PROCESSES TO MAKE APOPTOSIS PROMOTERS
FIELD OF THE INVENTION
The present invention relates to, among other things, novel compounds and synthetic
processes, including those useful for making N-acylsulfonamide apoptosis promoters.
BACKGROUND OF THE INVENTION
Novel N-acylsulfonamide apoptosis promoters are described in, for example, U. S.
Patent Publication US2005/0159427A1, U. S. Patent 7,390,799 B2 (referred to hereinafter as
the '"799 Patent") and elsewhere. Synthetic routes for the preparation of N-acylsulfonamide
apoptosis promoters are described in the'799 Patent and K. Ding, et al. (Synthesis, 2008, 15,
2398-2404).
SUMMARY OF THE INVENTION
The present invention provides, among other things, safe, efficient and cost-effective
processes for making N-acylsulfonamide apoptosis promoters.
One aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyI)-5,5-dimethyI-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-1 -(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
1
(d) reacting the first protected (2E)-l-(4-chIorophenyl)-2-(hydroxymethyIene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -ene- 1-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l -en-1 -
yl)methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yI)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1 -cyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
2
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid;
(m) reacting 2-fluorobenzenesulfonyl chloride, and a first fluoride source to
provide 2-fluorobenzenesulfonyl fluoride and isolating or not isolating the 2-
fluorobenzenesulfonyl fluoride;
(n) reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CH3SiCF3),
and a second fluoride source to provide l-fluoro-2-((trifluoromethyl)sulfonyl)benzene and
isolating or not isolating the l-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyI)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and a
first NH3 source to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and
isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
3
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcycIohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -ene-1 -carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid;
4
(r) reacting a first metal trifluoromethanesuifinate, a first aryl fluoride source, and
a first catalyst to provide l-fluoro-2-((trifluoromethyl)sulfonyl)benzene and isolating or not
isolating the l-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and a
first NH3 source to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and
isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methyIene)cyclohexanone, (2E)-4,4-dimethyl-2-
5
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyI)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
6
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethyIsiIyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
7
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid;
(m) reacting 2-fluorobenzenesulfonyl chloride, and tetra-«-butylammonium
fluoride to provide 2-fluorobenzenesulfonyl fluoride and isolating or not isolating the 2-
fluorobenzenesulfonyl fluoride;
(n) reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CH^SiCF^),
and tris(dimethylamino)sulfonium difluorotrimethylsilicate to provide l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and
aqueous ammonium hydroxide to provide 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and triethylamine to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
8
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyI)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-1 -cyclohex-1 -en-1 -yl)methyl)piperazin- l-yl)benzoyl)-4-(((l R)-3 -(morpholin-4-y 1)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyI)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyi)piperazin-l-yI)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
9
isolating or not isolating the (2E)-l-(4-chIorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cydohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-clilorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -ene-1 -carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid;
(r) reacting sodium trifluoromethanesulfinate, bis-(2-fluorophenyl)iodonium
tetrafluoroborate and copper(I) oxide to provide l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and
aqueous ammonium hydroxide to provide 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and triethylamine to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
10
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyI)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyI-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yI)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and a
first coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
1 -en-1 -yl)methyl)piperazin-l -yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-1 -
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5 -dimethyl-1 -cyclohex-1 -en-l-yl)methyl)piperazin-l -yl)benzoyl)-4-((( 1R)-
3-(morpholin-4-yl)-1 -((phenylsulfanyl)methyl)propyl)amino)-3-
11
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifIuoromethyl)sulfonyl)benzenesulfonamide.
Another aspect of this invention pertains to a compound, or a pharmaceutically
acceptable salt thereof, chosen from (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, and (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone.
Another aspect of this invention pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-
1-ene-l-carbaldehyde or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Variable moieties are represented by identifiers (capital letters with numerical and/or
alphabetical superscripts) and may be specifically embodied.
12
The term "alkyl," as used herein, means Ci-alkyl, C2-alkyl, C3-alkyl, C4-alkyl,
Cs-alkyl, and C6-alkyl.
The term "Ci-alkyl," as used herein, means methyl.
The term "C2-alkyl," as used herein, means ethyl.
The term "Cs-alkyi," as used herein, means prop-1-yl and prop-2-yl (isopropyl).
The term "C4-alkyl," as used herein, means but-l-yl, but-2-yl, 2-methylprop-l-yl, and
2-methylprop-2-yl (tert-butyl).
The term "C5-alkyl," as used herein, means 2,2-dimethylprop-l-yl (neo-pentyl), 2-
methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, pent-1-yl, pent-2-yl,
and pent-3-yl.
The term "Cs-alkyl," as used herein, means 2,2-dimethylbut-l-yl, 2,3-dimethylbut-lyl,
2,3-dimethylbut-2-yl, 3,3-dimethylbut-l-yl, 3,3-dimethylbut-2-yl, 2-ethylbut-l-yl, hex-1-
yl, hex-2-yl, hex-3-yl, 2-methylpent-l-yl, 2-methylpent-2-yl, 2-methylpent-3-yl, 3-
methylpent-1-yl, 3-methylpent-2-yl, 3-methylpent-3-yl, 4-methylpent-l-yl, and 4-
methylpent-2-yl.
