Process for making 5-substituted pyrazoles

The process of making compound of Formula Ia or Ib ##STR115## wherein:

• R.sub.1 is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and a 5 or 6 membered heterocycle substituted with one or more substituents selected from the group consisting of C.sub.1-3 alkyl, halo, OH, O-alkyl, cyano, CF.sub.3, OCF.sub.3 and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3, alkyl, SO.sub.2 CH.sub.3, SO.sub.2 NH.sub.2, SO.sub.2 NHCOalkyl, SO.sub.2 NHCOalkyl, alkenyl, and alkynyl;
• R.sub.2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3 alkyl, alkylamino, and dialkylamino;
• R.sub.3 is selected from the group selected from hydrogen, alkyl, and phenyl, wherein all but hydrogen may optionally be substituted by one or more of the group consisting of SO.sub.2 CH.sub.3, halo, alkyl, O-alkyl, S-alkyl, cyano, CF.sub.3, OCF.sub.3, and SO.sub.2 NH.sub.2 ;
• R.sub.4 is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH.sub.2, SH, O-alkyl, NHR.sub.7, N(R.sub.7).sub.2, alkoxycarbonyl, acyl and halo;
• R.sub.5 is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH.sub.2, SH, S-alkyl, O-alkyl, NHR.sub.7, N(R.sub.7).sub.2, CO.sub.2 H, halo, alkoxycarbonyl, acyl, heterocyclyl, cycloalkyl, heterocycloalkyl, and heterocyclyl;
• R.sub.4 and R.sub.5 taken together may form a ring selected from the group consisting of morpholine, aziridine, thiomorpholine, piperidine, piperazine, and N'-piperazine;
• R.sub.7 is selected from the group consisting of alkyl and cycloalkyl;
• comprising:
• reacting an organometallic reagent of the formula R.sub.2 CH.sub.2 M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula Ic;
• ##STR116## treating the ketone of Formula Ic with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce the dithietane derivative of Formula Id;
• ##STR117## reacting the dithietane derivative of Formula Id with an amine of formula R.sub.4 --NH--R.sub.5 to produce the thioamide of Formula Ie, If, or Ig;
• ##STR118## condensing the thioamide of Formula Ie, If or Ig with hydrazine or substituted hydrazine.