【结 构 式】 |
【药物名称】 【化学名称】4(S)-(tert-Butoxycarbonyl-L-valyl-L-leucyl-L-phenylalanylamino)-6-carbamoyl-2(E)-hexenoic acid methyl ester 【CA登记号】 【 分 子 式 】C33H51N5O8 【 分 子 量 】645.80312 |
【开发单位】Lilly (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Anti-Rhinovirus Drugs, Antiviral Drugs, HRV 3C Protease Inhibitors |
合成路线1
By deprotection of tripeptide (V) (hydrogenolysis of the benzyl group with H2 over Pd/C) followed by condensation with amino acid ester (XI) by means of diethyl cyanophosphonate (DECP) in DMF. The intermediates (V) and (XI) have been obtained as follows: 1.- The condensation of N-(tert-butoxycarbonyl)-L-valine (I) with L-leucine benzyl ester (II) by means of DCC, NMM and NHS gives the dipeptide (III), which is condensed with L-phenylalanine benzyl ester (IV) by first debenzylation and condensation as before yielding the desired tripeptide (V). 2.- The cyclization of N-(tert-butoxycarbonyl)-L-glutamine (VI) by means of DCC and NHS gives the glutarimide (VII), which is partially reduced with NaBH4 to the cyclic Boc-glutaminal (VIII). The condensation of (VIII) with the phosphonate (IX) by means of NaH in THF affords the unsaturated protected aminoester (X), which is finally deprotected with trifluoroacetic acid in dichloromethane providing the desired amino acid ester (XI).
【1】 Shepherd, T.A.; Furness, K.; Venkatraman, S.; Wang, Q.M.; Aubé, J.; Nimkar, S.; Kong, J.; Hanzlik, R.P.; Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication. J Med Chem 1998, 41, 14, 2579. |
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) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
(II) | 27691 | benzyl (2S)-2-amino-5-methylhexanoate | C14H21NO2 | 详情 | 详情 | |
(III) | 27692 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-5-methylhexanoate | C24H38N2O5 | 详情 | 详情 | |
(IV) | 27693 | benzyl (2S)-2-amino-3-phenylpropanoate;L-phenylalanine benzyl ester | C16H17NO2 | 详情 | 详情 | |
(V) | 27694 | benzyl (6S,9S,12S)-12-benzyl-9-isopentyl-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate | C33H47N3O6 | 详情 | 详情 | |
(VI) | 27695 | (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]-6-oxohexanoic acid | C11H20N2O5 | 详情 | 详情 | |
(VII) | 27696 | tert-butyl (3S)-2,6-dioxopiperidinylcarbamate | C10H16N2O4 | 详情 | 详情 | |
(VIII) | 27697 | tert-butyl (3S)-2-hydroxy-6-oxopiperidinylcarbamate | C10H18N2O4 | 详情 | 详情 | |
(IX) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
(X) | 27699 | methyl (E,4S)-8-amino-4-[(tert-butoxycarbonyl)amino]-8-oxo-2-octenoate | C14H24N2O5 | 详情 | 详情 | |
(XI) | 27700 | methyl (E,4S)-4,8-diamino-8-oxo-2-octenoate | C9H16N2O3 | 详情 | 详情 |