Process for preparing antiviral compounds

Patent metadata

Field	Value
Publication number	US-2016332973-A1
Application number	US-201615221156-A
Country	US
Kind code	A1
Filing date	Jul 27, 2016
Priority date	Jul 16, 2010
Publication date	Nov 17, 2016
Grant date	—

Abstract

This disclosure is directed to: (a) processes for preparing compounds and salts thereof that, inter alia, are useful for inhibiting hepatitis C virus (HCV); (b) intermediates useful for the preparation of the compounds and salts; (c) pharmaceutical compositions comprising the compounds or salts; and (d) methods of use of such compositions.

First claim

1 . A compound of formula (4), or salt thereof:

wherein R 4 is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -hydroxyalkyl, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, and 3-furanyl; and
R 5 is selected from the group consisting of hydrogen, fluoro, chloro, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyloxy.

2 . The compound or salt of claim 1 , wherein the compound has a structure corresponding to formula (4a):

3 . A process for preparing the compound or salt of claim 1 , wherein the process comprises:
coupling compound (1) with compound (3):

wherein
LG 2 of compound (1) is a leaving group, and
Y 1 of compound (3) is a coupling moiety.

4 . The process of claim 3 , wherein LG 2 of compound (1) is selected from the group consisting of chlorine, bromine, iodine, and —OSO 2 R 1b , wherein R 1b is selected from the group consisting of p-tolyl, phenyl, methyl, ethyl, trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluorooctyl, and perfluoroethoxyethyl.

5 . The process of claim 3 , wherein Y 1 of compound (3) is selected from the group consisting of an organoborane; boronic acid; borate ester; borate salt; zinc halide; zincate; organomagnesium; magnesium halide; magnesium alkoxide; lithium; —Si(Ri 1c ) 4 and —Sn(R 1d ) 4 , wherein R 1c and R 1d are selected from the group consisting of alkyl, phenyl, hydroxy, halide, hydride, and alkoxy.

6 . The process of claim 3 , wherein compound (1) is 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

7 . The process of claim 3 , wherein compound (3) is 6-hydroxynaphthalen-2-ylboronic acid.

8 . The process of claim 3 , wherein compound (4) has a structure corresponding to formula (4a):

9 . The process of claim 3 , wherein the coupling agent comprises a transition metal catalyst or a transition metal catalyst precursor and a phosphine ligand.

10 . The process of claim 9 , wherein the phosphine ligand is selected from the group consisting of tri-t-butylphosphine, tricylcohexylphosphine, tris(2-furyl)phosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 3,7 ]decane, biphenyl-2-yldicyclohexylphosphine, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine.

11 . The process of claim 9 , wherein the transition metal catalyst or the transition metal catalyst precursor is a palladium catalyst or a palladium catalyst precursor selected from the group consisting of tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylidineacetone)dipalladium, palladium(II) diacetate, dichlorobis(triphenylphosphine)palladium, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane.

12 . The process of claim 3 , wherein 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (1c)) is reacted with 6-hydroxynaphthalen-2-ylboronic acid (compound (3a)) in tetrahydrofuran in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 3,7 ]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a)); or 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (1c)) is reacted with 6-hydroxynaphthalen-2-ylboronic acid (compound (3a)) in a mixture of tetrahydrofuran and water in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 3,7 ]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyppyrimidine-2,4(1H,3H)-dione (compound (4a)).

13 . The process of claim 3 , wherein compounds (1) and (3) are coupled in the presence of a base selected from the group consisting of potassium phosphate tribasic, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide and cesium fluoride.

14 . The process claim 3 , wherein compounds (1) and (3) are coupled in the presence of a solvent selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, 1,2-dimethoxyethane, 1,4-dioxane, ethanol, toluene, water and mixtures thereof.

15 . A process for preparing the compound or salt of claim 1 , wherein the process comprises:
coupling compound (1-Y 2 ) with compound (3-LG 3 ):

wherein LG 3 of compound (3-LG 3 ) is selected from the group consisting of chlorine, bromine, iodine, and —OSO 2 R 1b , wherein R 1b is selected from the group consisting of p-tolyl, phenyl, methyl, ethyl, trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluorooctyl, and perfluoroethoxyethyl; and wherein Y 2 of compound (1-Y 2 ) is selected from the group consisting of an organoborane; boronic acid; borate ester; borate salt; zinc halide; zincate; organomagnesium; magnesium halide; magnesium alkoxide; lithium; —Si(R 1c )4 and —Sn(R 1d ) 4 , wherein R 1c and R 1d are selected from the group consisting of alkyl, phenyl, hydroxy, halide, hydride, and alkoxy.

16 . The process of claim 15 , wherein compound (3-LG 3 ) is selected from the group consisting of 6-chloronaphthalen-2-ol, 6-bromonaphthalen-2-ol and 6-iodonaphthalen-2-ol.

17 . The process of claim 15 , wherein compound (I-Y 2 ) is selected from the group consisting of 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylboronic acid, potassium (3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)trifluoroborate, and 1-(3-tert-butyl-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

18 . The process of claim 15 , wherein compound (4) has a structure corresponding to formula (4a):

19 . The process of claim 15 , wherein 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylboronic acid (compound (1-Y 2 a)) is reacted with 6-iodonaphthalen-2-ol (compound (3-LG 3 c)) in tetrahydrofuran in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 3,7 ]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a)).

20 . A composition comprising the compound or salt of claim 2 .

21 . The composition of claim 20 , further comprising N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenypnaphthalen-2-yl)methanesulfonamide (compound (A-1)) or a salt thereof.

22 . A composition comprising 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4)) and N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-m

Assignees

• Abbvie Inc

Inventors

• Shekhar Shashank
• Franczyk Thaddeus S
• Barnes David M
• Dunn Travis B
• Haight Anthony R
• Chan Vincent S

Classifications

• B01J2231/49

  Esterification or transesterification · CPC title

• C07D239/54 Primary

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D239/10

  Oxygen or sulfur atoms · CPC title