Efficient method for the conversion of nitriles to amidines

A process for the formation of a compound of the formula (I):

• 30
• or a pharmaceutically acceptable salt form thereof;
• wherein:
• R1 is selected from H or NHR1a;
• R1a is selected from the group consisting of:
• —C(═O)—O—R1b,
• —C(═O)—R1b,
• —C(═O)N(R1b)2,
• —C(═O)NHSO2R1b,
• —C(═O)NHC(═O)R1b,
• —C(═O)NHC(═O)OR1b,
• —C(═O)NHSO2NHR1b,
• —C(═S)—NH—R1b,
• —NH—C(═O)—O—R1b,
• —NH—C(═O)R1b,
• —NH—C(═)—NH—R1b,
• —SO2—O—R1b,
• —SO2—R1b,
• —SO2—N(Rb)2,
• —SO2—NHC(═O)OR1b,
• —P(═S)(OR1b)2,
• —P(═O)(OR1b)2,
• —P(═S)(R1b)2,
• —P(═O)(R1b)2, and
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• R1b is selected from the group consisting of:
• C1-C8 alkyl substituted with 0-2 R1c,
• C2-C8 alkenyl substituted with 0-2 R1c,
• C2-C8 alkynyl substituted with 0-2 R1c,
• C3-C8 cycloalkyl substituted with 0-2 R1c,
• aryl substituted with 0-4 R1c,
• aryl(C1-C6 alkyl)-substituted with 0-4 R1c,
• a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and
• C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c;
• R1c is H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl;
• R2 is selected from H or C1-C10 alkyl;
• R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a;
• R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c;
• R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d;
• R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
• R5 is selected from the group consisting of:
• hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
• C6-C10 aryloxy, C7-C11 arylalkyloxy,
• C3-C10 alkylcarbonyloxyalkyloxy,
• C3-C10 alkoxycarbonyloxyalkyloxy,
• C3-C10 alkoxycarbonylalkyloxy,
• C5-C10 cycloalkylcarbonyloxyalkyloxy,
• C5-C10 cycloalkoxycarbonyloxyalkyloxy,
• C5-C10 cycloalkoxycarbonylalkyloxy,
• C8-C11 aryloxycarbonylalkyloxy,
• C8-C12 aryloxycarbonyloxyalkyloxy,
• C8-C12 arylcarbonyloxyalkyloxy,
• C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
• 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy,
• (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and
• (R5a)HN—(C1-C10 alkoxy)-;
• R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl;
• n is 0-4;
• a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4;
• said process comprising:
• contacting a compound of formula (VI):
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• wherein:
• Z is selected from R6SO2— or (R7)3Si—;
• R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, aryloxy and aryl substituted with 0-5 R6c;
• R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl;
• R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
• R7 is selected independently from C1-C10 alkyl or aryl substituted 0-3 R7a;
• and
• R7a is C1-C10 alkyl;
• with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

A process for the preparation of compound (I)

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• or a pharmaceutically acceptable salt form thereof, said process comprising:
• (a) heating a compound of the formula (IV):
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• wherein:
• R1 is selected from H or NHR1a;
• R1a is selected from the group consisting of:
• —C(═O)—O—R1b,
• —C(═O)—R1b,
• —C(═O)N(R1b)2,
• —C(═O)NHSO2R1b,
• —C(═O)NHC(═O)R1b,
• —C(═O)NHC(═O)OR1b,
• —C(═O) NHSO2NHR1b,
• —C(═S)—NH—R1b,
• —NH—C(═O)—O—R1b,
• —NH—C(═O)R1b,
• —NH—C(═)—NH—R1b,
• —SO2—O—R1b,
• —SO2—O—R1b,
• —SO2—R1b,
• —SO2—N(R1b)2,
• —SO2—NHC(═O)OR1b,
• —P(═S)(OR1b)2,
• —P(═O)(OR1b)2,
• —P(═S)(R1b)2,
• —P(═O)(R1b)2, and
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• R1b is selected from the group consisting of:
• C1-C8 alkyl substituted with 0-2 R1c,
• C2-C8 alkenyl substituted with 0-2 R1c,
• C2-C8 alkynyl substituted with 0-2 R1c,
• C3-C8 cycloalkyl substituted with 0-2 R1c,
• aryl substituted with 0-4 R1c,
• aryl(C1-C6 alkyl)-substituted with 0-4 R1C,
• a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and
• C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c;
• R1c is H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl;
• R2 is selected from H or C1-C10 alkyl;
• R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a;
• R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c;
• R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d;
• R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
• R5 is selected from the group consisting of:
• hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
• C6-C10 aryloxy, C7-C11 arylalkyloxy,
• C3-C10 alkylcarbonyloxyalkyloxy,
• C3-C10 alkoxycarbonyloxyalkyloxy,
• C3-C10 alkoxycarbonylalkyloxy,
• C5-C10 cycloalkylcarbonyloxyalkyloxy,
• C5-C10 cycloalkoxycarbonyloxyalkyloxy,
• C5-C10 cycloalkoxycarbonylalkyloxy,
• C8-C11 aryloxycarbonylalkyloxy,
• C8-C12 aryloxycarbonyloxyalkyloxy,
• C8-C12 arylcarbonyloxyalkyloxy,
• C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
• 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy,
• (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and
• (R5a)HN—(C1-C10 alkoxy)-;
• R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl;
• R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, aryloxy and aryl substituted with 0-5 R6c;
• R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl;
• R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
• n is 0-4;
• a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4;
• for a time sufficient, and to a temperature sufficient to form a compound of formula (V):
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• and;
• (b) contacting said compound of formula (V) with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a salt thereof.