The term "alcohol," as used herein, means methanol, ethanol, isopropanol,
tert-butanol, and the like or a mixture thereof.
The term, "bis-(2-fluorophenyl)iodonium alkyl-sulfonate," as used herein means bis-
(2-fluorophenyl)iodoniummethylsulfonate, bis-(2-fluorophenyl)iodonium
hexanesulfonate,bis-(2-fIuorophenyl)iodonium dodecanesulfonate, bis-(2-
fluorophenyl)iodonium trifluromethylsulfonate, bis-(2-fluorophenyl)iodonium allylsulfonate,
bis-(2-fluorophenyl)iodonium poly(vinyl)sulfonate and the like.
13
The term, "bis-(2-fluorophenyl)iodonium aryl-sulfonate," as used herein means bis-
(2-fluorophenyl)iodonium benzenesulfonate, bis-(2-fluorophenyl)iodonium ptoluenesulfonate,
bis-(2-fluorophenyl)iodonium mesitylsulfonate, bis-(2-
fluorophenyl)iodonium naphthylsulfonate and the like.
The term, "bis-(2-fluorophenyl)iodonium cycloalkyl-sulfonate," as used herein means
bis-(2-fluorophenyl)iodonium cyclopropylsulfonate, bis-(2-fluorophenyl)iodonium
cyclohexylsulfonate and the like.
The term, "bis-(2-fluorophenyl)iodonium heterocycle-sulfonate," as used herein
means bis-(2-fIuorophenyl)iodonium thiophenylsulfonate, bis-(2-fluorophenyl)iodonium-2-
pyridylsulfonate, bis-(2-fluorophenyl)iodonium-3-pyridylsulfonate, bis-(2-
fluorophenyl)iodonium furfuryl-5-sulfonate, bis-(2-fluorophenyl)iodonium indonylsulfonate,
and the like.
Compounds of this invention can have one or more than one asymmetrically
substituted carbon atoms in the R or S configuration. Compounds having asymmetrically
substituted carbon atoms enriched with one configuration over the other are assigned the
configuration which is present in the higher amount, preferably 85% to 95% enrichment,
more preferably 95% to 99% enrichment, and still more preferably greater than 99%
enrichment. Accordingly, compounds of this invention can exist as enantiomers, mixtures of
enantiomers, diastereomers having relative stereochemistry, diastereomers having absolute
stereochemistry, diastereomers having at least one asymmetrically substituted carbon atom
which is enriched in one configuration and at least one asymmetrically substituted carbon
atom which is not enriched, and mixtures of the preceding.
Compounds of this invention can also have one or more than one carbon-carbon
double bond or carbon-nitrogen double bond. Accordingly, compounds of this invention can
exist as geometric isomers of either Z or E configuration or as mixtures of geometric isomers.
The terms "R", "S", "Z", and "E" are as defined by the lUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,
13-10.
14
Compounds of this invention may exist as acid addition salts or base addition salts
and may be prepared during their isolation or following their purification. Acid addition salts
of compounds are prepared by reaction with acid. For example, the acetate, adipate, alginate,
bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsufonate, citrate, digluconate, formate, fumarate, glycerophosphate, glutamate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate,
lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,
oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate,
thiocyanate, trichloroacetate, trifluoroacetate, para-toluenesulfonate, and undecanoate salts of
compounds of this invention are meant to be embraced thereby. Base addition salts of
compounds of this invention may be prepared by reaction with a base such as the hydroxide,
carbonate, bicarbonate, phosphate, hydrogen phosphate, or dihydrogen phosphate of cations
such as calcium, iron, lithium, potassium, sodium or magnesium.
The term "isolating" as used herein, means separating a compound from a solvent,
anti-solvent, or a mixture of solvent and anti-solvent to provide a solid, semisolid or syrup.
This is typically accomplished by means such as centrifugation, filtration with or without
vacuum, filtration under positive pressure, distillation, evaporation or a combination thereof.
Isolating may or may not include purifying during which the chemical, chiral or chemical and
chiral purity of the isolate is increased. Purifying is typically conducted by means such as
crystallization, distillation, extraction, filtration through acidic, basic or neutral alumina,
filtration through acidic, basic or neutral charcoal, column chromatography on a column
packed with a chiral stationary phase, filtration through a porous paper, plastic or glass
barrier, column chromatography on silica gel, ion exchange chromatography,
recrystallization, normal-phase high performance liquid chromatography, reverse-phase high
performance liquid chromatography, trituration and the like.
The phrase "isolating or not isolating" as used herein, means that during the practice
of this invention, it is optional to isolate a particular compound after each step prior to the
next step. Such a decision can easily be made by one of ordinary skill in the art, based on
stability, purity, solvent conditions of the next step, etc.
15
The exemplified compounds and intermediates were named using ACD/ChemSketcii
Version 5.06 (05 June 2001, Advanced Chemistry Development Inc.,Toronto, Ontario), or
ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). N-(4-(4-((2-(4-chlorophenyl)-
5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-
yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide was named as in the '799 Patent.
Synthetic routes to prepare 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, and 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid, intermediates in the
synthesis of apoptosis promoters are described in the '799 Patent, and K. Ding, et al.
