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【结 构 式】 
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【分子编号】16575 【品名】1-ethynylcyclopropane; cyclopropyl acetylene 【CA登记号】6746-94-7 |
【 分 子 式 】C5H6 【 分 子 量 】66.10264 【元素组成】C 90.85% H 9.15% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |
合成路线2
该中间体在本合成路线中的序号：(VII)The acylation of 4-methoxyaniline (I) with pivaloyl chloride (II) and TEA in CH2Cl2 gives the anilide (III), which is condensed with ethyl trifluoroacetate (IV) by means of n-BuLi in THF yielding the trifluoroacetyl derivative (V). The hydrolysis of the amido group of (V) with 6N HCl in refluxing DMF affords the 2-aminoacetophenone (VI), which is condensed with cyclopropylacetylene (VII) by means of n-BuLi in THF to give the tertiary alcohol (VIII). Finally, this compound is cyclized with phosgene and DIPEA in toluene yielding the racemic form of target compound.
| 【1】 Ko, S.S.; Patel, M.; Cordova, B.C.; Klabe, R.M.; Srivastava, A.S.; Markwalder, J.A.; McHugh, R.J. Jr.; Seitz, S.P.; Trainor, G.L.; Erickson-Vittanen, S.; Synthesis and evaluation of analogs of efavirenz (Sustiva(TM)) as HIV-1 reverse transcriptase inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2805. |
| 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) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 40412 | N-(4-methoxyphenyl)-2,2-dimethylpropanamide | C12H17NO2 | 详情 | 详情 | |
| (IV) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (V) | 40413 | N-[4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl]-2,2-dimethylpropanamide | C14H16F3NO3 | 详情 | 详情 | |
| (VI) | 40414 | 1-(2-amino-5-methoxyphenyl)-2,2,2-trifluoro-1-ethanone | C9H8F3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 40415 | 2-(2-amino-5-methoxyphenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C14H14F3NO2 | 详情 | 详情 |