Granted Patent B2

US 11,066,407 · App. 16/711,790 · Granted Jul 20, 2021

Inventors: John Charles Tomesch (Succasunna, NJ); Peng Li (New Milford, NJ); Wei Yao (New Milford, NJ); Qiang Zhang (Somerset, NJ); James David Beard (New York, NY); Andrew S. Thompson (Mountainside, NJ); Hua Cheng (Plainsboro, NJ); Lawrence P. Wennogle (Hillsborough, NJ)

Assignee: INTRA-CELLULAR THERAPIES, INC.

C07D471/16C07D471/04

Abstract

Claims (80)

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 claim 1 , wherein the compound of Formula 2F is in free base form.

10. The method according to claim 1 , wherein the compound of Formula 2F is in hydrochloride salt form.

Assignments (2)

Continuity (8)

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