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【结 构 式】 
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【药物名称】Ritonavir, A-84538, ABT-538, Norvir 【化学名称】N-[N-(2-Isopropylthiazol-4-ylmethyl)-N-methylcarbamoyl]-L-valine 1(S)-benzyl-3(S)-hydroxy-5-phenyl-4(S)-(thiazol-5-ylmethoxycarbonylamino)pentylamide 【CA登记号】155213-67-5 【 分 子 式 】C37H48N6O5S2 【 分 子 量 】720.96031 |
【开发单位】Abbott (Originator), Dainippon Pharmaceutical (Licensee) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors |
合成路线1
The oxidation of N-(benzyloxycarbonyl)-L-phenylalaninol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which by dimerization with Zn dust in dichloromethane yields (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexane-3,4-diol (III) [along with the (2S,3S,4S,5S)-isomer]. The reaction of (III) with alpha-acetoxyisobutyryl bromide (IV) in hexane/dichloromethane affords (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexan-3-ol acetate ester (V), which is converted into the corresponding epoxide (VI) with NaOH in dioxane/water. The reduction of the epoxide (VI) with NaBH4 in THF affords (2S,3S,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexan-3-ol (VII), which is deprotected with Ba(OH)2 in refluxing dioxane/water yielding the corresponding diamine (VIII). The cyclization of (VIII) with phenylboronic acid (IX) in refluxing toluene gives (4S,6S)-6-[1(S)-amino-2-phenylethyl]-4-benzyl-2-phenyl-1,3,2-oxaazaborinane (X), which is condensed with (5-thiazolylmethyl)(4-nitrophenyl)carbonate (XI) in THF to afford (2S,3S,5S)-5-amino-1,6-diphenyl-2-(5-thiazolylmethoxycarbonylamino) hexan-3-ol (XII). Finally, this compound is condensed with N-[N-(2-isopropylthiazol-4-ylmethyl)-N-methylaminocarbonyl]-L-valine (XIII) by means of 1-hydroxybenzotriazole (HBT) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (DEC) in THF.
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【3】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 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) | 16585 | benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (III) | 16587 | benzyl (1S,2R,3R,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (IV) | 12806 | 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide | 40635-67-4 | C6H9BrO3 | 详情 | 详情 |
| (V) | 16589 | (1R,2R,3S)-3-[[(benzyloxy)carbonyl]amino]-1-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2-bromo-4-phenylbutyl acetate | C36H37BrN2O6 | 详情 | 详情 | |
| (VI) | 16590 | benzyl (1S)-1-[(2R,3R)-3-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)oxiranyl]-2-phenylethylcarbamate | C34H34N2O5 | 详情 | 详情 | |
| (VII) | 16591 | benzyl (1S,2S,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2-hydroxy-5-phenylpentylcarbamate | C34H36N2O5 | 详情 | 详情 | |
| (VIII) | 16592 | (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol | C18H24N2O | 详情 | 详情 | |
| (IX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (X) | 16594 | (1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenylethylamine; (1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenyl-1-ethanamine | C24H27BN2O | 详情 | 详情 | |
| (XI) | 16595 | 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate | 144163-97-3 | C11H8N2O5S | 详情 | 详情 |
| (XII) | 16596 | 1,3-thiazol-5-ylmethyl N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]carbamate | C23H27N3O3S | 详情 | 详情 | |
| (XIII) | 16597 | (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid | C14H23N3O3S | 详情 | 详情 |
合成路线2
The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 16595 | 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate | 144163-97-3 | C11H8N2O5S | 详情 | 详情 |
| (XIV) | 16598 | Formamide | 75-12-7 | CH3NO | 详情 | 详情 |
| (XV) | 16599 | Thioformamide | CH3NS | 详情 | 详情 | |
| (XVI) | 16600 | ethyl 2-chloro-3-oxopropanoate | C5H7ClO3 | 详情 | 详情 | |
| (XVII) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (XVIII) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XIX) | 16603 | ethyl 1,3-thiazole-5-carboxylate | 32955-22-9 | C6H7NO2S | 详情 | 详情 |
| (XX) | 16604 | 1,3-thiazol-5-ylmethanol;5-thiazolylmethanol;Thiazole-5-methanol | 38585-74-9 | C4H5NOS | 详情 | 详情 |
| (XXI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
合成路线3
The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 16597 | (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid | C14H23N3O3S | 详情 | 详情 | |
| (XXI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XXII) | 16606 | Isobutyramide; 2-methylpropanamide | 563-83-7 | C4H9NO | 详情 | 详情 |
| (XXIII) | 16607 | 2-methylpropanethioamide | 13515-65-6 | C4H9NS | 详情 | 详情 |
| (XXIV) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XXV) | 16609 | 4-(chloromethyl)-2-isopropyl-1,3-thiazole | C7H10ClNS | 详情 | 详情 | |
| (XXVI) | 16610 | (2-isopropyl-1,3-thiazol-4-yl)-N-methylmethanamine; N-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-N-methylamine | 154212-60-9 | C8H14N2S | 详情 | 详情 |
| (XXVII) | 16611 | methyl (2S)-3-methyl-2-[[(4-nitrophenoxy)carbonyl]amino]butanoate | C13H16N2O6 | 详情 | 详情 | |
| (XXVIII) | 16612 | methyl (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutanoate | C15H25N3O3S | 详情 | 详情 | |
| (XXIX) | 16613 | methyl (2S)-2-amino-3-methylbutanoate | C6H13NO2 | 详情 | 详情 |
合成路线4
A new method for the preparation of a key diaminoalcohol intermediate in the synthesis of ritonavir has been described: The reaction of L-phenylalanine (XXIX) with benzyl chloride by means of K2CO3 and KOH in hot water gives N,N-dibenzyl-L-phenylalanine benzyl ester (XXX), which is condensed first with acetonitrile by means of NaNH2 and then with benzylmagnesium chloride, both reactions in methyl tert-butyl ether, yielding 5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one (XXXI). The reduction of (XXXI) with NaBH4 with an accurate control of the solvent and acidity, results in an enhanced enantioselectivity towards the desired (S,S,S)-enantiomer of 5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol (XXXII). Finally, this compound is deprotected by hydrogenation with ammonium formate over Pd/C in methanol/water to provide the target chiral diaminoalcohol (VIII).
