Preparation of certain substituted 1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

Patent metadata

Field	Value
Publication number	US-11066407-B2
Application number	US-201916711790-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Mar 12, 2007
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The present invention provides methods for the preparation of certain optionally substituted heterocycle fused gamma-carbolines of Formula 2F, as shown below and as further defined herein:

First claim

What is claimed is:

1. A method for preparing a compound of Formula 2F:

or a pharmaceutically acceptable salt thereof,
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, C 1-6 alkylaryl, OR, or aryl; 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—Y— is —(R′)N—CH 2 — or —(R′)N—C(O)—; and
R′ is H or CH 3 ;

comprising the steps of:
A) reacting a compound of Formula 2E:

wherein:
k is 1;
m is 1;
n is 1;
A is F, Cl, Br, 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, C 1-6 alkylaryl, OR, or aryl; 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—Y— is —(R′)N—CH 2 — or —(R′)N—C(O)—; and
R′ is H or CH 3 ;

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 the compound of Formula 2F above; and
B) optionally reacting the compound of Formula 2F with an acid, to give a pharmaceutically acceptable salt of the compound of Formula 2F.

2. 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)—; 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, CuCl, Cu 2 Cl 2 , CuBr, CuBr 2 , CuI, 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

Assignees

• Intra Cellular Therapies Inc

Inventors

• Tomesch John Charles
• Li Peng
• Yao Wei
• Zhang Qiang
• Beard James David
• Thompson Andrew S
• Cheng Hua
• Wennogle Lawrence P

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D471/02

  in which the condensed system contains two hetero rings · CPC title

• C07D471/16 Primary

  Peri-condensed systems · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title