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【结 构 式】 
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【分子编号】16586 【品名】benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate 【CA登记号】 |
【 分 子 式 】C17H17NO3 【 分 子 量 】283.32692 【元素组成】C 72.07% H 6.05% N 4.94% O 16.94% |
合成路线1
该中间体在本合成路线中的序号：(XVII)The reduction of N-(benzyloxycarbonyl)-L-phenylalanine (XVI) gives the corresponding aldehyde (XVII), which is cyclized with 2-sulfanylethylamine (XVIII) to yield the thiazolidine (XIX). The dehydrogenation of (XIX) by means of MnO2 affords the thiazole derivative (XX). Finally, the amino group of (XX) is deprotected with HBr to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XXI). Alternatively, N-(benzyloxycarbonyl)-L-phenylalanine (XVI) can be converted into the corresponding amide (XXII), which is treated with the Lawesson's reagent to yield the thioamide (XXIII). Finally, the cyclization of (XXIII) with 2-bromoacetaldehyde (XXIV) gives already reported thiazole derivative (XX) (partial racemization occurs during the synthetic process). Enantiomeric separation takes place in a later stage.
| 【1】 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 | ||
| (XVI) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (XVII) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (XVIII) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (XX) | 54604 | benzyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate | C19H22N2O2S | 详情 | 详情 | |
| (XXI) | 24802 | 2-bromoacetaldehyde | C2H3BrO | 详情 | 详情 | |
| (XXII) | 54603 | benzyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | 4801-80-3 | C17H18N2O3 | 详情 | 详情 |
| (XXIII) | 54605 | benzyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate | C19H18N2O2S | 详情 | 详情 | |
| (XXIV) | 54606 | benzyl (1S)-2-amino-1-benzyl-2-thioxoethylcarbamate | C17H18N2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(II)Reductive alkylation of aminoester (I) with N-Cbz-L-phenylalaninal (II) using NaBH3CN and AcOH in DMF provided compound (III). Subsequent deprotection of the Cbz group of (III) with HBr in AcOH afforded the diamine salt (IV), which upon basification with diisopropylamine resulted in lactamization to produce piperazinone (V). The secondary amine of (V) was then protected by alkylation with benzyl bromide to give (VI), which was condensed with the epoxisulfonamide (VII) in the presence of NaH in DMF to furnish (VIII). Finally, hydrogenolysis of the N-benzyl group in the presence of Pd(OH)2 yielded the target compound.
| 【1】 Salituro, F.G.; Baker, C.T.; Court, J.J.; Deininger, D.D.; Kim, E.E.; Li, B.; Novak, P.M.; Rao, B.G.; Pazhanisamy, S.; Porter, M.D.; Schairer, W.C.; Tung, R.D.; Design and synthesis of novel conformationally restricted HIV protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3637. |
| 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) | 20164 | methyl 1-aminocyclohexanecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (II) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (III) | 20166 | methyl 1-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropyl)amino]cyclohexanecarboxylate | C25H32N2O4 | 详情 | 详情 | |
| (IV) | 20167 | methyl 1-[[(2S)-2-amino-3-phenylpropyl]amino]cyclohexanecarboxylate hydrobromide | C17H27BrN2O2 | 详情 | 详情 | |
| (V) | 20168 | (3S)-3-benzyl-1,4-diazaspiro[5.5]undecan-5-one | C16H22N2O | 详情 | 详情 | |
| (VI) | 20169 | (3S)-1,3-dibenzyl-1,4-diazaspiro[5.5]undecan-5-one | C23H28N2O | 详情 | 详情 | |
| (VII) | 20163 | N-(cyclopentylmethyl)-4-methoxy-N-[(2R)oxiranylmethyl]benzenesulfonamide | C16H23NO4S | 详情 | 详情 | |
| (VIII) | 20171 | N-(cyclopentylmethyl)-N-[(2S)-3-[(3S)-1,3-dibenzyl-5-oxo-1,4-diazaspiro[5.5]undec-4-yl]-2-hydroxypropyl]-4-methoxybenzenesulfonamide | C39H51N3O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Wittig reaction of N-(benzyloxycarbonyl)-L-phenylalaninal (I) with methyl (triphenylphosphoranylidene)acetate produced unsaturated ester (II). Double bond reduction in (II) with concomitant cyclization and N-deprotection upon treatment with Mg in MeOH furnished (R)-5-benzyl-2-pyrrolidinone (III), which was further protected as the N-Boc derivative (IV) (1). Alkylation of (IV) with benzyl bromide in the presence of LDA in THF at -78 C provided the trans-3,5-dimethylpyrrolidinone (V) as the predominant diastereoisomer. After Boc group cleavage using trifluoroacetic acid, pyrrolidinone (VI) was coupled with epoxide (VII) yielding adduct (VIII). The acetonide protecting group of (VIII) was finally hydrolyzed with HCl to give the title compound.