(Synthesis, 2008, 15, 2398-2404, referred to hereinafter as the Ding reference). The '799
Patent describes a synthesis using trifluoromethyl iodide, a gas with toxicity concerns. Also,
the subsequent oxidation step uses RuCb and NaI04, creating a highly exothermic reaction.
The Ding reference describes numerous chemical steps to make 4-(4-((2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid and lower overall yield.
In addition, the very high reaction temperatures are not readily achievable or ideal on a large
scale. Finally, the synthesis described in the Ding reference utilizes a relatively expensive
starting material.
The present inventors previous explorations of the synthesis described in the Ding, et
al. reference identified a number of problems. First of all, the chemistry used is burdened
with a potential genotoxic liability due to brominated products created when hydrobromic
and trifluoroacetic acids are used together. Also, when these or other acids such as
methanesulfonic acid were used, multiple impurities were generated which were inefficiently
and ineffectively removed by typical purification methods such as crystallization. Yield,
purity and processing time were compromised as a result. Finally, poor physical properties of
isolated intermediates made filtrations slow and inefficient.
The present invention avoids these disadvantages.
EMBODIMENTS
One embodiment of this invention, therefore, pertains to a process for making a
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, comprising:
16
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; and
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, and (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, or a pharmaceutically
acceptable salt thereof, prepared as described in the preceding embodiment.
Another embodiment pertains to the compound (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone or a pharmaceutically acceptable salt
thereof.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, or a pharmaceutically acceptable salt
thereof, for use in making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or
a pharmaceutically acceptable salt thereof.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, or a pharmaceutically acceptable salt
thereof, for use in making compounds such as those described in , for example, U. S. Patent
Publication U"S2005/0159427AI, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203, which are hereby incorporated by
reference.
17
Another embodiment pertains to the compound (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or a pharmaceutically acceptable salt
thereof.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cycIohexanone, or a pharmaceutically acceptable salt
thereof, for use in making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or
a pharmaceutically acceptable salt thereof.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or a pharmaceutically acceptable salt
thereof, for use in making compounds such as those described in, for example, U. S. Patent
Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203.
Another embodiment pertains to the compound (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, or a pharmaceutically
acceptable salt thereof.
Another embodiment pertains to (2E)-2-(((tert-butyl(dimethyl)silyl)oxy)methylene)-
4,4-dimethylcyclohexanone, or a pharmaceutically acceptable salt thereof, for use in making
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l -cyclohex-1 -en- l-yl)methyl)piperazin-1 -
yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.
Another embodiment pertains to (2E)-2-(((tert-butyl(dimethyl)silyl)oxy)methylene)-
4,4-dimethylcyclohexanone, or a pharmaceutically acceptable salt thereof, for use in making
compounds such as those described in , for example, U. S. Patent Publication
US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications 61/145611,
61/120275, 61/181180, and 61/181203.
18
Compounds described in U. S. Patent Publication US2005/0159427A1, the '799
Patent, and U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and 61/181203,
include 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-
((4-(((lR)-3-(dimethylamino)-l-((phenylthio)methyl)propyl)amino)-3-
nitrophenyl)sulfonyl)benzamide, 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)-N-((4-(((lR)-3-(isopropyl(methyl)amino)-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide ,
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-((5-
(((lR)-3-(isopropyl(methyl)amino)-l-((phenylthio)methyl)propyl)amino)-4-nitrothien-2-
yl)sulfonyl)benzamide, 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-
phenoxybenzamide, 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
ylmethyl)amino)phenyl)sulfonyl)-2-(lH-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide, and the
like.
One embodiment of this invention, therefore, pertains to a process for making 2-(4-
chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde.
19
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
or a pharmaceutically acceptable salt thereof.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, for use in making N-(4-(4-((2-(4-
chlorophenyl)-5,5 -dimethyl-1-cyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoyl)-4-((( 1R)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, for use in making compounds
such as those described in, for example, U. S. Patent Publication US2005/0159427A1, the
'799 Patent, and U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and
61/181203.
Examples of alkyl formates useful for the practice of this invention are methyl
formate, ethyl formate, n-propyl formate, tert-butyl formate and the like.
Examples of first bases useful for the practice of this invention are sodium hydride,
sodium tert-butoxide, potassium tert-butoxide and the like.
Examples of second bases useful for the practice of this invention are triethylamine,
2,6-lutidine, pyridine, imidazole, diisopropylethylamine, N-methylmorpholine,
dimethylaniline and the like.
Examples of first silyl ether protecting group reagents useful for the practice of this
invention include trimethylchlorosilane, tert-butylchlorodimethylsilane,
triisopropylchlorosilane, tert-butylchlorodiphenylsilane, and the like.
20
Examples of first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanones
useful for the practice of this invention include (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, and the like.
Examples of first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanols useful for the practice of this invention include (2E)-l-(4-
chlorophenyl)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-
chlorophenyl)-4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanol, (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and the
like.
Examples of first acids useful for the practice of this invention are
tetra-n-butylammonium fluoride, trifluoroacetic acid, hydrochloric acid,
trifluoromethanesulfonic acid, sulfuric acid and the like.
Step (a) is typically conducted for about 6 to about 18 hours in a solvent such as
tetrahydrofuran, N,N-dimethylformamide, mixtures thereof and the like.
