US 9,751,883 B2Granted

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

AssigneeIntra-Cellular Therapies, Inc.

InventorsJohn Charles Tomesch, Peng Li, Wei Yao, Qiang Zhang, James David Beard, Andrew S. Thompson, Hua Cheng, Lawrence P. Wennogle

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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:

Claims28

Dependent claims

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) R5 is H;
(vi) R7, R8 and R9 are H;
(vii) R10 is H or C1-4alkyl;
(viii) R6a a and R6b are H;
and
(ix) R1 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 C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(vi) R5 is H;
(vii) R7, R8 and R9 are H;
and
(viii) X—Y— is a H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-C4alkyl;
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 C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(iv) R5 is H;
and
(v) R7, R8 and R9 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. R12 is C1-4alkyl;
and
(b) a base;
into a Compound of Formula 2G:
wherein:
(i) k, m, n, B, R5, R7, R8, and R9 are as defined for Formula 2E;
(ii) X is N, and Y is —C(O)—;
and
(iii) R10 is H or C1-4alkyl;
and
B) converting the Compound of Formula 2G into a Compound of Formula 2H:
wherein:
(i) k, m, n, B, R5, R7, R8, R9 and R10 are as defined for Formula 2G;
(ii) X is N;
and
(iii) R6a and R6b 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, R5,R6a, R6b, R7, R8, R9 and Rl0 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.

67 more elements

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) Xis N;
(v) R5 is H;
(vi) R7, R8 and R9 are H;
(vii) R10 is H or C1-4alkyl;
(viii) R6a and R6b are H;
and
(ix) R1 is 4-(4-fluorophenyl)-4-oxobutyl or 3-(4-fluorophenoxy)propyl;
comprising the steps of:
A) treating a compound of Formula 2D:
wherein:
(i) k is 1;
(ii) m is 1;
(iii) A is Cl, Br, F or I;
(iv) B is benzyl or triphenylmethyl, or is a moiety of the formula:
wherein:
a) Z is C1-6alkyl, aryl, C1-6alkylaryl or —OR, wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
and
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(v) R5 is H;
and
(vi) R7, R8 and R9 are H;
with (a) a nucleophilic alkyl halide having the formula:
wherein:
(i) A is Cl, Br, F or I;
(ii) X—Y— is H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-4alkyl;
and
(iii) n is 1;
and
(b) a base;
to form a Compound of Formula 2E:
wherein:
(i) k, m, A, B, R5, R7, R8 and R9 are as defined for Formula 2D;
(ii) n is 1;
and
(iii) X—Y— is H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-4alkyl;
B) converting the Compound of Formula 2E by treatment with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium;
and (b) a base;
or
converting 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 C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
(b) P is —C(O)—, —C(O)O— or —S(O)2—;
(iv) R5 is H;
and
(v) R7, R8 and R9 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. R12 is C1-4alkyl;
and
(b) a base;
into a Compound of Formula 2G:
wherein:
(i) k, m, n, B, R5, R7, R8, and R9 are as defined for Formula 2E;
(ii) X is N, and Y is —C(O)—;
and
(iii) R10 is H or C1-4alkyl;
and
(C) converting the Compound of Formula 2G into a Compound of Formula 2H:
wherein:
(i) k, m, n, B, R5, R7, R8, R9 and R10 are as defined for Formula 2G;
(ii) X is N;
and
(iii) R6a and R6b are H;
by reduction of the ketone of the Compound of Formula 2G to a methylene using a reducing agent;
(D) converting the Compound of Formula 2H into a Compound of Formula 2I:
wherein:
(i) k, m, n, R5, R6a, R6b, R7, R8, R9 and R10 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;
E) 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
F) optionally reacting the Compound of Formula 2J with an acid to give a pharmaceutically acceptable salt of the Compound of Formula 2J.

81 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/066,962Filed 10 Mar 2016 · continuation
Priority: 12 Mar 2007
Published: US 2016/0194326 A17 Jul 2016
Granted: 5 Sep 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 471/16
In which the condensed system contains three hetero rings: peri-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/906,473Us provisional application · filed 12 Mar 2007
PCT/US2008/003340Parent of this division · filed 12 Mar 2008
Application13/593,097Parent of this continuation · filed 23 Aug 2012
US 8,309,722 B2Parent of this division · filed 13 Nov 2012
Application14/323,545Parent of this continuation · filed 3 Jul 2014
US 8,779,139 B2Parent of this continuation · filed 15 Jul 2014
US 2016/0194326 A1Pre-grant publication · published 7 Jul 2016
US 9,315,504 B2Parent of this continuation
Application12/531,016Parent of this division
Application13/593,097Parent of this division
US 2010/0113781 A1Published application
US 2013/0046097 A1Published application
US 2014/0364609 A1Published application
US 9,751,883 B2This patent

From the US filing history. Foreign family members aren’t listed.

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