Patent GB-851972-A (GB)
Title: Acid addition salts of esters of substituted piperidyl phenyl methanols and processes for their production
IPC: A61K31/00
Filed: 1958-07-02
Abstract: The invention comprises acid addition salts of the racemates and optically active isomers of esters of substituted 2-piperidyl phenyl methanols (form B) of the general formula :  <FORM:0851972/IV(b)/1> wherein R represents hydrogen, methyl or ethyl and Ar represents a phenyl group carrying one or more of the substituents : halogen atoms and alkyl, alkoxy, aralkoxy, methylenedioxy, acyloxy, nitro and acylamino groups.  Specified salts include the hydrohalides, sulphates, nitrates, phosphates, maleates, fumarates, citrates, tartrates, methane sulphonates and ethane disulphonates.  They may be prepared by one of the following methods : (1) esterification of an acid addition salt of an appropriately substituted 2-piperidyl phenyl methanol (form B) by known methods for the esterification of salts of amino-alcohols without concomitant acylation of an <FORM:0851972/IV(b)/2> group ; (2) chlorination of an appropriately substituted 2-piperidyl phenyl methanol (form A or mixture of forms A and B) or an acid addition salt thereof, followed by conversion of the resulting acid salt of the 1-chloro-1-substituted phenyl-1-(2-piperidyl) methane to the desired final product either by (a) hydrolysis followed by esterification of the resulting methanol (form B) in the form of its acid addition salt as in (1) or (b) the action of at least 2 moles of a metal salt of the appropriate acid R COOH, followed, if desired, by conversion of the resulting acid addition salt into another salt.  The term "appropriately substituted" denotes that the substituent is such that under the conditions of the reaction it will become or remain a substituent chosen from those which may be present in Ar ; thus, in process (1) an amino substituent is converted into an acylamino group.  The salts are of use therapeutically as nerve stimulants (see Group VIII).  The salts of racemic esters may be resolved into the optical isomers.  In examples : (1) 1-acetoxy-1-(4-methyl phenyl)-1-(2-piperidyl) methane hydrochloride (form B) is prepared by acylating the hydrochloride of the corresponding methanol with a mixture of acetyl chloride and acetic anhydride ; (2) the analogous 3-methyl phenyl, (3) 2-methyl phenyl, (4) 4-methoxy phenyl, (5) 4-chlorophenyl, (6) 4-nitro phenyl, (7) 3-chlorophenyl, (8) 4-bromo phenyl, (9) 3:4-dimethyl phenyl, (10) 4-benzyloxyphenol, (12) 3:4-methylene dioxy phenyl and (13) 4-ethoxy phenyl compounds are prepared similarly.  In further examples : (11) 1-acetoxy-1-(4-benzyloxyphenyl)-1-(2-piperidyl) methane hydrochloride is debenzylated by means of acetic acid in the presence of palladised charcoal and then esterified with a mixture of acetic anhydride and acetyl chloride yielding the hydrochloride of 1-acetoxy-1-(4-acetoxyphenyl)-1-(2-piperidyl) methane (form B) ; (14) 1-acetoxy-1-(4-acetamido phenyl)-1-(2-piperidyl) methane hydrochloride (form B) is prepared by reacting acetyl chloride with the hydrochloride of 1-(4-amino phenyl)-1-(2-piperidyl) methanol (form B).  1-(4-methyl phenyl)-1-(2-piperidyl) methanol (form B) is prepared by hydrolysis with silver nitrate of 1-(4-methyl phenyl)1-(2-piperidyl chloro methane hydrochloride, itself obtained by catalytic hydrogenation of 2-(4-methyl benzoyl) pyridine followed by chlorination with thionyl chloride.  The 3-methyl phenyl, 2-methyl phenyl, 4-methoxyphenyl, 4-chloro phenyl, 3-chlorophenyl, 4-bromo phenyl, 3:4-dimethyl phenyl, 4-benzyloxyphenyl, 3:4-methylene dioxy phenyl and 4-ethoxy phenyl analogues are similarly prepared 1-(4-nitrophenyl)-1-(2-piperidyl) methanol is obtained by nitration of 1-phenyl-1-acetoxy-(1-acetyl-2-piperidyl) methane followed by hydrolysis.  1-(4-amino phenyl)-1-(2-piperidyl) methanol is prepared by catalytic reduction of the corresponding 4-nitro phenyl compound.ALSO:Pharmaceutical preparations having central nervous system stimulant properties comprise at least one acid addition salt of an ester (form B) of the general formula:  <FORM:0851972/VI/1> wherein R represents hydrogen, methyl or ethyl and Ar represents a phenyl group carrying one or more of the substituents: halogen atoms and alkyl, alkoxy, aralkoxy, methylene dioxy, acyloxy, nitro and acylamino groups, the acid anion being that of a pharmaceutically acceptable acid, and a pharmaceutical carrier. Specified salts include sulphates, nitrates, phosphates, hydrohalides, maleates, fumarates, citrates, tartrates, methane sulphonates and ethane disulphonates.  The preparations may be in powder, tablet, capsule, solution, suspension or emulsion form. Specified diluents are water, starch, lactose, stearic acid, magnesium stearate and dextrin.  The specified esters (in hydrochloride salt form) exemplify all the classes of substituents listed above, and may be used in the form of separate optical isomers or racemic mixtures.