Step (b) is typically conducted for about 4 to about 16 hours in solvents such as
tetrahydrofuran, DMF, toluene, 2-methyltetrahydrofuran, ethyl acetate, mixtures thereof and
the like.
Step (c) is typically conducted from about 2 to about 4 hours in a solvent including
toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide and the like or mixtures
thereof.
Step (d) is typically conducted from about 1 to about 4 hours in solvents such as
toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, water, methanol, and the
like or mixtures thereof.
Still another embodiment pertains to a process for making ethyl 4-(4-((2-(4-
chlorophenyl)-5,5-/dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, comprising:
21
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate.
Examples of first reducing agents useful for the practice of this invention include
sodium triacetoxyborohydride and sodium cyanoborohydride.
Step (e) is typically conducted from about 10 to about 16 hours in solvents such as
dichloromethane, acetonitrile, toluene, diethyl ether, tetrahydrofuran,
N,N-dimethylformamide, methyl tert-butyl ether, mixtures thereof and the like.
Still another embodiment pertains to ethyl 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate prepared as described in the
preceding embodiment.
Still another embodiment pertains to ethyl 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate , or a pharmaceutically
acceptable salt thereof, for use in making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide , or
a pharmaceutically acceptable salt thereof.
Another embodiment pertains to ethyl 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, or a pharmaceutically
acceptable salt thereof, for use in making compounds such as those described in , for
example, U. S. Patent Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional
Applications 61/145611, 61/120275, 61/181180, and 61/181203.
Still another embodiment pertains to a process for making 4-(4-((2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid, comprising:
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and a third base and isolating or not isolating the 4-(4-((2-
(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid.
22
Examples of third bases useful for the practice of this invention are sodium hydroxide,
potassium hydroxide and the like.
Step (f) is typically conducted from about 10 hours to about 20 hours in solvents such
as ethanol, tetrahydrofuran, heptanes, 2-methyltetrahydrofuran, water, mixtures thereof and
the like.
Still another embodiment pertains to 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoic acid, or a pharmaceutically acceptable salt thereof,
prepared as described in the preceding embodiment.
Still another embodiment pertains to 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoic acid, or a pharmaceutically acceptable salt thereof,
for use in making N-(4-(4-((2-(4-chIorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide , or
a pharmaceutically acceptable salt thereof.
Another embodiment pertains to 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-len-
l-yl)methyl)piperazin-l-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, for
use in making compounds such as those described in , for example, U. S. Patent Publication
US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications 61/145611,
61/120275, 61/181180, and 61/181203.
Still another embodiment of this invention, therefore, pertains to a process for making
(2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium
tert-butoxide to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and
isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; and
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
23
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, and 2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone , or a pharmaceutically
acceptable salt thereof, prepared as described in the preceding embodiment.
Still another embodiment of this invention pertains to a process for making 2-(4-
chlorophenyl)-5,5-dimethylcyclohex-1 -ene-1 -carbaldehyde, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
24
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tert-"
butyl(dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethyIcyclohex-l-ene-lcarbaldehyde.
Still another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-
1-carbaldehyde, or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Still another embodiment pertains to a process for making ethyl 4-(4-((2-(4-
chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate.
Still another embodiment pertains to ethyl 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, or a pharmaceutically
acceptable salt thereof, prepared as described in the preceding embodiment.
Still another embodiment pertains to a process for making 4-(4-((2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid, comprising:
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and sodium hydroxide and isolating or not isolating the 4-
(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid.
25
Still another embodiment pertains to 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoic acid, or a pharmaceutically acceptable salt thereof,
prepared as described in the preceding embodiment.
Still another embodiment of this invention, therefore, pertains to a process for making
(2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone at about -10°C
to about 0°C and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone; and
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane at about -10°C to about 0°C to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methyIene)-4,4-dimethylcyclohexanone.
Another embodiment pertains to (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, and 2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone, or a pharmaceutically
acceptable salt thereof, prepared as described in the preceding embodiment.
Still another embodiment pertains to a process for making 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium
tert-butoxide at about -10°C to about 0°C to provide (2E)-2-(hydroxymethylene)-4,4-
26
dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane at about -10°C to about 0°C to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide at about -10°C to about 5°C to provide ((2E)-l-(4-chlorophenyl)-4,4-
dimethyl-2-(((triisopropylsilyI)oxy)methyIene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-
dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)siIyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol, and
(d) reacting ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid at about 5°C to about 20°C to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde.
27
Still another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-
1-carbaldehyde, or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Still another embodiment pertains to a process for making ethyl 4-(4-((2-(4-
chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, comprising:
(e) reacting 2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -ene- 1-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoate.
Still another embodiment pertains to ethyl 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate, or a pharmaceutically
acceptable salt thereof, prepared as described in the preceding embodiment.
Still another embodiment pertains to a process for making 4-(4-((2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic acid, comprising:
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and sodium hydroxide at about 55°C to about 75°C, and
isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid.
Still another embodiment pertains to 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoic acid, or a pharmaceutically acceptable salt thereof,
prepared as described in the preceding embodiment.
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyI-l-cycIohex-l-en-l-yI)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyI)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide comprising:
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and a
28
first coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, such as those described in, for example, U. S. Patent
Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203, comprising:
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, a first appropriate benzenesulfonamide and a first
coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the apoptosis promoter.
