Preparation of certain substituted 1-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-YL)butan-1-ones and pharmaceutically acceptable salts thereof
The present invention provides methods for the preparation of certain optionally substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below and as further defined herein:
1. A method for preparing a compound of Formula 2J:
or a pharmaceutically acceptable salt thereof,
wherein:
k is 1;
m is 1;
n is 1;
R 1 is 4-(4-fluorophenyl)-4-oxobutyl;
R 5 is H;
R 6a and R 6b are independently H;
R 7 , R 8 and R 9 are independently H;
R 10 is H or CH 3 ; and
X is —N—;
comprising the steps of:
A) reacting a compound of Formula 2E:
wherein:
k is 1;
m is 1;
n is 1;
A is Cl, Br, F, or I;
B is benzyl, triphenylmethyl, or toluenesulfonyl; or
B is a moiety of the formula:
wherein:
P is —C(O)—, —C(O)O—, or —S(O) 2 —;
Z is C 1-6 alkyl, aryl, C 1-6 alkylaryl, or —OR; and
R is C 1-6 alkyl, aryl, arylC 1-6 alkyl, or heteroarylC 1-6 alkyl;
R 5 is H;
R 7 , R 8 and R 9 are independently H;
X is —NH(R′);
R′ is H or CH 3 ; and
Y is —C(O)—;
with:
(a) a transition metal catalyst selected from the group consisting of palladium, copper, nickel, platinum, ruthenium, and rhodium;
(b) a base; and optionally
(c) a monodentate or bidentate ligand selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, an aryl alcohol, a 1,2-diamine, 2-(dimethylamino)glycine, (methylimino)diacetic acid, 8-aminoquinoline, a 1,2-aminoalcohol, an imidazolium carbene, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1, 10-phenanthroline, 5-chloro-1,10-phenanthroline, and 5-nitro-1,10-phenanthroline;
to give a compound of Formula 2G:
wherein:
k is 1;
m is 1;
n is 1;
B is benzyl, triphenylmethyl, or toluenesulfonyl; or
B is a moiety of the formula:
wherein:
P is —C(O)—, —C(O)O—, or —S(O) 2 —;
Z is C 1-6 alkyl, aryl, C 1-6 alkylaryl, or —OR; and
R is C 1-6 alkyl, aryl, arylC 1-6 alkyl, or heteroarylC 1-6 alkyl;
R 5 is H;
R 7 , R 8 and R 9 are independently H;
R 10 is H or CH 3 ;
X is —N—; and
Y is —C(O)—;
B) reacting the compound of Formula 2G above with a reducing agent, to give a compound of Formula 2H:
wherein:
k is 1;
m is 1;
n is 1;
B is benzyl, triphenylmethyl, or toluenesulfonyl; or
B is a moiety of the formula:
wherein:
P is —C(O)—, —C(O)O—, or —S(O) 2 —;
Z is C 1-6 alkyl, aryl, C 1-6 alkylaryl, or —OR; and
R is C 1-6 alkyl, aryl, arylC 1-6 alkyl, or heteroarylC 1-6 alkyl;
R 5 is H;
R 6a and R 6b are independently H;
R 7 , R 8 and R 9 are independently H;
R 10 is H or CH 3 ; and
X is —N—;
C) deprotecting the compound of Formula 2H above with an acid catalyst, a base catalyst, or via catalytic hydrogenation, to give a compound of Formula 2I:
wherein:
k is 1;
m is 1;
n is 1;
R 5 is H;
R 6a and R 6b are independently H;
R 7 , R 8 and R 9 are independently H;
R 10 is H or CH 3 ; and
X is —N—;
D) reacting the compound of Formula 2I above with (a) 4-chloro-4′-fluorobutyrophenone, and (b) a base, to give the compound of Formula 2J above; and
E) optionally reacting the compound of Formula 2J with an acid, to give a pharmaceutically acceptable salt of the compound of Formula 2J.
2. The method according to claim 1 , wherein:
B is B is benzyl, triphenylmethyl, or toluenesulfonyl; or
B is a moiety of the formula:
wherein:
(a) P is —C(O)—; and
Z is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , or CH 2 CH 2 CH 2 CH(CH 3 ) 2 ; or
(b) P is —C(O)O—; and
Z is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , or CH 2 CH 2 CH 2 CH(CH 3 ) 2 ; or
(c) P is —S(O) 2 —; and
Z is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , or CH 2 CH 2 CH 2 CH(CH 3 ) 2 ; or
(d) P is —C(O)—; and
Z is phenyl or naphthyl; or
(e) P is —C(O)O—; and
Z is phenyl or naphthyl; or
(f) P is —S(O) 2 —; and
Z is phenyl or naphthyl; or
(g) P is —C(O)—; and
Z is CH 2 -phenyl, CH 2 CH 2 -phenyl, CH 2 CH(phenyl)CH 3 , CH 2 CH(phenyl)CH 2 CH 3 , CH 2 -naphthyl, CH 2 CH 2 -naphthyl, CH 2 CH(naphthyl)CH 3 , or CH 2 CH(naphthyl)CH 2 CH 3 ; or
(h) P is —C(O)O—; and
Z is CH 2 -phenyl, CH 2 CH 2 -phenyl, CH 2 CH(phenyl)CH 3 , CH 2 CH(phenyl)CH 2 CH 3 , CH 2 -naphthyl, CH 2 CH 2 -naphthyl, CH 2 CH(naphthyl)CH 3 , or CH 2 CH(naphthyl)CH 2 CH 3 ; or
(i) P is —S(O) 2 —; and
Z is CH 2 -phenyl, CH 2 CH 2 -phenyl, CH 2 CH(phenyl)CH 3 , CH 2 CH(phenyl)CH 2 CH 3 , CH 2 -naphthyl, CH 2 CH 2 -naphthyl, CH 2 CH(naphthyl)CH 3 , or CH 2 CH(naphthyl)CH 2 CH 3 .
