Preparation of antifibrinolytically active isomer of 4-aminomethylcyclohexane carboxylic acid

Abstract

Disclosed and claimed is the preparation of the 4-aminomethyl-cyclohexane carboxylic acid isomer assaying at least about 90% antifibrinolytically active material from specific para-disubstituted cyclohexane starting material. For example, in 4-aminomethyl-cyclohexane methanol such as its isomer melting at 118° C. in a series of steps its methanol group is converted to carboxyl. More specifically its amino group is blocked by reaction with benzoyl halide and the methanol group then oxidized to carboxyl, and the benzoyl group removed to yield the end product isomer. 1-4-dimethyl-cyclohexane dicarboxylate melting at 69°-71° C., another such cyclohexane starting material, is hydrolyzed to its mono-ester which with thionyl halide is converted to the halide of the half-ester, which latter reacted with ammonia gives the corresponding ester amide. The latter is heated with thionyl halide and converted to methyl 4-cyano-cyclohexane carboxylate which then is hydrolyzed to yield 4-cyano-cyclohexane carboxylic acid which catalytically reduced using a compatible reduction catalyst such as Raney nickel is converted to the 4-aminomethyl-cyclohexane carboxylic acid end product.

We claim: 
     
       1. The method of preparing the 4-aminomethyl-cyclohexane carboxylic acid isomer which in substantially pure state assays at least about 90 percent antifibrinolytically active material, which method comprises reacting the 4-aminomethyl-cyclohexane methanol isomer melting at 118° C., in an inert solvent for it and the presence of sufficient alkali metal carbonate to neutralize later formed hydrogen halide, with sufficient benzoyl halide dissolved in an inert solvent for it, and while cooling, to benzoylate its amino group, heating the reaction mixture until substantially complete benzoylation of said group occurs; recovering the resulting 4-benzoylaminomethyl-cyclohexane methanol and admixing it with water and sufficient alkali metal hydroxide to provide oxidizing conditions, adding sufficient of a compatible oxidizing agent to oxidize the methanol group to the carboxylic acid group while controlling the temperature below about 40° C. until substantial completion of the oxidation; removing the resulting 4-benzoylaminomethyl-cyclohexane carboxylic acid from the reaction mixture, heating it with sufficient mineral acid to split off the benzoyl group; and separating the resulting 4-aminomethyl-cyclohexane carboxylic acid antifibrinolytically active isomer. 
     
     
       2. The method of preparing the 4-aminomethyl-cyclohexane carboxylic acid isomer which in substantially pure state assays at least about 90 percent antifibrinolytically active material, which method comprises reacting the isomer of 1,4-dimethyl-cyclohexane dicarboxylate melting at 69°-71° C., dissolved in a water-miscible lower alkanol solvent for it, with sufficient of an aqueous solution of an alkali metal hydroxide to hydrolyze said diester to the corresponding mono-ester and while cooling at a rate to avoid undesirable temperature rise; heating the resulting reaction mixture until conversion to the mono-ester is substantially completed; cooling and neutralizing the reaction mixture with mineral acid thereby precipitating the mono-ester; reacting the latter with sufficient thionyl halide to provide the corresponding acid halide of said half-ester heating their mixture until sufficiently complete formation of the corresponding cyclohexane methyl half-ester acid halide results; evaporating off any unreacted thionyl halide and distilling from the residue the cyclohexane methyl half-ester acid halide; reacting the latter half-ester acid halide under conditions to maintain the temperature below about 10° C. with concentrated ammonia to convert said half-ester acid halide to the corresponding ester amide; allowing the reaction mixture to stand while cold for the corresponding cyclohexane methyl half-ester amide to precipitate out; separating said precipitated half-ester and heating it in an inert solvent with thionyl halide until said half-ester amide is converted to methyl 4-cyano-cyclohexane carboxylate, filtering off any insoluble material in the reaction mixture and evaporating off the solvent from the clear filtrate reaction mixture, and distilling off from the residue the methyl 4-cyano-cyclohexane carboxylate; reacting the latter dissolved in a water-miscible lower alkanol solvent for it under ester-hydrolyzing conditions with an aqueous solution of an alkali metal hydroxide to hydrolyze said ester to 4-cyano-cyclohexane carboxylic acid; separating the latter from the reaction mixture and dissolving said carboxylic acid in sufficient of a water-soluble alkaline agent suitable for use in catalytic reduction, and feeding in hydrogen gas in the presence of sufficient of a compatible reduction catalyst until the desired reduction is substantially complete; thereafter separating the insoluble material from the reaction solution and concentrating said solution to recover from it said 4-aminomethyl-cyclohexane carboxylic acid end product. 
     
     
       3. The method as claimed in claim 2, wherein the reduction catalyst is Raney nickel. 
     
     
       4. The method of preparing the 4-aminomethyl-cyclohexane carboxylic acid isomer which in substantially pure state assays at least about 90 percent antifibrinolytically active material, which method comprises adding to a cold reaction mixture of 4-aminomethyl-cyclohexane methanol and sufficient alkali metal carbonate to neutralize the later formed hydrogen halide, in an inert solvent for said cyclohexane methanol, sufficient benzoyl halide to form the corresponding benzoylaminomethyl derivative, the benzoyl halide being added in a suitable inert solvent advantageously miscible with said first solvent and cautiously while cooling the reaction mixture to avoid undesirable temperature rise; then heating said mixture until substantially complete formation of said benzoyl-derivative occurs; removing any insoluble material from the reaction solution and distilling off the solvents, from their residue recovering the resulting 4-benzoylaminomethyl-cyclohexane methanol; admixing the latter with water and sufficient alkali metal hydroxide to provide oxidation conditions and to the resulting mixture adding a compatible oxidizing agent to oxidize the methanol group to the carboxylic group while controlling the temperature advantageously below about 40° C. until addition of said agent is completed, and then beneficially with agitation until substantial completion of the oxidation; removing any insoluble material from the reaction mixture and acidifying it with mineral acid and cooling it; removing the separated oily layer of 4-benzoylaminomethyl-cyclohexane carboxylic acid and heating it with sufficient mineral acid to split off the benzoyl group; then concentrating the resulting mixture to about the original volume of said oily intermediate, and removing any insoluble material therefrom; thereafter evaporating the filtrate to dryness, dissolving it in distilled water and passing it through a bed of chromatography resin; evaporating the filtrate therefrom to about concentrated state and adding sufficient acetone to precipitate the said antifibrinolytically active 4-aminomethyl-cyclohexane carboxylic acid isomer.