US 7,514,557 B2
Process for preparing acyclic HCV protease inhibitors
Carl Alan Busacca, Poughkeepsie, N.Y. (US); Rogelio Perez Frutos, Sandy Hook, Conn. (US); Nizar Haddad, Danbury, Conn. (US); Suresh R. Kapadia, Danbury, Conn. (US); Jon Charles Lorenz, New Milford, Conn. (US); Anjan Saha, Hamden, Conn. (US); Chris Hugh Senanayake, Brookfield, Conn. (US); and Xudong Wei, Ridgefield, Conn. (US)
Assigned to Boehringer Ingelheim International GmbH, Ingelheim (Germany)
Filed on May 23, 2005, as Appl. No. 11/135,533.
Claims priority of provisional application 60/574182, filed on May 25, 2004.
Claims priority of provisional application 06/652018, filed on Feb. 11, 2005.
Claims priority of provisional application 60/660745, filed on Mar. 11, 2005.
Prior Publication US 2005/0267151 A1, Dec. 01, 2005
Int. Cl. C07D 215/38 (2006.01); A61K 31/44 (2006.01)
U.S. Cl. 546—154  [546/153; 514/312; 514/18] 12 Claims
 
1. A process for preparing a compound of formula II:

OG Complex Work Unit Drawing
wherein Het is a five-, six- or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said heterocycle being substituted with R1 at any available position on the heterocycle;
R1 is R20, —NR22COR20, —NR22COOR20 —NR22R21 and —NR22CONR21R23, wherein
R20 is selected from (C1-8)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl(C1-4)alkyl-, wherein said cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substituted with (C1-3)alkyl;
R21 is H or has one of the meanings of R20 as defined above,
R22 and R23 are independently selected from H and methyl,
Alk is a C1-C6 alkyl group;
RA is PG wherein PG is an amino-protecting group, or RA is a moiety of the formula:

OG Complex Work Unit Drawing
wherein:
A is O or NH;
B is (C1-10)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-4)alkyl,
a) wherein said cycloalkyl, cycloalkylalkyl may be mono-, di- or tri-substituted with (C1-C3)alkyl; and
b) wherein said alkyl, cycloalkyl, cycloalkylalkyl may be mono- or di-substituted with substituents selected from hydroxy and (C1-4)alkoxy; and
c) wherein all said alkyl-groups may be mono-, di- or tri-substituted with halogen; and
d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7-membered) —CH2-groups not directly linked to each other replaced by —O— such that the O-atom is linked to the group A via at least two C-atoms; and
R2 is (C1-8)alkyl, (C3-7)cycloalkyl or (C3-7)cycloalkyl(C1-3)alkyl, wherein said cycloalkyl groups may be mono-, di- or tri-substituted with (C1-4)alkyl;
RB is CO2H or a moiety of the formula:

OG Complex Work Unit Drawing
wherein:
R3 is ethyl or vinyl; and
RC is hydroxyl, C1-C6 alkoxy or NHSO2RS wherein RS is (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-6)alkyl, phenyl, naphthyl, pyridinyl, phenyl(C1-4)alkyl, naphthyl(C1-4)alkyl or pyridinyl(C1-4)alkyl; all of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C1-4)alkyl, (C1-6)alkoxy, —CO—NH2, —CO—NH(C1-4-alkyl), —CO—N(C1-4-alkyl)2, —NH2, —NH(C1-4-alkyl) and —N(C1-4-alkyl)2; and all of which optionally being monosubstituted with nitro;
or RS can be further selected from: —NH(C1-6alkyl), N(C1-6alkyl)2, -Het,

OG Complex Work Unit Drawing
said process comprising reacting a compound of formula QUIN, wherein X is an SO2R group, wherein R is C1-6alkyl, C6 or C10 aryl or heteroaryl, with a compound of formula P2 to obtain a compound of formula II:

OG Complex Work Unit Drawing
wherein Alk, Het, R1, RA and RB in formulas QUIN and P2 are the same as defined above for formula II.