Processes for Preparing 1,2-Substituted Cyclopropyl Derivatives

A process for preparing a chiral compound of formula:

• wherein R2, R3, R3a, R3b, are hydrogen;
• R1 is a 5- to 6-membered heteroaryl ring, cyanophenyl, a 8- to 12-membered bicyclic heteroaryl ring, or a 4- to 12-membered heterocyclic ring;
• and R4 and R5 taken together with the nitrogen atom to which they are attached form an amine moiety represented by structure:
• wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
• R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
• Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
• Q is O or S;
• and m is an integer from 1 to 5;
• comprising the steps of:
• a) providing enantiomerically pure chiral salts using chiral resolution with a chiral amine:
• wherein the chiral amine is selected from R-(−)-1-cyclohexylethylamine, (R)-(+)-α-methylbenzylamine, (S)-(−)-α-methylbenzylamine, (R)-(+)-N-benzyl-α-methylbenzylamine, (S)-(−)-N-benzyl-α-methylbenzylamine, (R)-(+)-N,N-dimethyl-1-phenylethylamine, (S)-(−)-N,N-dimethyl-1-phenylethylamine, [R-(R*,R*)]-(+)-bis(α-methylbenzyl)amine, [S-(R*,R*)]-(−)-bis(α-methylbenzyl)amine, (S)-(+)-1-cyclohexylethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(−)-1-(1-naphthyl)ethylamine, (1R,2R,3R,5S)-(−)-isopinocamphenylamine, (1S,2S,3S,5R)-(+)-isopinocamphenylamine, (1R2R)-(−)-pseudoephedrine, (1S,2S)-(+)-pseudoephedrine, (1R,2S)-(−)-ephedrine, (1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine, (1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-norephedrine, (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2-indanol, (1S,2R)-(−)- cis-1-amino-2-indanol, quinine, and cinchonine;
• b) reacting the chiral pure arylcyclopropanecarboxylic acid after released from the chiral salt obtained from chiral resolution with an amine of formula:
• wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
• R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
• Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
• Q is O or S;
• and m is an integer from 1 to 5;
• and N,N′-carbonyldiimidazole in tetrahydrofuran to provide a chiral compound of structure:
• wherein X is chloro, bromo, iodo, or trifluoromethanesulfonate, and the amine moiety in the structure above is represented by:
• wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
• R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
• Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
• Q is O or S;
• and m is an integer from 1 to 5;
• c) reducing the product of step b to provide a compound of structure:
• wherein X and the amine moiety are as described above for compounds of step b);
• and
• d) treating the product of step c with a reagent selected from the group consisting of 5- to 6-membered heteroaryl, 8- to 12-membered bicyclic heteroaryl, and 4- to 12-membered heterocycloalkyl, and N,N′-dimethylethylenediamine, a copper catalyst, and base, in a basic solvent;
• to provide a compound of formula (II).