinically a relevant target for chemotherapy of retroviral infections. [0003] Many compounds are effective in treating human immunodeficiency virus (HIV), a retrovirus that progressively destroys the human immune system, resulting in AIDS. Known therapeutics effective in the treatment by inhibiting HIV reverse tra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/16A61P31/18A61P37/04C07C213/00C07C213/02C07C215/68C07C215/70C07C217/58C07C221/00C07C225/22C07D265/18
CPCC07C213/02C07C221/00C07C2101/02C07C213/00C07D265/18C07C2601/02A61P31/18A61P37/04C07C215/68C07C217/58C07C225/22
Inventor M·E·皮尔斯C·Y·陈A·乔杜里L·A·拉德斯卡L·谭D·赵
Owner DU PONT PHARMA CO
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