Process for synthesizing phosphonic and phosphinic acid compounds

Abstract

The present invention is directed to an improved process for synthesizing phosphonic and phosphinic acid chymase inhibitor compounds.

1 . A process for preparing a compound of Formula (I) and a salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of heteroaryl and benzo fused heterocyclyl, optionally substituted with R 2  and R 3 ;
 R 2  is one to three substituents independently selected from the group consisting of C 1-4 alkyl, methoxy, C 2-6 alkoxy, —OCH 2 —C 2-6 alkenyl, NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 )dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro, 
 wherein said C 1-4 alkyl, C 2-6 alkenyl and C 2-6 alkoxy substituents of R 2  are optionally substituted with a substituent independently selected from the group consisting of —NR 11 R 12 , aryl, heteroaryl, one to three halogens and hydroxy; 
 R 11  and R 12  are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl; wherein said C 1-6 alkyl substituent of R 11  or R 12  is optionally substituted with substituent selected from the group consisting of hydroxy, aryl, —C(═O)C 1-4 alkoxy, and —NR 15 R 16 ; 
 R 15  and R 16  are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, and said R 15  and R 16  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 R 3  is one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —OCH 2 (C 2-6 )alkenyl, NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 )dialkyl, —NHC(═O)Cy, —N(C 1-6 alkyl)C(═O)Cy, —C(═O)C 1-4 alkoxy, —C(═O)NR 17 R 18 , —C(═O)NHcycloalkyl, —C(═O)N(C 1-6 alkyl)cyclo alkyl, —C(═O)NHCy, —C(═O)N(C 1-6 alkyl)Cy, —C(═O)Cy, —OC(═O)NR 19 R 20 , halogen, hydroxy, nitro, cyano, aryl and aryloxy, 
 wherein said C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one to three substituents independently selected from the group consisting of —NR 21 R 22 , —NHcycloalkyl, —N(C 1-6 alkyl)cycloalkyl, —NHCy, —N(C 1-6 alkyl)Cy, —NHC(O)—C 1-6 alkyl-C 1-6 alkoxy, aryl, heteroaryl, halogen, —C(═O)NR 23 R 24 , —OC(═O)NR 25 R 26 , —C(═)(C 1-4 )alkoxy, and —C(═O)Cy, 
 wherein each instance of said C 2-6 alkenyl is optionally substituted on a terminal carbon with aryl or —C(═O)NR 27 R 28 , and 
 wherein said aryl and cycloalkyl are optionally substituted with one to three substituents independently selected from R 14 ; 
 R 14  is independently hydrogen, C 1-6 alkyl, C 1-6  alkoxy, C 2-6 alkenyl, C 1-6 alkylthio, —NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro, and 
 any one of the foregoing C 1-6 alkyl- or C 1-6 alkoxy-containing substituents of R 14  is optionally substituted on a terminal carbon atom with a substituent selected from —NR 29 R 30 , aryl, heteroaryl, one to three halogen atoms, or hydroxy; 
 R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25  and R 26  are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl and aryl, wherein C 1-6 alkyl and aryl are each optionally substituted with hydroxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C 1-4 alkoxy, NH 2 , —NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and said R 17  and R 18 , R 19  and R 20 , R 21  and R 22 , R 23  and R 24  or R 25  and R 26  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 R 27  and R 28  are independently hydrogen; C 1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , —NH(C 1-6 alkyl) or —N(C 1-6 )dialkyl; or aryl; and said R 27  and R 28  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 R 29  and R 30  are independently hydrogen; C 1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , —NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; or aryl; and R 29  and R 30  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 Cy is a heterocyclyl optionally substituted with a substituent selected from the group consisting of oxo, C 1-6 alkyl, —C 1-6 alkylC(═O)C 1-6 alkyl, —C 1-6 alkylC(═O)C 1-6 alkoxy, —C 1-6 alkyl-aryl, —C 1-6 alkylC(═O)aryl, —C(═O)(C 1-6 )alkyl, —C(═O)(C 1-6 )alkoxy, —C(═O)aryl, —SO 2 aryl, aryl, heteroaryl and heterocyclyl, 