| 【1】 Kazmierski, W.; Andrews, W. III; Baker, C.; et al.; Heterocyclic isosteres of the P1/P2 domain of amprenavir: Discovery of novel, picomolar HIV-1 protease inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 126. |
| 【2】 Tung, R.D.; Salituro, F.G.; Deininger, D.D.; Bhisetti, G.R.; Baker, C.T.; Spaltenstein, A.; Kazmierski, W.M.; Andrews, C.W. III (Vertex Pharmaceuticals Inc.); Aspartyl protease inhibitors. JP 2000501111; US 5945413; WO 9727180 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 | |
| (I) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (II) | 38970 | methyl (E,4S)-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2-pentenoate | C20H21NO4 | 详情 | 详情 | |
| (III) | 38971 | (5R)-5-benzyl-2-pyrrolidinone | C11H13NO | 详情 | 详情 | |
| (IV) | 38972 | tert-butyl (2R)-2-benzyl-5-oxo-1-pyrrolidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (V) | 38973 | tert-butyl (3S,5R)-3,5-dibenzyl-2-oxo-1-pyrrolidinecarboxylate | C23H27NO3 | 详情 | 详情 | |
| (VI) | 38974 | (3S,5R)-3,5-dibenzyl-2-pyrrolidinone | C18H19NO | 详情 | 详情 | |
| (VII) | 16243 | (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO3 | 详情 | 详情 | |
| (VIII) | 38975 | (3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone | C42H46N2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was subsequently deprotected by treatment with HCl in MeOH-dioxan to give (VIII) (1). The stereoselective hydroxyl inversion of the diol was then achieved Swern by oxidation to the ketol (IX), followed by reduction with NaBH4 in EtOH, and purification of the major isomer by column chromatography.
| 【1】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514. |
| 【2】 Kaltenbach, R.F. III; Nugiel, D.A.; Lam, P.Y.; Klabe, R.M.; Seitz, S.P.; Stereoisomers of cyclic urea HIV-1 protease inhibitors: Synthesis and binding affinities. J Med Chem 1998, 41, 25, 5113. |
| 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) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (II) | 19618 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (IV) | 19920 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate | C46H64N2O8Si2 | 详情 | 详情 | |
| (V) | 19921 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine | C30H52N2O4Si2 | 详情 | 详情 | |
| (VI) | 19922 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one | C31H50N2O5Si2 | 详情 | 详情 | |
| (VII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (VIII) | 19924 | (4R,5S,6S,7R)-1,3,4,7-tetrabenzyl-5,6-dihydroxy-1,3-diazepan-2-one | C33H34N2O3 | 详情 | 详情 | |
| (IX) | 19925 | (4R,6S,7R)-1,3,4,7-tetrabenzyl-6-hydroxy-1,3-diazepane-2,5-dione | C33H32N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was finally deprotected by treatment with HCl in MeOH-dioxan.
| 【1】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514. |
| 【2】 Trussardi, R.; Karpf, M. (F. Hoffmann-La Roche AG); Process for the preparation of mixed anhydrides. EP 0847994 . |
| 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) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (IV) | 19920 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate | C46H64N2O8Si2 | 详情 | 详情 | |
| (V) | 19921 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine | C30H52N2O4Si2 | 详情 | 详情 | |
| (VI) | 19922 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one | C31H50N2O5Si2 | 详情 | 详情 |