Examples of first coupling reagents are l-ethyl-3-(3-(dimethylamino)propyl)-
carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide,
l,r-carbonyldiimidazole and the like.
Examples of first auxiliary coupling reagents include 4-dimethylaminopyridine,
hydroxybenzotriazole, l-hydroxy-7-aza-benzotriazole and the like.
Examples of fourth bases include l,8-diazabicyclo(5.4.0)undec-7-ene, potassium tertbutoxide
and the like.
Examples of apoptosis promoters include 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-((4-(((lR)-3-(dimethylamino)-l-
((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide, 4-(4-((2-(4-
chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-((4-(((lR)-3-
29
(isopropyl(methyl)amino)-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide , 4-(4-((2-(4-chlorophenyl)-5,5-
dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-N-((5-(((lR)-3-
(isopropyl(methyl)amino)-l-((phenylthio)methyl)propyl)amino)-4-nitrothien-2-
yl)sulfonyl)benzamide, 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-
phenoxybenzamide, 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
ylmethyl)amino)phenyl)sulfonyl)-2-(lH-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide, and the
like.
Examples of first appropriate benzenesulfonamides include 4-(((lR)-3-morphoIin-4-
yl-l-((phenylthio)methyl)propyI)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
(R)-4-(4-(dimethylamino)-l-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide, and
the like.
Step (g) is typically conducted from about 36 to about 50 hours in solvents such as
dichloromethane, acetonitrile, dioxane, tetrahydrofuran, mixtures thereof and the like.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, compounds such as those described in , for
example, U. S. Patent Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional
Applications 61/145611, 61/120275, 61/181180, and 61/181203, comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, a first appropriate benzenesulfonamide and a first
30
coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the apoptosis promoter.
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethyIcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and a
first coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyI)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide comprising:
31
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, such as those described in, for example, U. S. Patent
Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203, comprising:
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, a first appropriate amine, l-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, and
isolating or not isolating the apoptosis promoter.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, for use in making compounds, such as those
described in, for example, U. S. Patent Publication US2005/0159427A1, the '799 Patent, and
U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and 61/181203,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
32
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, a first appropriate amine, l-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, and
isolating or not isolating the apoptosis promoter.
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
33
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide comprising:
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride, and
4-dimethylaminopyridine at about 25°C to about 35°C and isolating or not isolating the N-(4-
(4-((2-(4-chlorophenyl)-5,5 -dimethyl-1 -cyclohex-1 -en-1 -yl)methyl)piperazin-1 -y l)benzoy 1)-
4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
1 -en-1 -yl)methyl)piperazin-l -yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-1 -
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, such as those described in, for example, U. S. Patent
Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203,comprising:
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, a first appropriate amine, l-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride and 4-dimethylaminopyridine at about
25°C to about 35°C, and isolating or not isolating the apoptosis promoter.
Still another embodiment pertains to a process for making an apoptosis promoter, or a
pharmaceutically acceptable salt thereof, such as those described in, for example, U. S. Patent
Publication US2005/0159427A1, the '799 Patent, and U.S. Provisional Applications
61/145611, 61/120275, 61/181180, and 61/181203, comprising:
34
(e) reacting 2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -ene-1 -carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-
1 -en-1 -yl)methy l)piperazin-1 -y l)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and sodium hydroxide at about 55°C to about 75°C, and
isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, a first appropriate amine, l-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride and 4-dimethylaminopyridine at about
25°C to about 35°C, and isolating or not isolating the apoptosis promoter.
Still another embodiment pertains to a process for making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof,
comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and sodium hydroxide at about 55°C to about 75°C, and
isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride, and
4-dimethylaminopyridine at about 25°C to about 35°C and isolating or not isolating the N-(4-
(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-
35
4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethy]-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yI)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5 -dimethyl-1 -cyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoy l)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyI)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethyIcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
36
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex- 1-en-1 -yl)methyl)piperazin-1 -yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
37
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimetiiyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcycIohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsi]y])oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
38
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
at about -10°C to about 0°C to provide (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane at about -10°C to about 0°C to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide at about -10°C to about 5°C to provide ((2E)-l-(4-chlorophenyl)-4,4-
dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-
dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
39
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-lr(4-chlorophenyl)-4,4-dimethylcyclohexanol, and
(d) reacting (2E)-l-(4-chlorophenyI)-4,4-dimethyI-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid at about 5°C to about 20°C to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chIorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide at about 55°C to about
75°C, and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-enl-
yl)methyl)piperazin-l-yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyI-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine at about 25°C to about 35°C and isolating or not isolating the N-(4-
(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-
4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-
cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)ben2enesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
40
One embodiment of this invention, therefore, pertains to a process for making 2-(4-
chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and a
fifth base to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not
isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide to provide l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-
dimethylcyclohexanol and isolating or not isolating the l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol; and
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethyIcyclohexanol
and a second acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, for use in making N-(4-(4-((2-(4-
chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, for use in making compounds
such as those described in , for example, U. S. Patent Publication US2005/0159427A1, the
'799 Patent, and U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and
61/181203.
