Process for synthesizing phosphonic and phosphinic acid compounds

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 R2 and R3;
• R2 is one to three substituents independently selected from the group consisting of C1-4alkyl, methoxy, C2-6alkoxy, —OCH2—C2-6alkenyl, NH2, —NH(C1-6alkyl), —N(C1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro,
• wherein said C1-4alkyl, C2-6alkenyl and C2-6alkoxy substituents of R2 are optionally substituted with a substituent independently selected from the group consisting of —NR11R12, aryl, heteroaryl, one to three halogens and hydroxy;
• R11 and R12 are substituents independently selected from the group consisting of hydrogen, C1-6alkyl, and aryl;
• wherein said C1-6alkyl substituent of R11 or R12 is optionally substituted with substituent selected from the group consisting of hydroxy, aryl, —C(═O)C1-4alkoxy, and —NR15R16;
• R15 and R16 are substituents independently selected from the group consisting of hydrogen, C1-6alkyl, and aryl, and said R15 and R16 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• R3 is one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, —OCH2(C2-6)alkenyl, NH2, —NH(C1-6alkyl), —N(C1-6)dialkyl, —NHC(═O)Cy, —N(C1-6alkyl)C(═O)Cy, —C(═O)C1-4alkoxy, —C(═O)NR17R18, —C(═O)NHcycloalkyl, —C(═O)N(C1-6alkyl)cyclo alkyl, —C(═O)NHCy, —C(═O)N(C1-6alkyl)Cy, —C(═O)Cy, —OC(═O)NR19R20, halogen, hydroxy, nitro, cyano, aryl and aryloxy,
• wherein said C1-6alkyl and C1-6alkoxy are optionally substituted with one to three substituents independently selected from the group consisting of —NR21R22, —NHcycloalkyl, —N(C1-6alkyl)cycloalkyl, —NHCy, —N(C1-6alkyl)Cy, —NHC(O)—C1-6alkyl-C1-6alkoxy, aryl, heteroaryl, halogen, —C(═O)NR23R24, —OC(═O)NR25R26, —C(═)(C1-4)alkoxy, and —C(═O)Cy,
• wherein each instance of said C2-6alkenyl is optionally substituted on a terminal carbon with aryl or —C(═O)NR27R28, and
• wherein said aryl and cycloalkyl are optionally substituted with one to three substituents independently selected from R14;
• R14 is independently hydrogen, C1-6alkyl, C1-6 alkoxy, C2-6alkenyl, C1-6alkylthio, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro, and
• any one of the foregoing C1-6alkyl- or C1-6alkoxy-containing substituents of R14 is optionally substituted on a terminal carbon atom with a substituent selected from —NR29R30, aryl, heteroaryl, one to three halogen atoms, or hydroxy;
• R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are substituents independently selected from the group consisting of hydrogen, C1-6alkyl and aryl, wherein C1-6alkyl and aryl are each optionally substituted with hydroxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl), or —N(C1-6)dialkyl;
• and said R17 and R18, R19 and R20, R21 and R22, R23 and R24 or R25 and R26 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• R27 and R28 are independently hydrogen;
• C1-6alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl) or —N(C1-6)dialkyl;
• or aryl;
• and said R27 and R28 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• R29 and R30 are independently hydrogen;
• C1-6alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl), or —N(C1-6)dialkyl;
• or aryl;
• and R29 and R30 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, C1-6alkyl, —C1-6alkylC(═O)C1-6alkyl, —C1-6alkylC(═O)C1-6alkoxy, —C1-6alkyl-aryl, —C1-6alkylC(═O)aryl, —C(═O)(C1-6)alkyl, —C(═O)(C1-6)alkoxy, —C(═O)aryl, —SO2aryl, aryl, heteroaryl and heterocyclyl,
• wherein aryl and the aryl portion of —C1-6alkylC(═O)aryl, —C(═O)aryl and —SO2aryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, hydroxy, NH2, —NH(C1-6alkyl), and —N(C1-6)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;
• R5 is selected from the group consisting of hydrogen or C1-3alkyl optionally substituted with NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, C1-6alkylcarbonyloxy-, C1-6alkoxycarbonyloxy-, C1-6alkylcarbonylthio-, (C1-6)alkylaminocarbonyl-, di(C1-6)alkylaminocarbonyl-, one to three halogens, or hydroxy;
• and said aryl is optionally substituted with C1-6alkyl, C1-6alkoxy, C1-6alkylthio-, C2-6alkenyl, NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
• alternatively, when R6 is C1-8alkoxy, said R5 and R6 are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring,
• provided that R5 is other than C1-3alkyl substituted with di(C1-6)alkylamino-carbonyl- when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z—R4 is 5-chloro-benzothiophen-3-yl;
• and provided that R5 is other than C1-3alkyl substituted with C1-6alkylcarbonylthio- when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z—R4 is 5-chloro-benzothiophen-3-yl;
• R6 is selected from the group consisting of C1-6alkyl, C1-8alkoxy, heteroaryl, aryl, and hydroxy;
• wherein C1-6alkyl is optionally substituted on a terminal carbon atom with a substituent selected from C1-3alkoxy, aryl, or hydroxy;
• and C1-8alkoxy is optionally substituted on a terminal carbon atom with a substituent independently selected from the group consisting of C1-6alkylcarbonyloxy- and di(C1-6)alkylaminocarbonyl-;
• and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C1-6alkoxy, and halogen;
• Z is a bicyclic aryl or bicyclic heteroaryl;
• wherein aryl and heteroaryl are optionally substituted with the group R4;
• R4 is one to three substituents selected from the group consisting of C1-6alkyl, C2-6alkenyl, C1-6alkoxy, aryl(C2-6)alkenyl, halogen, —C(═O)Cy, —C(═O)NR31R32, aryl, —CO2H, oxo and cyano,
• wherein said C1-6alkyl, C2-6alkenyl and C1-6alkoxy are optionally substituted with a substituent independently selected from the group consisting of —NR33R34, 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, C1-6alkyl, C1-6alkoxy, aryl, halogen, hydroxy, and nitro;
• and
• R31, R32, R33 and R34 are substituents independently selected from the group consisting of hydrogen, C1-6alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• and said R31 and R32 or R33 and R34 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 R5 is C1-3alkyl) with a Compound A2, wherein Compound A1 and Compound A2 are present in a first ratio, in toluene, to provide a Compound A3 (wherein R5 is C1-3alkyl), 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 R5 is C1-3alkyl) 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 R5 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.