Preparation of certain [((6BR,10AS)-2,3,6B,7,8,9,10, 10A-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

Patent metadata

Field	Value
Publication number	US-9751883-B2
Application number	US-201615066962-A
Country	US
Kind code	B2
Filing date	Mar 10, 2016
Priority date	Mar 12, 2007
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines, such methods comprising the preparation of a Compound of Formula 2G, as shown below, and use of said compound to produce the fused gamma-carbolines of Formula 2J, as defined herein:

First claim

What is claimed is:

1. A method for preparing a Compound of Formula 2J:

or a pharmaceutically acceptable salt thereof, wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) X is N;
(v) R 5 is H;
(vi) R 7 , R 8 and R 9 are H;
(vii) R 10 is H or C 1-4 alkyl;
(viii) R 6a a and R 6b are H; and
(ix) R 1 is 4-(4-fluorophenyl)-4-oxobutyl or 3-(4-fluorophenoxy)propyl;
comprising the steps of:
A) converting a Compound of Formula 2E:

wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) A is Cl, Br, F or I;
(v) B is benzyl or triphenylmethyl, or is a moiety of the formula:

wherein:
a) Z is C 1-6 alkyl, aryl, C 1-6 alkylaryl or —OR wherein R is C 1-6 alkyl, aryl, arylC 1-6 alkyl or heteroarylC 1-6 alkyl;
b) P is —C(O)—, —C(O)O— or —S(O) 2 —;

(vi) R 5 is H;
(vii) R 7 , R 8 and R 9 are H; and
(viii) X—Y— is a H(R′)N—CH 2 — or H(R′)N—C(O)—, wherein R′ is H or C 1 -C 4 alkyl;
by treating the Compound of Formula 2E with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium; and (b) a base;

or a Compound of Formula 2E′:

wherein:
(i) k is 1;
(ii) m is 1;
(iii) B is benzyl or triphenylmethyl, or is a moiety of the formula:

wherein:
a) Z is C 1-6 alkyl, aryl, C 1-6 alkylaryl or —OR wherein R is C 1-6 alkyl, aryl, arylC 1-6 alkyl or heteroarylC 1-6 alkyl;
b) P is —C(O)—, —C(O)O— or —S(O) 2 —;

(iv) R 5 is H; and
(v) R 7 , R 8 and R 9 are H;
by reacting the Compound of Formula 2E′ with:
(a) an alkyl haloacetate having a formula of:

wherein:
i. A is Cl, Br or I; and
ii. R 12 is C 1-4 alkyl; and

(b) a base;

into a Compound of Formula 2G:

wherein:
(i) k, m, n, B, R 5 , R 7 , R 8 , and R 9 are as defined for Formula 2E;
(ii) X is N, and Y is —C(O)—; and
(iii) R 10 is H or C 1-4 alkyl; and

B) converting the Compound of Formula 2G into a Compound of Formula 2H:

wherein:
(i) k, m, n, B, R 5 , R 7 , R 8 , R 9 and R 10 are as defined for Formula 2G;
(ii) X is N; and
(iii) R 6a and R 6b are H;
by reduction of the ketone of the Compound of Formula 2G to a methylene using a reducing agent;
C) converting the Compound of Formula 2H into a Compound of Formula 2I:

wherein:
(i) k, m, n, R 5 ,R 6a , R 6b , R 7 , R 8 , R 9 and R l0 are as defined for Formula 2H; and
(ii) X is N;
by deprotection of the Compound of Formula 2H using an acid catalyst, a base catalyst or catalytic hydrogenation;

D) reacting the Compound of Formula 2I with (a) 4-chloro-4′-fluorobutyrophenone or 1-(3-chloropropoxy)-4-fluorobenzene, and (b) a base, to give the Compound of Formula 2J, as defined 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 step A) comprises treating the Compound of Formula 2E with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium; and (b) a base.

3. The method according to claim 2 , wherein the base for step A) is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and potassium phosphate.

4. The method according to claim 3 , wherein the base is potassium carbonate.

5. The method according to claim 2 , wherein said transition metal catalyst is a copper catalyst.

6. The method according to claim 5 , further comprising the use of a monodentate ligand or bidentate ligand, wherein such ligand is selected from a group consisting of:
(1) phenolic or amine ligands selected from a group consisting of aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, 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;
(2) ligand represented by structure 1:

wherein

A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
X represents NR 2 , P(alkyl) 2 , P(cycloalkyl) 2 , AsR 2 , or OR;
Y represents H, alkyl, NR 2 , or AsR 2 ;
X and Y are not identical;
R, R a , R b , R c , and R d , for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 ;
R e and R f , for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 80 ;
A and B independently are unsubstituted or substituted with R e and R f respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R a and R b , or R c and R d , or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone;
R 80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers o

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/24

  Antidepressants · CPC title