Convergent synthesis of alpha-aryl-beta-ketonitriles

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

• 52
• or a pharmaceutically acceptable salt form thereof;
• wherein:
• r is an integer from 0 to 4;
• R1 is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NR1cR1d, —OR1e, and —SR1e;
• R1c and R1d are independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
• C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl;
• alternatively, R1c and R1d are taken together to form a heterocyclic ring selected from the group consisting of:
• piperidine, pyrrolidine, piperazine, N-methylpiperazine,
• morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C1-C4 alkyl groups;
• R1e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• R2 is selected from the group consisting of:
• H, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and
• C1-C4 alkyl substituted with 0-5 R2a;
• R2a is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN,
• C1-C4 haloalkyl, —OR2e, and —SR2e;
• and
• R2e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• the process comprising the steps of:
• (1) contacting a compound of formula (II):
• 53
• with a halogenating agent to form a compound of formula (III):
• 54
• wherein X is a halogen derived from the halogenating agent;
• (2) contacting the compound of formula (III) with a strong base followed by addition of an alkylborate to form a compound of formula (IV):
• 55
• (3) contacting the compound of formula (IV) with a compound of formula (V):
• 56
• wherein Y is a second halogen;
• in the presence of a catalyst and a weak base to form a compound of formula (VI):
• 57
• (4) contacting the compound of formula (VI) with an isomerization base to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof;
• wherein the compound of formula (V) is prepared by contacting a compound of formula (VII):
• 58
• with a halogenating agent in an organic acid to form a compound of formula (V).

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

• 59
• or a pharmaceutically acceptable salt form thereof;
• wherein:
• r is an integer from 0 to 4;
• R1 is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NR1cR1d, —OR1e, and —SR1e;
• R1c and R1d are independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
• C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl;
• alternatively, R1c and R1d are taken together to form a heterocyclic ring selected from the group consisting of:
• piperidine, pyrrolidine, piperazine, N-methylpiperazine,
• morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C1-C4 alkyl groups;
• R1e is selected from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• R2 is selected from the group consisting of:
• H, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and
• C1-C4 alkyl substituted with 0-5 R2a;
• R2a is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN,
• C1-C4 haloalkyl, —OR2e, and —SR2e;
• and
• R2e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• the process comprising the steps of:
• (1) contacting a compound of formula (IV):
• 60
• with a compound of formula (V):
• 61
• wherein Y is a halogen;
• in the presence of a catalyst and a weak base to give a compound of formula (VI):
• 62
• (2) contacting the compound of formula (VI) with an isomerization base to give a compound of formula (I), or a pharmaceutically acceptable salt form thereof.

A process for the preparation of a compound of formula (VI):

• 63
• or a pharmaceutically acceptable salt form thereof;
• wherein:
• r is an integer from 0 to 4;
• R1 is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NR1cR1d, —OR1e, and —SR1e;
• R1c and R1d are independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
• C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl;
• alternatively, R1c and R1d are taken together to form a heterocyclic ring selected from the group consisting of:
• piperidine, pyrrolidine, piperazine, N-methylpiperazine,
• morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C1-C4 alkyl groups;
• R1e is selected from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• R2 is selected from the group consisting of:
• H, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and
• C1-C4 alkyl substituted with 0-5 R2a;
• R2a is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN,
• C1-C4 haloalkyl, —OR2e, and —SR2e;
• and
• R2e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• the process comprising contacting a compound of formula (IV):
• 64
• with a compound of formula (V):
• 65
• in the presence of [1,1′-Bis(diphenylphosphino)ferrocene] palladium (II) chloride, sodium bicarbonate and a suitable solvent to give a compound of formula (VI).

A compound of formula (VI):

• 67
• wherein:
• r is an integer from 0 to 4;
• R1 is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NR1cR1d, —OR1e, and —SR1e;
• R1c and R1d are independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
• C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl;
• alternatively, R1c and R1d are taken together to form a heterocyclic ring selected from the group consisting of:
• piperidine, pyrrolidine, piperazine, N-methylpiperazine,
• morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C1-C4 alkyl groups;
• R1e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• R2 is selected from the group consisting of:
• H, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and
• C1-C4 alkyl substituted with 0-5 R2a;
• R2a is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN,
• C1-C4 haloalkyl, —OR2e, and —SR2e;
• and
• R2e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl.

A compound of formula (I):

• 68
• wherein:
• r is an integer from 0 to 4;
• R1 is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NR1cR1d, —OR1e, and —SR1e;
• R1c and R1d are independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
• C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl;
• alternatively, R1c and R1d are taken together to form a heterocyclic ring selected from the group consisting of:
• piperidine, pyrrolidine, piperazine, N-methylpiperazine,
• morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C1-C4 alkyl groups;
• R1e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl;
• R2 is selected from the group consisting of:
• H, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and
• C1-C4 alkyl substituted with 0-5 R2a;
• R2a is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN,
• C1-C4 haloalkyl, —OR2e, and —SR2e;
• and
• R2e is independently selected at each occurrence from the group consisting of:
• H, C1-C10 alkyl, C3-C6 cycloalkyl, and C4-C6 cycloalkylalkyl.