Preparation of asymmetric cyclic ureas through a monoacylated diamine intermeidate

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

• 59
• wherein:
• R1 is C1-C4 haloalkyl;
• R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a;
• R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano;
• and
• G taken together along with the oxygen atoms to which G is attached forms a group selected from:
• —O—C(—CH2CH2CH2CH2CH2—)—O—, —O—C(CH2CH3)2—O—,
• —O—C(CH3)(CH2CH3)—O—, —O—C(CH2CH2CH2CH3)2—O—,
• —O—C(CH3)(CH2CH(CH3)CH3)—O—, —O—CH(phenyl)—O—, —OCH2O—,
• —OC(CH3)2O—, and —OC(OCH3)(CH2CH2CH3)O—;
• the process, comprising:
• (1) contacting a compound of formula (I):
• 60
• with an acylating agent of formula R1C(═O)R2;
• wherein:
• R2 is —OR3, —SR3, O-succinimide, or imidazolyl;
• R3 is selected from the group:
• C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne,
• C1-C4 haloalkyl, C3-C10 cycloalkyl, pentafluorophenyl,
• pyridin-2-yl, and phenyl substituted with 0-3 R3a;
• R3a is selected from the group:
• C1-C4 alkyl, C1-C4 alkoxy, halo, —CN, and —NO2;
• to form a compound of formula (II).

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

• 63
• wherein:
• R1 is C1-C4 haloalkyl;
• R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a;
• R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano;
• and
• G taken together along with the oxygen atoms to which G is attached forms a group selected from:
• —O—C(—CH2CH2CH2CH2CH2—)—O—, —O—C(CH2CH3)2—O—,
• —O—C(CH3)(CH2CH3)—O—, —O—C(CH2CH2CH2CH3)2—O—,
• —O—C(CH3)(CH2CH(CH3)CH3)—O—, —O—CH(phenyl)—O—, —OCH2O—,
• —OC(CH3)2O—, and —OC(OCH3)(CH2CH2CH3)O—;
• the process, comprising:
• (1B) contacting a compound of formula (XI):
• 64
• with a suitable base to form a compound of formula (II).

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

• 67
• wherein:
• R7 is selected from the following:
• C1-C8 alkyl substituted with 0-3 R11;
• C2-C8 alkenyl substituted with 0-3 R11;
• C2-C8 alkynyl substituted with 0-3 R11;
• and
• a C3-C14 carbocyclic ring system substituted with 0-3 R11;
• R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a;
• R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano;
• R11 is selected from one or more of the following:
• C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
• —C(═O)R13, keto, cyano, nitro, —CH2NR13R14, —NR13R14, —CO2R13, —OC(═O)R13, —OR13, —OCH2CO2R13, —S(O)2R13, —C(═O)NR13R14, _NR14C(═O)R13, ═NOR14, —NR14C(═O)OR14, —OC(═O)NR13R14, —NR13C(═O)NR13R14, —NR14SO2NR13R14, —NR14SO2R13, —SO2NR13R14;
• C1-C4 alkyl substituted with —NR13R14;
• and
• C3-C14 carbocyclic residue substituted with 0-3 R16;
• R13 is independently selected from:
• C1-C6 alkyl substituted with 0-3 R15;
• C2-C6 alkenyl substituted with 0-3 R15;
• and
• phenyl substituted with 0-3 R16;
• R14 is independently selected from:
• C1-C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, and
• C1-C6 alkyl substituted with 0-3 C1-C4 alkoxy;
• or
• R13 and R14 can alternatively join to form —(CH2)4—, —(CH2)5—, —CH2CH2N(CH3)CH2CH2—, or —CH2CH2OCH2CH2—;
• R15 is selected from one or more of the following:
• C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
• —C(═O)R23, cyano, nitro, —CH2NR23R24, —NR23R24, —CO2R23, —OC(═O)R23, —OR23, —OCH2CO2R23, —S(O)2R23, —C(═O)NR23R24, —NR24C(═O)R23, ═NOR24, —NR24C(═O)OR24, —OC(═O)NR23R24, —NR23C(═O)NR23R24, —NR24SO2NR23R24, —NR24SO2R23—SO2NR23R24;
• C1-C4 alkyl substituted with —NR23R24;
• and
• phenyl substituted with 0-3 R16;
• R16 is selected from one or more of the following:
• H, halogen, cyano, nitro, —CH2NR23R24, —NR23R24, —CO2R23, —OC(═O)R23, —OR23, —S(O)2R23, —C(═O)NR23R24, —NR24C(═O)R23, ═NOR24, —NR24C(═O)OR24, —OC(═O)NR23R24, —NR23C(═O)NR23R24, —NR24SO2NR23R24, —NR24SO2R23, —SO2NR23R24;
• C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkylmethyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, C3-C6 cycloalkoxy, methylenedioxy, ethylenedioxy, C1-C4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
• and
• C1-C4 alkyl substituted with —NR23R24;
• R23 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy;
• R24 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy;
• or
• R23 and R24 can alternatively join to form —(CH2)4—, —(CH2)5—, —CH2CH2N(CH3)CH2CH2—, or —CH2CH2OCH2CH2—;
• and
• G taken together along with the oxygen atoms to which G is attached forms a group selected from:
• —O—C(—CH2CH2CH2CH2CH2—)—O—, —O—C(CH2CH3)2—O—,
• —O—C(CH3)(CH2CH3)—O—, —O—C(CH2CH2CH2CH3)2—O—,
• —O—C(CH3)(CH2CH(CH3)CH3)—O—, —O—CH(phenyl)—O—, —OCH2O—,
• —OC(CH3)2O—, and —OC(OCH3)(CH2CH2CH3)O—;
• said process comprising:
• (5) contacting a compound of formula (V):
• 68
• with a cyclizing agent selected from phosgene, diphosgene, and triphosgene, in the presence of a suitable base to form a compound of formula (VI).

A compound of formula:

• 74
• and acid addition salts thereof, wherein:
• R1 is —CF3, —CF2CF3, —CF2CF2CF3, —CF2Cl, —CF2Br, —CCl3, —CBr3 or CH2F;
• and
• R7 is propyl or phenyl.