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【结 构 式】 
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【分子编号】37936 【品名】(2S)-2-(dibenzylamino)-3-phenylpropanal 【CA登记号】 |
【 分 子 式 】C23H23NO 【 分 子 量 】329.44176 【元素组成】C 83.85% H 7.04% N 4.25% O 4.86% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)An alternative procedure for the preparation of the intermediate urea (IX) has been reported. Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV), which was reduced to amino alcohol (XVI) using DIBAL in cold toluene. In an improved large-scale process, amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII). Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII). Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX). Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b). After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization]. Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
| 【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 . |
| 【2】 Liu, C.; et al.; Development of large-scale process for an HIV protease inhibitor. Org Process Res Dev 1997, 1, 1, 45. |
| 【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288. |
| 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 | |
| (XXIa) | 37939 | (2S,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIb) | 37940 | (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIIa) | 37941 | N'-(tert-butyl)-N-[(2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (XXIIb) | 37942 | N'-(tert-butyl)-N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (V) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (IX) | 37931 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea | C19H33N3O2 | 详情 | 详情 | |
| (XIV) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XV) | 37935 | (2S)-2-(dibenzylamino)-3-phenylpropionic acid | C23H23NO2 | 详情 | 详情 | |
| (XVI) | 30457 | (2S)-2-(dibenzylamino)-3-phenyl-1-propanol | 111060-52-7 | C23H25NO | 详情 | 详情 |
| (XVII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (XVIII) | 37936 | (2S)-2-(dibenzylamino)-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (XIX) | 37937 | N,N-dibenzyl-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2R)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 | |
| (XX) | 37938 | N,N-dibenzyl-N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2S)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of N,N-dibenzyl-L-alaninal (I) with nitromethane, catalyzed by the chiral ammonium salt (II) and KF in THF gives the chiral nitroalcohol (III), which is reduced with NiCl2 and NaBH4 to yield the aminoalcohol (IV). The condensation of (IV) with isobutyraldehyde (V) affords the Schiff base (VI), which is reduced with NaBH4 to provide the secondary amine (VII). The reaction of (VII) with 4-nitrobenzenesulfonyl chloride (VIII) and TEA in dichloromethane furnishes the sulfonamide (IX), which is deprotected by hydrogenation with H2 over Pd/C in methanol, giving the diamino compound (X). Finally, this compound is condensed with 3(S)-tetrahydrofuryl (N-oxysuccinimidyl) carbonate (XI) by means of TEA in dichloromethane to afford the target carbamate.
| 【1】 Corey, E.J.; Zhang, F.-Y.; Re- and si-face-selective nitroaldol reactions catalyzed by a rigid chiral quaternary ammonium salt: A highly stereoselective synthesis of the HIV protease inhibitor amprenavir (Vertex 478). Angew Chem. Int Ed Engl 1999, 38, 13-14, 1931. |
| 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) | 37936 | (2S)-2-(dibenzylamino)-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (II) | 45528 | 1-(9-anthrylmethyl)-2-[(benzyloxy)(4-quinolinyl)methyl]-5-vinyl-1-azoniabicyclo[2.2.2]octane fluoride | C41H39FN2O | 详情 | 详情 | |
| (III) | 45529 | (2R,3S)-3-(dibenzylamino)-1-nitro-4-phenyl-2-butanol | C24H26N2O3 | 详情 | 详情 | |
| (IV) | 45530 | (2R,3S)-1-amino-3-(dibenzylamino)-4-phenyl-2-butanol | C24H28N2O | 详情 | 详情 | |
| (V) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (VI) | 45531 | (2R,3S)-3-(dibenzylamino)-1-[[(E)-2-methylpropylidene]amino]-4-phenyl-2-butanol | C28H34N2O | 详情 | 详情 | |
| (VII) | 37940 | (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (VIII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (IX) | 45532 | N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | C34H39N3O5S | 详情 | 详情 | |
| (X) | 45533 | 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide | C20H29N3O3S | 详情 | 详情 | |
| (XI) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 |