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【结 构 式】 
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【分子编号】23446 【品名】(2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol 【CA登记号】 |
【 分 子 式 】C22H26N4O 【 分 子 量 】362.4748 【元素组成】C 72.9% H 7.23% N 15.46% O 4.41% |
合成路线1
该中间体在本合成路线中的序号：(X)1) The reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate (II) and p-toluenesulfonic acid in methanol gives ketal (III), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIII) in hot isopropanol gives the expected addition product (IX), which by treatment with HCl or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF.
| 【1】 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387. |
| 【2】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 . |
| 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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (II) | 23438 | (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene | C9H11BrO2 | 详情 | 详情 | |
| (III) | 23439 | bromo(2-pyridinylmethyl)magnesium | C6H6BrMgN | 详情 | 详情 | |
| (IV) | 23440 | 4-(2-pyridinyl)benzaldehyde | C12H9NO | 详情 | 详情 | |
| (V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (VI) | 23442 | tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate | C17H19N3O2 | 详情 | 详情 | |
| (VII) | 23443 | tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C17H21N3O2 | 详情 | 详情 | |
| (VIII) | 23444 | tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (IX) | 23445 | tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C32H42N4O5 | 详情 | 详情 | |
| (X) | 23446 | (2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol | C22H26N4O | 详情 | 详情 | |
| (XI) | 23447 | (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid | C8H15NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The intermediate carbazate (VI) has been obtained as follows. The condensation of phenylboronic acid (I) with 2-bromopyridine (II) by means of Pd(PPh3)4 gives 4-(2-pyridyl)benzaldehyde (III), which is condensed with tert-butyl carbazate (IV) in hot toluene/isopropyl alcohol to yield the benzylidenehydrazone (V). Finally, this compound is reduced with sodium formate over Pd/C in ethanol to afford the target intermediate; the carbazate (VI). The selective monosilylation of the primary OH group of diol (VII) with Tbdms-Cl, TEA and DMAP followed by reaction of the secondary OH group with MsCl gives the protected mesylate (VIII), which is desilylated with NH4F and AcOH yielding the primary alcohol (IX). The epoxidation of (IX) with t-BuOK in isopropyl alcohol affords the chiral epoxide (X), which is condensed with the intermediate carbazate (VI) in refluxing isopropanol to provide the adduct (XI). Elimination of the two Boc protecting groups of (XI) with HCl in hot THF gives the diamino compound (XII), which is finally condensed with two moles of N-(methoxycarbonyl)-L-tert-leucine (XIII) by means of WSC, HOBt and DIEA in dichloromethane to provide the target Atazanavir.
| 【1】 Xu, Z.; Singh, J.; Schwinden, M.D.; Zheng, B.; Kissick, T.P.; Patel, B.; Humora, M.J.; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes, J.E.; Pudipeddi, M.; Lindrud, M.D.; Srivastava, S.K.; Kronenthal, D.R.; Mueller, R.H.; Process research and development for an efficient synthesis of the HIV protease inhibitor BMS-232632. Org. Proc. Res. & Develop. 2002, 6, 3, 323. |
| 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) | 61564 | 4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid | 87199-17-5 | C7H7BO3 | 详情 | 详情 |
| (II) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (III) | 23440 | 4-(2-pyridinyl)benzaldehyde | C12H9NO | 详情 | 详情 | |
| (IV) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (V) | 23442 | tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate | C17H19N3O2 | 详情 | 详情 | |
| (VI) | 23443 | tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C17H21N3O2 | 详情 | 详情 | |
| (VII) | 61565 | tert-butyl (1S,2S)-1-benzyl-2,3-dihydroxypropylcarbamate | C15H23NO4 | 详情 | 详情 | |
| (VIII) | 61566 | (1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenylpropyl methanesulfonate | C22H39NO6SSi | 详情 | 详情 | |
| (IX) | 61567 | (1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)-3-phenylpropyl methanesulfonate | C16H25NO6S | 详情 | 详情 | |
| (X) | 23444 | tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (XI) | 23445 | tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C32H42N4O5 | 详情 | 详情 | |
| (XII) | 23446 | (2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol | C22H26N4O | 详情 | 详情 | |
| (XIII) | 23447 | (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid | C8H15NO4 | 详情 | 详情 |