Examples of fifth bases useful for the practice of this invention include N,Ndiisopropylethylamine,
l,8-diazabicyclo(5.4.0)undec-7-ene and the like.
41
Examples of second acids useful for the practice of this invention include aqueous
hydrochloric acid, sulfuric acid and the like.
Step (h) is typically conducted for about 1 to about 3 hours in a solvent such as
dichloromethane and the like.
Step (i) is typically conducted for about 1 to about 3 hours in a solvent such as
tetrahydrofuran, diethyl ether, mixtures thereof and the like.
Step (j) is typically conducted for about 15 to about 20 hours in a solvent such as
tetrahydrofuran, diethyl ether, mixtures thereof and the like.
Still another embodiment of this invention, therefore, pertains to a process for making
2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and
N,N-diisopropylethylamine to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and
isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide to provide l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-
dimethylcyclohexanol and isolating or not isolating the l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol; and
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol
and aqueous hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-lene-
1-carbaldehyde.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Still another embodiment of this invention, therefore, pertains to a process for making
2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and
N,N-diisopropylethylamine at about -60°C to -90°C to provide (2-(diethoxymethyl)-4,4-
42
dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-
dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide at about -60°C to -10°C to provide l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol and isolating or not isolating the l-(4-
chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol; and
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol
and aqueous hydrochloric acid at about 50°C to 80°C to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-1 -cyclohex-1 -en-1 -yl)methyl)piperazin-1 -y l)benzoy l)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and a
fifth base to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not
isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide to provide l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-
dimethylcyclohexanol and isolating or not isolating the l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol;
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol
and a second acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethyIcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoate;
43
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l -cyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and
N,N-diisopropylethylamine to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and
isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide to provide l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-
dimethylcyclohexanol and isolating or not isolating the l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol;
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol
and aqueous hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-lene-
1-carbaldehyde;
44
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex- 1-en-1 -yl)methyl)piperazin-1 -
yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(h) reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and
N,N-diisopropylethylamine at about -60°C to -90°C to provide (2-(diethoxymethyl)-4,4-
dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-
dimethylcyclohexanone;
(i) reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-
chlorophenyl magnesium bromide at about -60°C to -10°C to provide l-(4-chlorophenyl)-2-
(diethoxymethyl)-4,4-dimethylcyclohexanol and isolating or not isolating the l-(4-
chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol;
45
(j) reacting the l-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol
and aqueous hydrochloric acid at about 50°C to 80°C to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chIorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide at about 55°C to about
75°C, and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-enl-
yl)methyl)piperazin-l-yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine at about 25°C to about 35°C and isolating or not isolating the N-(4-
(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-
4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsuIfanyl)methyl)propyl)amino)-3-((trifluoromethyI)sulfonyI)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
One embodiment of this invention, therefore, pertains to a process for making 2-(4-
chlorophenyl)-5,5-dimethylcyclohex-1 -ene-1 -carbaldehyde, comprising:
(k) reacting 4,4-dimethylcyclohexanone, and phosphorus oxychloride to provide
2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or not isolating the 2-chloro-
5,5-dimethylcyclohex-l-enecarbaldehyde; and
46
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium
catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde and
isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, for use in making N-(4-(4-((2-(4-
chlorophenyl)-5,5 -dimethyl- 1-cyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoyl)-4-((( 1R)-
3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide , or a pharmaceutically acceptable salt
thereof.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
, or a pharmaceutically acceptable salt thereof, for use in making compounds
such as those described in , for example, U. S. Patent Publication US2005/0159427A1, the
'799 Patent, and U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and
61/181203.
Examples of first phase transfer catalysts useful for the practice of this invention
include tetrabutyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl
ammonium chloride, tetraethyl ammonium bromide, tetraoctyl ammonium bromide, tetra
butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium chloride, benzyl triethyl
ammonium chloride, tetrabutyl ammonium acetate, tetrabutyl ammonium iodide, and the like.
Examples of fifth bases useful for the practice of this invention include potassium
carbonate, potassium phosphate, potassium fluoride, potassium f-butoxide and the like.
Examples of first palladium catalysts useful for the practice of this invention include
palladium (II) acetate, tris(dibenzylideneacetone)dipaIladium(0),
47
tetrakis(triphenylphosphine)palladium(0), (1,1'-
bis(diphenylphosphino)ferrocene)dichloropalladium(II), and the like.
Step (k) is typically conducted for about 15 to about 20 hours in a solvent such as
dichloromethane, N,N-dimethylformamide, mixtures thereof and the like.
Step (1) is typically conducted for about 5 to about 10 hours in a solvent such as water,
or mixtures of water and one or more organic solvents such as toluene, methylene chloride,
DMF, and the like.
Another embodiment of this invention, therefore, pertains to a process for making
2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(k) reacting 4,4-dimethylcyclohexanone, and phosphorus oxychloride to provide
2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or not isolating the 2-chloro-
5,5-dimethylcyclohex-l-enecarbaldehyde; and
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, tetrabutyl ammonium bromide, potassium carbonate, and
palladium (II) acetate to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-lene-
1 -carbaldehy de.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Another embodiment of this invention, therefore, pertains to a process for making 2-
(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde, comprising:
(k) reacting 4,4-dimethylcyclohexanone and phosphorus oxychloride at about
20°C to 45°C to provide 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or
not isolating the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde; and
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, tetrabutyl ammonium bromide, potassium carbonate, and
palladium (II) acetate at about 20°C to 45°C to provide 2-(4-chlorophenyl)-5,5-
48
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde.