 wherein aryl and the aryl portion of —C 1-6 alkylC(═O)aryl, —C(═O)aryl and —SO 2 aryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 )dialkyl; and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents; and, wherein heterocyclyl is optionally spiro-fused to said Cy; 
 R 5  is selected from the group consisting of hydrogen or C 1-3 alkyl optionally substituted with NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, C 1-6 alkylcarbonyloxy-, C 1-6 alkoxycarbonyloxy-, C 1-6 alkylcarbonylthio-, (C 1-6 )alkylaminocarbonyl-, di(C 1-6 )alkylaminocarbonyl-, one to three halogens, or hydroxy; and said aryl is optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio-, C 2-6 alkenyl, NH 2 , —NH(C 1-6 )alkyl, —N(C 1-6 )dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R 6  is C 1-8 alkoxy, said R 5  and R 6  are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring, 
 provided that R 5  is other than C 1-3 alkyl substituted with di(C 1-6 )alkylamino-carbonyl- when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is OH, and Z—R 4  is 5-chloro-benzothiophen-3-yl; and provided that R 5  is other than C 1-3 alkyl substituted with C 1-6 alkylcarbonylthio- when ring system A is 3,4-difluoro-phenyl, n is 1, R 6  is CH 3 , and Z—R 4  is 5-chloro-benzothiophen-3-yl; 
 R 6  is selected from the group consisting of C 1-6 alkyl, C 1-8 alkoxy, heteroaryl, aryl, and hydroxy; wherein C 1-6 alkyl is optionally substituted on a terminal carbon atom with a substituent selected from C 1-3 alkoxy, aryl, or hydroxy; and C 1-8 alkoxy is optionally substituted on a terminal carbon atom with a substituent independently selected from the group consisting of C 1-6 alkylcarbonyloxy- and di(C 1-6 )alkylaminocarbonyl-; and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C 1-6 alkoxy, and halogen; 
 Z is a bicyclic aryl or bicyclic heteroaryl; wherein aryl and heteroaryl are optionally substituted with the group R 4 ; 
 R 4  is one to three substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, aryl(C 2-6 )alkenyl, halogen, —C(═O)Cy, —C(═O)NR 31 R 32 , aryl, —CO 2 H, oxo and cyano, 
 wherein said C 1-6 alkyl, C 2-6 alkenyl and C 1-6 alkoxy are optionally substituted with a substituent independently selected from the group consisting of —NR 33 R 34 , aryl, one to three halogen atoms and hydroxy, and 
 wherein said aryl is optionally substituted with a substituent independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, aryl, halogen, hydroxy, and nitro; and 
 R 31 , R 32 , R 33  and R 34  are substituents independently selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C 1-4 alkoxy, NH 2 , NH(C 1-6 alkyl), or —N(C 1-6 )dialkyl; and said R 31  and R 32  or R 33  and R 34  are optionally taken together with the atoms to which they are attached to form a ring of five to seven members; 
 comprising the steps of: 
 Step 1. reacting a Compound A1 (wherein R 5  is C 1-3 alkyl) with a Compound A2, wherein Compound A1 and Compound A2 are present in a first ratio, in toluene, to provide a Compound A3 (wherein R 5  is C 1-3 alkyl), representative of a compound of Formula (I): 
 
