Patent ID: 6476235
Filing Date: 2002-11-05
Classification: A61P,C07D

Abstract:
A process for the preparation of a compound of Formula (13) which comprises:Step (a) reacting a compound of Formula (1) wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with a compound of Formula (2) R1â€”Hâ€ƒâ€ƒ(2) wherein R1 is â€”XR wherein X is O, S, or Se, or R1 is wherein R2 or R3 is independently alkyl, cycloalkyl, arylalkyl, or aryl, or R2 and R3 together are â€”(CH2)4â€”, â€”(CH2)5â€”, â€”(CH(R4)â€”CH2)3â€”, â€”(CH(R4)â€”CH2)4â€”, â€”(CH(R4)â€”(CH2)2â€”CH(R4))â€”, â€”(CH(R4)â€”(CH2)3â€”CH(R4))â€”, â€”CH2â€”CH2â€”Aâ€”CH2â€”CH2â€”, â€”CH(R4)â€”CH2â€”Aâ€”CH2CH2â€”, â€”CH(R4)â€”CH2â€”Aâ€”CH2â€”CH(R4)â€”wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above to afford a compound of Formula (3) wherein R1 is as defined above; Step (b) reacting a compound of Formula (3) with hydrogen in the presence of a catalyst and a strong acid in a solvent to afford a compound of Formula (4) wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 is as defined above; Step (c) reacting a compound of Formula (4) with a base in a solvent followed by the addition of a compound of Formula (5) Râ€”CO2Hâ€ƒâ€ƒ(5) wherein R is as defined above in a solvent to afford a compound of Formula (6) wherein R and R1 are as defined above; Step (d) reacting a compound of Formula (6) with Compound (7) in a solvent with removal of water to afford a compound of Formula (8) wherein R1 is as defined above; Step (e) reacting a compound of Formula (8) with a compound of Formula (9) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum, and R1 is as defined above in a solvent in the presence of a strong base to afford a compound of Formula (10) wherein R1 is as defined above; Step (f) reacting a compound of Formula (10) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (11) wherein R1 is as defined above or a compound of Formula (11a) Step (g) reacting a compound of Formula (11b) wherein R1a is OH, XR wherein X is O, S, or Se, or R1a is wherein R2 or R3 is independently alkyl, cycloalkyl, arylalkyl, or aryl, or R2 and R3 together are â€”(CH2)4â€”, â€”(CH2)5â€”, â€”(CH(R4)â€”CH2)3â€”, â€”(CH(R4)â€”CH2)4â€”, â€”(CH(R4)â€”(CH2)2â€”CH(R4))â€”, â€”(CH(R4)â€”(CH2)3â€”CH(R4))â€”, â€”CH2â€”CH2â€”Aâ€”CH2â€”CH2â€”, â€”CH(R4)â€”CH2â€”Aâ€”CH2CH2â€”, â€”CH(R4)â€”CH2â€”Aâ€”CH2â€”CH(R4)â€”wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent in the presence of an acid, followed by reaction with a base, an acylating agent, and an acylation catalyst in a solvent to afford a compound of Formula (12) Step (h) reacting a compound of Formula (12) with HOâ€”M in an alcohol of Formula (17) or (17b) HOCH2-Arylâ€ƒâ€ƒ(17) orHO-Allylâ€ƒâ€ƒ(17b) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum, or with a compound of Formula (16) or (16b) MâŠ•&ominus;OCH2-Arylâ€ƒâ€ƒ(16) orMâŠ•&ominus;O-Allylâ€ƒâ€ƒ(16b) wherein M is as defined above in an alcohol of Formula (17) or (17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is the same, in a solvent followed by the addition of hydrogen in the presence of a catalyst and an acid to afford the compound of Formula (13).