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   Synthesis Schemes
Drug Name
Indinavir sulfate;MK-639;L-735524;Crixivan
Description of the Scheme
6) The chiral piperazine (VII) can be obtained by several different ways: 6a) The sequential protection of piperazine-2(S)-carboxylic acid (XXIX) gives 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2(S)-carboxylic acid (XXX), which is condensed with tert-butylamine by means of EDC and HOBt to afford the tert-butylamide (XXXI). Finally, this compound is selectively deprotected by hydrogenation with H2 over Pd/C in methanol, yielding the chiral piperazine (VII). 6b) The partial hydrogenation of N-tert-butylpyrazine-2-carboxamide (XXXII) with H2 over Pd/C gives the tetrahydro derivative (XXXIII), which is sequentially protected as usual to the 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrazin e -2-carboxamide (XXXIV). Finally, this compound is hydrogenated using the chiral catalyst [R-BINAP(COD)Rh]OTf to afford the chiral piperazine (XXXI), already obtained. 6c) The N-tert-butylpyrazine-2-carboxamide (XXXII) is fully reduced with H2 over Pd/C in propanol, giving the racemic N-tert-butylpiperazine-2-carboxamide (XXXV), which is submitted to optical resolution with (S)-(+)-camphosulfonic acid, yielding the (S)-isomer (XXXVI), which is then selectively protected with tert-butoxycarbonyl anhydride to give the desired chiral amide (VII).
Route of the Synthesis
Synthesisi Route of Indinavir sulfate;MK-639;L-735524;Crixivan
Intermediate
tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate (VII)
(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid (XXIX)
(2S)-1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)hexahydro-2-pyrazinecarboxylic acid (XXX)
1-benzyl 4-(tert-butyl) (2S)-2-[(tert-butylamino)carbonyl]tetrahydro-1,4-pyrazinedicarboxylate (XXXI)
N-(tert-butyl)-2-pyrazinecarboxamide (XXXII)
N-(tert-butyl)-1,4,5,6-tetrahydro-2-pyrazinecarboxamide (XXXIII)
4-benzyl 1-(tert-butyl) 5-[(tert-butylamino)carbonyl]-2,3-dihydro-1,4-pyrazinedicarboxylate (XXXIV)
N-(tert-butyl)-2-piperazinecarboxamide; Piperazine-2-carboxylic acid tert-butylamide (XXXV)
(2S)-N-(tert-butyl)hexahydro-2-pyrazinecarboxamide (XXXVI)
References1:
    Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
References2:
    Rossen, K.; Weissman, S.A.; Sager, J.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir. Tetrahedron Lett 1995, 36, 36, 6419-22.
References3:
    Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 .
References4:
    Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 .
References5:
    Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 .
References6:
    Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 .
References7:
    Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51.
References8:
    Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.
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