       
         
           
           
               
               
           
         
         wherein in the first ratio, the amount of Compound A1 exceeds the amount of Compound A2 by about 0.2 equivalents; and 
         Step 2. reacting the Compound A3 (wherein R 5  is C 1-3 alkyl) in the presence of TMSBr, in acetonitrile and optionally present pyridine, wherein TMSBr and Compound A3 are in a second ratio, and wherein TMSBr and pyridine, when pyridine is present, are in a third ratio, to provide a Compound A4 (wherein R 5  is hydrogen), representative of a compound of Formula (I): 
       
       
         
           
           
               
               
           
         
         wherein the second ratio of TMSBr:Compound A3 is in a range of about 2.5:1 to about 2:1; and 
         wherein the third ratio of TMSBr:pyridine, when pyridine is present, is in a range of from about 1:1 to about 1:2. 
       
     
     
         2 . The process of  claim 1 , further comprising the step of:
 Step 3. reacting the Compound A4 (wherein R 5  is hydrogen) with a cationic salt-forming compound, in a solvent mixture, wherein the solvents in the mixture are in a fourth ratio, to provide a Compound A5 as a salt, representative of a compound Formula (I), wherein the salt is obtained by direct crystallization:   
       
         
           
           
               
               
           
         
       
     
     
         3 . The process of  claim 2 , wherein an amount of Compound A1 is in a range of from about 1.2 equivalents to about 1 equivalent and an amount of Compound A2 is in a range of from about 1 equivalent to about 0.8 equivalents according to said first ratio. 
     
     
         4 . The process of  claim 1 , wherein the ratio of TMSBr:Compound A3 is in a range of about 2.5:1 to about 2:1, according to said second ratio, and wherein the third ratio of TMSBr:pyridine is in a range of about 1:1 to about 1:2. 
     
     
         5 . The process of  claim 1 , wherein in the third ratio of TMSBr:pyridine is about 1:2. 
     
     
         6 . The process of  claim 1 , wherein the ratio of TMSBr:Compound A3 is in a range of about 2.5:1 to about 2:1, according to said second ratio, wherein pyridine is not present. 
     
     
         7 . The process of  claim 2 , wherein the salt of the compound of  claim 1  is a choline salt precipitated from a solvent mixture of MeOH and EtOAc, wherein the solvents are in said fourth ratio of about 1:3 MeOH:EtOAc. 
     
     
         8 . The process of  claim 1 , wherein the compound is selected from the group consisting of:
 (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-3-yl-vinylcarbamoyl)-methyl]-phosphonic acid,   [(benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-phosphonic acid,   [(5-chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylthiocarbamoyl)-methyl]-phosphonic acid,   [(benzo[b]thiophen-5-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-phosphonic acid,   [naphthalen-1-yl-(quinolin-3-ylcarbamoyl)-methyl]-phosphonic acid,   [(benzo[b]thiophen-6-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [(benzo[b]thiophen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [(2-amino-benzothiazol-6-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-phosphonic acid,   [naphthalen-1-yl-(quinolin-6-ylcarbamoyl)-methyl]-phosphonic acid,   [(indan-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [naphthalen-1-yl-(quinolin-2-ylcarbamoyl)-methyl]-phosphonic acid,   [(1H-indol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [(benzo[1,3]dioxol-5-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [(isoquinolin-3-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid,   [(5-chloro-benzo[b]thiophen-3-yl)-(2-phenyl-trans-cyclopropylcarbamoyl)-methyl]-methyl-phosphinic acid,   [(benzofuran-2-ylcarbamoyl)-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid,   (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-methyl]-methyl-phosphinic acid,   (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-methyl]-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)ester,   (E)-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3-nitro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid (tert-butylcarbonyloxymethyl)ester,   (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-methyl]-phosphonic acid bis-(tert-butylcarbonyloxymethyl)ester,   (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-methyl]-phosphonic acid (tert-butylcarbonyloxymethyl)ester,   (E)-2-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-ylvinylcarbamoyl)-methyl]-1,3,2-dioxaphosphorinane 2-oxide, and   (E)-[(5-chloro-benzo[b]thiophen-3-yl)-(2-pyridin-2-yl-vinylcarbamoyl)-methyl]-phosphonic acid (isopropyloxycarbonyloxymethyl)ester.