| 【1】 Allen, M.S.; Stuk, T.L.; Haight, A.R.; et al.; Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir. Org Process Res Dev 1999, 3, 2, 94. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 16592 | (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol | C18H24N2O | 详情 | 详情 | |
| (XXIX) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XXX) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (XXXI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (XXXII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 |
合成路线5
The reaction of N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester (I) with trimethylphosphonate lithium salt (II) in THF gives the dimethyl L-phenylalanylmethylphosphonate (III), which is condensed with 2-phenylacetaldehyde (IV) by means of Na2CO3 in ethanol yielding the diphenylhexenone (V). The reduction of the carbonyl group of (V) with NaBH4 in methanol affords a diastereomeric mixture of alcohols (VI) and (VII) from which the desired major isomer (VII) is separated by column chromatography.. The epoxidation of the double bond of (VII) with MCPBA in dichloromethane gives the epoxide (VIII) (1), which is cleaved with Red-Al in THF providing the diol (IX). The reaction of (IX) with Ms-Cl and DIEA yields the intermediate dimesylate (X) which, without isolation, affords oxazolidinone (XI). The reaction of (XI) with sodium azide and 18-C-6 in DMSO gives the azide (XII), which is treated with NaH and Boc2O in THF in order to cleave the oxazolidine ring and furnish the protected aminoalcohol (XIII). Finally the azido group of (XIII) is hydrogenate with H2 over Pd/C in methanol to afford the monoprotected diaminoalcohol (XIV) the target compound.
| 【1】 Norbedo, S.; Benedetti, F.; Epoxyalcohol route to hydroxyethylene dipeptide isosteres: A new synthesis of the diaminoalcohol core of HIV-protease inhibitor ABT-538 (ritonavir). Chem Commun (London) 2001, 2, 203. |
| 【2】 Benedetti, F.; et al.; Versatile and stereoselective synthesis of diamino diol dipeptide isosteres, core units of pseudopeptide HIV protease inhibitors. J Org Chem 1997, 62, 26, 9348. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (III) | 47117 | dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbutylphosphonate | C17H26NO6P | 详情 | 详情 | |
| (IV) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (V) | 47118 | tert-butyl (1S,3E)-1-benzyl-2-oxo-5-phenyl-3-pentenylcarbamate | C23H27NO3 | 详情 | 详情 | |
| (VI) | 47119 | tert-butyl (1S,2S,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VII) | 47120 | tert-butyl (1S,2R,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VIII) | 47121 | tert-butyl (1S,2S)-1-benzyl-2-[(2R,3S)-3-benzyloxiranyl]-2-hydroxyethylcarbamate | C23H29NO4 | 详情 | 详情 | |
| (IX) | 47122 | tert-butyl (1S,2R,4R)-1-benzyl-2,4-dihydroxy-5-phenylpentylcarbamate | C23H31NO4 | 详情 | 详情 | |
| (X) | 47123 | (1R,3R)-1-[(1S)-1-[(3,3-dimethylbutanoyl)amino]-2-phenylethyl]-3-[(methylsulfonyl)oxy]-4-phenylbutyl methanesulfonate | C26H37NO7S2 | 详情 | 详情 | |
| (XI) | 47124 | (1R)-1-benzyl-2-[(4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl]ethyl methanesulfonate | C20H23NO5S | 详情 | 详情 | |
| (XII) | 47125 | (4S,5S)-5-[(2S)-2-azido-3-phenylpropyl]-4-benzyl-1,3-oxazolidin-2-one | C19H20N4O2 | 详情 | 详情 | |
| (XIII) | 47126 | tert-butyl (1S,2S,4S)-4-azido-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H30N4O3 | 详情 | 详情 | |
| (XIV) | 47127 | tert-butyl (1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 |