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【结 构 式】

【分子编号】16582

【品名】6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

【CA登记号】

【 分 子 式 】C14H9ClF3NO2

【 分 子 量 】315.6789096

【元素组成】C 53.27% H 2.87% Cl 11.23% F 18.05% N 4.44% O 10.14%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.

1 Choudhury, A.; Moore, J.R.; Pierce, M.E.; Fortunak, J.M.; Valvis, I.; Confalone, P.N.; In situ recycling of chiral ligand and surplus nucleophile for a noncatalytic reaction: Amplification of process throughput in the asymmetric addition step of efavirenz (DMP 266). Org Process Res Dev 2003, 7, 3, 324.
2 Britcher, S.F.; Tran, L.O.; Young, S.D.; L-743,726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995, 39, 12, 2602-5.
3 Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726. Tetrahedron Lett 1995, 36, 49, 8937-40.
4 Graul, A.; Rabasseda, X.; Castañer, J.; Efavirenz. Drugs Fut 1998, 23, 2, 133.
5 Young, S.D.; Britcher, S.F.; Payne, L.S.; Tran, L.O.; Lumma, W.C. Jr. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. WO 9520389 .
6 Young, S.D.; Tran, L.O.; Britcher, S.F.; Lumma, W.C. Jr.; Payne, L.S. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. EP 0582455; JP 1994184124; WO 9403440 .
7 Thompson, A.S.; Corley, E.G.; Huntington, M. (Merck & Co., Inc.); Improved synthesis of cyclopropylacetylene. JP 1998512880; WO 9622955 .
8 Thompson, A.S.; Corley, E.G.; Grabowski, E.J.J.; Yasuda, N. (Merck & Co., Inc.); Asymmetric synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one. WO 9637457 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(II) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(III) 16571 4'-Chloro-2,2-dimethylpropionanilide; N-(4-Chlorophenyl)-2,2-dimethylpropanamide 65854-91-3 C11H14ClNO 详情 详情
(IV) 16572 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone C8H5ClF3NO 详情 详情
(V) 11910 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether 824-94-2 C8H9ClO 详情 详情
(VI) 16574 1-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-2,2,2-trifluoro-1-ethanone C16H13ClF3NO2 详情 详情
(VII) 16575 1-ethynylcyclopropane; cyclopropyl acetylene 6746-94-7 C5H6 详情 详情
(VIII) 16576 5-chloro-1-pentyne 14267-92-6 C5H7Cl 详情 详情
(IX) 16577 (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol C13H19NO 详情 详情
(X) 16578 (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol C21H19ClF3NO2 详情 详情
(XI) 16579 (4S)-6-chloro-4-(2-cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one C22H17ClF3NO3 详情 详情
(XII) 16580 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol 168834-43-3 C13H11ClF3NO 详情 详情
(XIII) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(XIV) 16582 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one C14H9ClF3NO2 详情 详情
(XV) 16583 (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride 39637-74-6 C10H13ClO3 详情 详情
(XVI) 16584 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one C24H21ClF3NO5 详情 详情
Extended Information