Patent ID: 6376649
Filing Date: 2002-04-23
Classification: C07C,Y02P,Y10T

Abstract:
A method of preparing a compound of formula (A): wherein(i) Rx is â€”PG or â€”C(O)R3 where PG is a protecting group; (ii) (a) R1, R2 and R3 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, alkenyl of 2 to about 12 carbon atoms, cycloalkenyl of 5 to about 12 carbon atoms, and alkynyl 3 to about 12 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from the group consisting of Y1, Y2 and Y3; aryl of about 5 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, or Y3; heteroaryl of about 5 to about 14 ring atoms, with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono-, di-, tri-substituted with Y1, Y2 or Y3; aralkyl of about 6 to about 18 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 or Y3; and heteroaralkyl of about 5 to about 18 carbon atoms having about 5 to about 14 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur and which is optionally mono, di- or tri-substituted on the ring with Y1, Y2 or Y3; (b) alternatively R1 is â€”CH(R5)C(O)W1 or a peptidyl substituent of the formula â€”(Xaa1)nW2, wherein R5 is hydrogen, alkyl of 1 to about 12 carbon atoms, cycloalkyl of 3 to about 12 carbon atoms, aryl of 5 to about 14 carbon atoms, or aralkyl of about 7 to about 15 carbon atoms, all optionally substituted with 1 to 3 substituents independently selected from hydroxy, sulfhydryl, alkylthio, carboxyl, amide, amino alkylamino, indolyl, 3-N-formylindolyl, benzyloxy, halobenzyloxy, guanidino, nitroguanidino or imidazolyl optionally substituted with alkoxyalkyl; W1 and W2 are independently selected from â€”OH, â€”OZ1, â€”SH, â€”SZ1, â€”NH2, â€”NHZ1 and â€”NZ1Z2; each Xaa1 is an independently selected amino acid residue and n is an integer from 1 to 10; or (c) alternatively R3C(O)â€” is W1CH(R5)C(O)â€” or R4 wherein R4 is a peptide substituent of the formula Z1X(Xaa2)râ€” wherein each Xaa2 is an independently selected amino acid residue, r is an integer from 1 to 10 and X is â€”C(O)â€”, â€”S(O)2â€”, â€”OC(O)â€”, or a direct link; (iii) each Y1, Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, â€”CH3, â€”CH2CH3, â€”CH2CH2CH3, â€”CH(CH3)2, â€”CH2CF3, â€”CH(CF3)2, â€”OCF3, â€”OCF2H, â€”OCF2CF3, â€”OC(O)NH2, â€”OC(O)NHZ1, â€”OC(O)NZ1Z2, â€”NHC(O) Z1, â€”NHC(O)NH2, â€”NHC(O)NHZ1, â€”NHC(O)NHZ1Z2, â€”C(O)OH, â€”C(O)OZ1, â€”C(O)NH2, â€”C(O)NHZ1, â€”C(O)NZ1Z2, â€”P(O)3H2, â€”P(O)3(Z1)2, â€”S(O)3H, â€”S(O)mZ1, â€”Z1, â€”OZ1, â€”OH, â€”NH2, â€”NHZ1, â€”NZ1Z2, and â€”S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5; and (iv) each Z1 and Z2 is independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms; comprising the steps: (a) reacting a protected amino-aldehyde of the formula PGNHCH(R2)CHO, an isonitrile of the formula R1NC and a carboxy compound of the formula YCO2H wherein Y is CF3 or R3 to give an aminoacyloxycarboxamide compound of formula (B): â€ƒand (b) (i) where Rx is PG, treating the amino acyloxycarboxamide intermediate from step (a) under acyloxy group removing conditions to give said compound of formula (A); or (ii) where Rx is â€”C(O)R3, treating the amino acyloxycarboxamide intermediate from step (a) under PG group removing conditions which include a pH of about 6 to about 9 to give said compound of formula (A).