3. The method according to claim 1 , wherein:
B is benzyl, triphenylmethyl, or toluenesulfonyl; or
B is a moiety of the formula:
wherein:
(a) P is —C(O)O—; and
Z is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , or CH 2 CH 2 CH 2 CH(CH 3 ) 2 ; or
(b) P is —C(O)O—; and
Z is phenyl or naphthyl; or
(c) P is —S(O) 2 —; and
Z is phenyl or naphthyl; or
(d) P is —C(O)O—; and
Z is CH 2 -phenyl, CH 2 CH 2 -phenyl, CH 2 CH(phenyl)CH 3 , CH 2 CH(phenyl)CH 2 CH 3 , CH 2 -naphthyl, CH 2 CH 2 -naphthyl, CH 2 CH(naphthyl)CH 3 , or CH 2 CH(naphthyl)CH 2 CH 3 .
4. The method according to claim 1 , wherein the transition metal catalyst is selected from the group consisting of Pd 2 (dibenzylideneacetone) 2 , Pd 2 (dibenzylideneacetone) 3 , Pd/C, PdCl 2 , Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , Pd(PPh 3 ) 4 , Ni(acetylacetonate) 2 , NiCl 2 (PPh) 2 , and Ni(1,5-cyclooctadiene) 2 .
5. The method according to claim 1 , wherein the transition metal catalyst is selected from the group consisting of Cu, CuI, CuCl, Cu 2 Cl 2 , CuBr, CuBr 2 , Cu 2 O, and Cu(OAc) 2 .
6. The method according to claim 1 , wherein the base for step A) is selected from the group consisting of trimethylamine, triethylamine, N,N′-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo [2.2.2]octane, sodium hydride, lithium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium bicarbonate, and potassium phosphate.
7. The method according to claim 1 , wherein step A) further comprises (c) a monodentate or bidentate ligand selected from the group consisting of an aryl alcohol, a 1,2-diamine, a 1,2-aminoalcohol, an imidazolium carbene, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, and 5-nitro-1,10-phenanthroline.
8. The method according to claim 1 , wherein step A) further comprises (c) a monodentate or bidentate ligand selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, 2-phenylphenol, 2-pyridylphenol, 2,6-dimethylphenol, 2-isopropylphenol, biphenyl-2-ol, 1-naphthol, 8-hydroxyquinoline, cis-1,2-diaminocyclohexane, trans-1,2-diaminocyclohexane, cis-N,N′-dimethyl-1,2-diaminocyclohexane, trans-N,N′-dimethyl-1,2-diaminocyclohexane, cis-N-tolyl-1,2-diaminocyclohexane, trans-N-tolyl-1,2-diaminocyclohexane, 1,2-diaminoethane, N,N′-dimethyl-1,2-diaminoethane, N,N,N′,N′-tetramethyl-1,2-diaminoethane, N-butylethylenediamine, 1,2-benzenediamine, N,N-dimethyl-2-hydroxybenzamide, N,N-diethyl-2-hydroxybenzamide, a phenyl-fluorinated N,N-diethyl-2-hydroxybenzamide, a phenyl-chlorinated N,N-diethyl-2-hydroxybenzamide, (2-hydroxyphenyl)(pyrrolidin-1-yl)methanone, ethanolamine, 2-(dimethylamino)ethanol, 2-(dimethylamino)glycine, (methylimino)diacetic acid, 8-aminoquinoline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, and 5-nitro-1,10-phenanthroline.
9. The method according to claim 1 , wherein the reducing agent for step B) is selected from the group consisting of hydrogen in the presence of a catalyst, zinc amalgam with aqueous mineral acid, a metal hydride, hydrazine hydrate in the presence of a base, a borane, and an organoborane.
10. The method according to claim 9 , wherein the reducing agent for step B) is selected from the group consisting of a metal hydride, a borane, and an organoborane.
11. The method according to claim 9 , wherein the reducing agent for step B) is a borane.
12. The method according to claim 9 , wherein the reducing agent for step B) is borane-tetrahydrofuran complex.
13. The method according to claim 1 , wherein step B) further comprises N-alkylating a compound of Formula 2H, wherein R 10 is H, with methyl iodide in the presence of potassium carbonate, to give a compound of Formula 2H, wherein R 10 is CH 3 .
14. The method according to claim 1 , wherein step C) further comprises deprotecting the compound of Formula 2H with an aqueous mineral acid catalyst.
15. The method according to claim 14 , wherein step C) further comprises deprotecting the compound of Formula 2H with aqueous hydrochloric acid.
16. The method according to claim 1 , wherein the base for step D) is potassium carbonate.
17. The method according to claim 1 , wherein the base for step D) is triethylamine.
18. The method according to claim 1 , wherein step D) further comprises (c) sodium iodide or potassium iodide.
19. The method according to claim 1 , wherein the method comprises the step E) of reacting the compound of Formula 2J with an acid, to give a pharmaceutically acceptable salt of the compound of Formula 2J, wherein the acid is a toluenesulfonic acid and the pharmaceutically acceptable salt is a toluenesulfonic acid addition salt.