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【结 构 式】 
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【药物名称】Telinavir, SC-52151 【化学名称】N-(Quinolin-2-ylcarbonyl)-asparagine 1(S)-benzyl-3-(3-tert-butyl-1-isobutylureido)-2(R)-hydroxypropylamide 【CA登记号】143224-34-4 【 分 子 式 】C33H44N6O5 【 分 子 量 】604.75583 |
【开发单位】Pfizer (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors |
合成路线1
Reduction of N-Cbz-L-phenylalaninyl chloromethyl ketone (I) with NaBH4 provided a 1:3 mixture of diastereoisomeric chlorohydrins (II) and (III), from which the required isomer (III) was isolated by recrystallization from ethyl acetate-hexane. Treatment of (III) with KOH afforded epoxide (IV), which was opened with isobutyl amine (V) in refluxing isopropanol to give amino alcohol (VI). Subsequent coupling of the amino group of (VI) with tert-butyl carbamate (VII) produced urea (VIII). Removal of the carbamate protecting group of (VIII) by hydrogenation over Pd/C and coupling of the free amine (IX) with N-Cbz-L-asparagine (X) yielded amide (XI). Further removal of the Cbz group of (XI) gave rise to amine (XII), which was finally coupled with 2-quinolinecarboxylic acid N-hydroxysuccinimidyl ester (XIII) to furnish the title quinolinecarboxamide.
| 【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】 Clare, M.; DeCrescenzo, G.A.; Freskos, J.N.; Getman, D.P.; Heintz, R.M.; Lin, K.-C.; Mueller, R.A.; Reed, K.L.; Talley, J.J.; Vazquez, M.L.; Sun, E.T.O. (Pharmacia Corp.); Retroviral protease inhibitors. EP 0558630; WO 9208701 . |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 37926 | benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | 26049-94-5 | C18H18ClNO3 | 详情 | 详情 |
| (II) | 37927 | benzyl (1S,2R)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | C18H20ClNO3 | 详情 | 详情 | |
| (III) | 37928 | benzyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | C18H20ClNO3 | 详情 | 详情 | |
| (IV) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (V) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VI) | 37929 | benzyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (VIII) | 37930 | benzyl (1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropylcarbamate | C27H39N3O4 | 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 | |
| (X) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (XI) | 37932 | benzyl (1S)-3-amino-1-[([(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]amino)carbonyl]-3-oxopropylcarbamate | C31H45N5O6 | 详情 | 详情 | |
| (XII) | 37933 | (2S)-2-amino-N(1)-[(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]butanediamide | C23H39N5O4 | 详情 | 详情 | |
| (XIII) | 37934 | 1-[(2-quinolinylcarbonyl)oxy]-2,5-pyrrolidinedione | C14H10N2O4 | 详情 | 详情 |
合成路线2
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 |