Another embodiment pertains to 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde,
or a pharmaceutically acceptable salt thereof, prepared as described in the
preceding embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(k) reacting 4,4-dimethylcyclohexanone, and phosphorus oxychloride to provide
2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or not isolating the 2-chloro-
5,5-dimethylcyclohex-l-enecarbaldehyde;
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium
catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde and
isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
49
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenyIsulfanyl)methyl)propyl)amino)-3-((trifluoromethyI)sulfonyl)benzenesuIfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(k) reacting 4,4-dimethylcyclohexanone, and phosphorus oxychloride to provide
2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or not isolating the 2-chloro-
5,5-dimethylcyclohex-l-enecarbaldehyde;
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, tetrabutyl ammonium bromide, potassium carbonate, and
palladium (II) acetate to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-lene-
1-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -ene-1 -carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
50
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyI-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
Still another embodiment of this invention pertains to a process for making N-(4-(4-
((2-(4-chlorophenyl)-5,5 -dimethyl-1 -cyclohex-1 -en- l-yl)methyl)piperazin-1 -yl)benzoyl)-4-
(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)suIfonyl)benzenesulfonamide, comprising:
(k) reacting 4,4-dimethylcyclohexanone and phosphorus oxychloride at about
20°C to 45°C to provide 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde and isolating or
not isolating the 2-chloro-5,5-dimethylcyclohex-l-enecarbaIdehyde;
(1) reacting the 2-chloro-5,5-dimethylcyclohex-l-enecarbaldehyde, 4-
chlorophenylboronic acid, tetrabutyl ammonium bromide, potassium carbonate, and
palladium (II) acetate at about 20°C to 45°C to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride at about 15°C to about
30°C and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide at about 55°C to about
75°C, and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-enl-
yl)methyl)piperazin-l-yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yI)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
l-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine at about 25°C to about 35°C and isolating or not isolating the N-(4-
(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-
51
4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Still another embodiment pertains to N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyI)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, prepared as described in the preceding
embodiment.
One embodiment of this invention, therefore, pertains to a process for making 4-
(((lR)-3-morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising:
(m) reacting 2-fluorobenzenesulfonyl chloride, and a first fluoride source to
provide 2-fluorobenzenesulfonyl fluoride and isolating or not isolating the 2-
fluorobenzenesulfonyl fluoride;
(n) reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CH3SiCF3),
and a second fluoride source to provide l-fluoro-2-((trifluoromethyl)sulfonyl)benzene and
isolating or not isolating the l-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and a
first NH3 source to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and
isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yl-1 -((phenyl thio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide.
Another embodiment pertains to 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or a
pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
52
Another embodiment pertains to 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)metliyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or a
pharmaceuticaily acceptable salt thereof, for use in making N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-1 -cyclohex- 1-en-l -yl)methyl)piperazin-1 -yl)benzoyl)-4-(((l R)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyI)amino)-3-((trifluoromethyl)sulfonyl)benzenesuIfonamide
or a salt thereof.
Another embodiment pertains to 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or a
pharmaceuticaily acceptable salt thereof, for use in making compounds such as those
described in , for example, U. S. Patent Publication US2005/0159427A1, the '799 Patent, and
U.S. Provisional Applications 61/145611, 61/120275, 61/181180, and 61/181203.
Examples of first fluoride sources useful for the practice of this invention include
tetra-«-butylammonium fluoride and potassium fluoride, and mixtures thereof.
Examples of second fluoride sources useful for the practice of this invention include
tris(dimethylamino)sulfonium difluorotrimethylsilicate, tetra-rt-butylammonium fluoride,
cesium fluoride, tetrabutylammonium triphenyldifluorosilicate, and tetrabutylammonium
triphenyldifluorsilicate.
Examples of first NH3 sources useful for the practice of this invention include
aqueous ammonium hydroxide, ammonia in methanol, ammonium carbamate, ammonia in
isopropyl alcohol, and hexamethyldisilazane.
Examples of sixth bases useful for the practice of this invention include triethylamine
and the like.

