Process and intermediates for making non-nucleoside HIV-1 reverse transcriptase inhibitors

A process for making a compound of the formula IV

• 20
• wherein:
• R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3,
• R4 is H or Me,
• R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et,
• R11 is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl,
• R12 is a cyano group or a group of the formula —COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
• R13 is a cyano group, a group of the formula —COOR15 (wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula —SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula —SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl),
• which process comprises the following steps:
• (a) reacting a starting compound of the formula II
• 21
• wherein R2, R4, R5 and R11 are as hereinbefore defined in this claim and wherein X is a chlorine, iodine, or bromine, or a fluorosulfonate moiety selected from the group consisting of —OSO2F and —OSO2(CF2)nCF3 wherein n is an integer between 0 and 10,
• with a malonate or malonate surrogate of the formula III
• 22
• wherein,
• R12 is a cyano group or a group of the formula —COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
• R13 is a cyano group, a group of the formula —COOR15 (wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula —SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula —SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl),
• in an organic solvent, in the presence of a palladium catalyst, a suitable ligand and strong base,
• to yield the compound of the formula IV.

A process for making a compound of the formula V

• 23
• wherein:
• R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3;
• R4 is H or Me;
• R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et;
• R11 is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl;
• and
• R19 is —COOH or a group of the formula —COOR14 wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl;
• which process comprises the following steps:
• (a) reacting a starting compound of the formula II
• 24
• wherein R2, R4, R5 and R11 are as hereinbefore defined in this claim and wherein X is a chlorine, iodine, or bromine, or a fluorosulfonate moiety selected from the group consisting of —OSO2F and —OSO2(CF2)nCF3 wherein n is an integer between 0 and 10,
• with a malonate or malonate surrogate of the formula III
• 25
• wherein,
• R12 is a cyano group or a group of the formula —COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
• R13 is a cyano group, a group of the formula —COOR15 (wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula —SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula —SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl),
• in an organic solvent, in the presence of a palladium catalyst, a suitable ligand and strong base,
• to yield an intermediate of the formula IV
• 26
• wherein R2, R4, R5, R11, R12 and R13 are as hereinbefore defined in this claim;
• (b) reductively cleaving the sulfur or phosphorus-containing group, if the intermediate of the formula IV contains a sulfur or phosphorus-containing group (because R13 in the reactant of the formula III was a group of the formula —SO2R15 or —P(O)(OR16)2);
• and,
• (c) hydrolyzing the intermediate of the formula IV to yield the compound of the formula V.

A compound of the formula IV

• 27
• wherein:
• R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3;
• R4 is H or Me;
• R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et;
• R11 is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl;
• R12 is a cyano group or a group of the formula —COOR4, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
• R13 is a cyano group, a group of the formula —COOR15 (wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula —SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula —P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula —SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).

A compound of the formula V

• 28
• wherein:
• R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3;
• R4is H or Me;
• R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et;
• R11 is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl;
• and
• R19 is —COOH or a group of the formula —COOR14 wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl.