Process for preparing antiviral compounds

Patent metadata

Field	Value
Publication number	US-9434698-B2
Application number	US-201414536192-A
Country	US
Kind code	B2
Filing date	Nov 7, 2014
Priority date	Jul 16, 2010
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

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

We claim:

1. A process for preparing compound (5-I), comprising:
reacting a compound of formula (4) or salt thereof with a sulfonylating agent in the presence of a solvent and a base:

wherein
R 1a is, at each occurrence, independently selected from the group consisting of aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl, —N(alkyl) 2 , fluoro and imidazolyl;
R 4 is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, 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;
wherein the sulfonylating agent corresponds in structure to

or

and X 1 is selected from the group consisting of bromine, chlorine, and fluorine.

2. The process of claim 1 , wherein R 1a is selected from the group consisting of p-tolyl, phenyl, methyl, ethyl, fluoro, trifluoromethyl, pentafluoroethyl, 1-heptafluoropropyl, 2-heptafluoropropyl, perfluorobutyl, isomers of perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluorooctyl, and perfluoroethoxyethyl.

3. The process of claim 1 , wherein R 1a is perfluorobutyl.

4. The process of claim 1 , wherein the sulfonylating agent is perfluorobutanesulfonyl fluoride.

5. The process of claim 1 , wherein compound (5-I) has a structure corresponding to formula (5a):

6. The process of claim 1 , wherein compound (5-I) has a structure corresponding to formula (5e):

7. The process of claim 1 , wherein compound (4) has a structure corresponding to formula (4a):

8. The process of claim 7 , wherein compound (4a) is reacted with perfluorobutanesulfonyl fluoride to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (compound (5a)).

9. The process of claim 7 , wherein compound (4a) is reacted with 1,1,2,2,3,3,3-heptafluoropropane-1-sulfonyl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,-heptafluoropropane-1-sulfonate (compound (5b)).

10. The process of claim 7 , wherein compound (4a) is reacted with 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (compound (5c)).

11. The process of claim 7 , wherein compound (4a) is reacted with 1,1,2,2,2-pentafluoroethanesulfonyl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide compound 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,2-pentafluoroethanesulfonate (compound (5d)).

12. The process of claim 7 , wherein compound (4a) is reacted with trifluoromethanesulfonyl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate (compound (5e)).

13. The process of claim 7 , wherein compound (4a) is reacted with perfluoro(2-ethoxyethane)sulfonyl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (compound (5f)).

14. The process of claim 7 , wherein compound (4a) is reacted with sulfuryl fluoride under an inert nitrogen atmosphere in N,N-dimethylformamide at ambient temperature in the presence of potassium carbonate to provide 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl sulfofluoridate (compound (5g)).

15. The process of claim 1 , wherein the sulfonylating agent is trifluoromethanesulfonyl fluoride.

16. The process of claim 1 , wherein the sulfonylating agent is perfluorobutanesulfonyl fluoride; and the base is selected from the group consisting of sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydride, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, and 2,6-dimethylpyridine.

17. The process of claim 1 , wherein the sulfonylating agent is perfluorobutanesulfonyl fluoride; and the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, and diethyl ether.

18. A compound or salt thereof, wherein the compound corresponds in structure to formula (5-I):

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;
R 5 is selected from the group consisting of hydrogen, fluoro, chloro, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyloxy; and
R 1a is selected from the group consisting of aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl, —N(alkyl) 2 , fluoro and imidazolyl.

19. The compound or salt of claim 18 , wherein R 4 is t-butyl, R 5 is methoxy, and R 1a is —C 4 F 9 .

20. A composition comprising the compound or salt of claim 18 and an excipient.

21. The composition of claim 20 , wherein R 4 is t-butyl, R 5 is methoxy, and R 1a is —C 4 F 9 .

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

23. The compound or salt of claim 18 , wherein the compound is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate.

24. The compound or salt of claim 18 , wherein the compound is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,-heptafluoropropane-1-sulfonate.

25. The compound or salt of claim 18 , wherein the compound is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropy

Assignees

• Abbvie Inc

Inventors

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

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• B01J2231/4211

  Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• B01J2231/49

  Esterification or transesterification · CPC title

• A61K45/06

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