WE CLAIM:
1. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2fe)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethyIcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethyIcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
95
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1 -cyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
2. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanoI and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chIorophenyl)-5,5-dimethylcyclohex-1 -en-l-yl)methyl)piperazin-1 -
yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
96
the4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid;
(m) reacting 2-fluorobenzenesulfonyl chloride, and a first fluoride source to
provide 2-fluorobenzenesulfonyl fluoride and isolating or not isolating the 2-
fluorobenzenesulfonyl fluoride;
(n) reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CH^SiCF^),
and a second fluoride source to provide l-fluoro-2-((trifluoromethyl)sulfonyl)benzene and
isolating or not isolating the l-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and a
first NH3 source to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and
isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((lR)-3-
morpholin-4-yI-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morphoIin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
3. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
97
(a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to
provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating
the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second
base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-
(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first
protected (2E)-2-(hydroxymethylene)-4,4-dimethyIcyclohexanone;
(c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-
dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first
protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
isolating or not isolating the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol; and
(d) reacting the first protected (2E)-l-(4-chlorophenyl)-2-(hydroxymethylene)-
4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-
dimethylcyclohex-1-ene-l-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-
5,5-dimethylcyclohex-l-ene-l-carbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyI)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yI)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid;
(r) reacting a first metal trifluoromethanesulfinate, a first aryl fluoride source, and
a first catalyst to provide l-fluoro-2-((trifluoromethyl)sulfonyl)benzene and isolating or not
isolating the l-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
98
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and a
first NH3 source to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and
isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyI)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((lR)-3-
morphoIin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyI)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first
coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not
isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
4. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsiIyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
99
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyI)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropyIsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chIorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsiIyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methy l)piperazin-1 -yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
100
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
5. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cycIohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
101
(((trimethyIsilyl)oxy)methyIene)cycIohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcycIohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid;
(m) reacting 2-fluorobenzenesulfonyl chloride, and tetra-n-butylammonium
fluoride to provide 2-fluorobenzenesulfonyl fluoride and isolating or not isolating the 2-
fluorobenzenesulfonyl fluoride;
(n) reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CHiSiCF-i),
and tris(dimethylamino)sulfonium difluorotrimethylsilicate to provide l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and
aqueous ammonium hydroxide to provide 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide;
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(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and triethylamine to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yI-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -
yl)methyl)piperazin-l-yl)benzoic acid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
6. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
comprising:
(a) reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tertbutoxide
to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or
not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
(b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone,
triethylamine and trimethylchlorosilane, tert-butylchlorodimethylsilane, or
triisopropylchlorosilane to provide (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and isolating or not
isolating the (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-
4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone;
(c) reacting the (2E)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanone, (2E)-4,4-dimethyl-2-
103
(((trimethylsilyl)oxy)methylene)cyclohexanone, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl
magnesium bromide to provide ((2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol; and
isolating or not isolating the (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-1 -(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-l-(4-chlorophenyl)-4,4-dimethylcyclohexanol;
(d) reacting (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((triisopropylsilyl)oxy)methylene)cyclohexanol, (2E)-l-(4-chlorophenyl)-4,4-dimethyl-2-
(((trimethylsilyl)oxy)methylene)cyclohexanol, or (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-1 -(4-chlorophenyl)-4,4-dimethylcyclohexanol and
hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde
and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde;
(e) reacting 2-(4-chlorophenyl)-5,5 -dimethylcyclohex-1 -ene-1 -carbaldehyde,
ethyl 4-piperazin-l-yIbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-
yl)methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoic acid;
(r) reacting sodium trifluoromethanesulfinate, bis-(2-fluorophenyl)iodonium
tetrafluoroborate and copper(I) oxide to provide l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the l-fluoro-2-
((trifluoromethyl)sulfonyl)benzene;
(o) reacting l-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic
acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating
or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
104
(p) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and
aqueous ammoniurn hydroxide to provide 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide;
(q) reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propylamine and triethylamine to provide 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((lR)-3-
morpholin-4-yl-l-((phenylthio)methyl)propyl)amino)-3-
((trifluoromethyl)sulfonyl)benzenesulfonamide; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcycIohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, 1-
ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride, and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
7. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and a first reducing agent and isolating or not isolating the
ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-l-yl)methyl)piperazin-lyl)
benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and an aqueous third base, and isolating or not isolating
the 4-(4-((2-(4-chlorophenyl)-5,5-dimethyIcycIohex-l-en-l-yl)methyl)piperazin-l-yl)benzoic
acid; and
(g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
105
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and a
first coupling reagent with or without a fourth base and with or without an auxiliary coupling
reagent, and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-lcyclohex-
1 -en-1 -yl)methyl)piperazin-1 -yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-1 -
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
8. A process for making N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexl-
en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-
((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, or
a pharmaceutically acceptable salt thereof, comprising:
(e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-l-carbaldehyde,
ethyl 4-piperazin-l-ylbenzoate and sodium triacetoxyborohydride and isolating or not
isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate;
(f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoate and aqueous sodium hydroxide, and isolating or not
isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -
yl)benzoic acid; and
(g) reacting 4-(4-((2-(4-chlorophenyI)-5,5-dimethylcyclohex-l-en-lyl)
methyl)piperazin-l-yl)benzoicacid, 4-(((lR)-3-morpholin-4-yl-l-
((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,
1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride and
4-dimethylaminopyridine and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-
dimethyl-l-cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-
l-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
9. A compound, or a pharmaceutically acceptable salt thereof, selected from the
group consisting of (2E)-4,4-dimethyl-2-(((triisopropylsilyl)oxy)methylene)cyclohexanone,
(2E)-4,4-dimethyl-2-(((trimethylsilyl)oxy)methylene)cyclohexanone, and (2E)-2-(((tertbutyl(
dimethyl)silyl)oxy)methylene)-4,4-dimethylcyclohexanone.
106
10. The compound 2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-ene-lcarbaldehyde
or a pharmaceutically acceptable salt thereof.
orAnand and Anand Advocates
Dated this 13* day of December 2010 Agents for the Applicant
107