PROCESS FOR PREPARING ALPHA-(ALKYLPHENYL)-4-(HYDROXYDIPHENYLMETHYL)-1-PIPERIDINE BUTANOL

Abstract: A process for preparing alpha-(alkylphenyl)-4-(hydroxy diphenylmethyl)-1-piperidine butanol of formula (I) in which R is a C₁-C₅ alkyl, consisting of reacting an isonipecotate of formula (II): in which R′ is a C₁-C₅ alkyl or an arylalkyl such as benzyl, with 1-(alkylphenyl)-4-chlorobutanol (III) or with 1-(alkylphenyl)-3-­ chloropropylketone (VI), in both of which the alkyl group is C₁-­ C₅, to obtain the compound (IV) either directly or after reduction of the ketone group: and reacting (IV) with phenylmagnesium halide (V) to obtain (I).

Description: This invention relates to a new process for preparing alpha-(alkylphenyl)-4-(hydroxy-diphenylmethyl)-1-piperidinyl butanol of formula (I). in which R is a C₁-C₅ alkyl radical. The process according to the present invention is particularly useful for preparing alpha-(p-tert.butyl-phenyl)-4-(hydroxydiphenylmethyl)-1-piperidinyl butanol, known as terfenadine, an important pharmaceutical principle demonstrating antihystaminic activity. Processes for preparing terfenadine are known. J. Castaner in "Drugs of the future" vol. III, No.3 describes processes starting from azacyclonol or alpha-diphenyl-4-piperidine methanol which is a very costly compound. ES 522610 describes a process for preparing terfenadine and comprising the following steps: a) reacting alkyl isonipecotate of formula (VIII) wherein R" is a C₁-C₄ alkyl radical; with 4-chloro or 4-bromo-1-(tert.butyl-phenyl)-1-butanone of formula (VI) with alkaline carbonates or bicarbonates in the presence of small quantities of KI as the catalyst, and of solvents selected from benzene, dioxane, toluene or polar solvents such as dimethylformamide or dimethylsulfoxide to obtain the compound of formula (IX) b) reducing the ketonic group of the compound of formula IX with NaBH₄ by using as the solvent methanol or ethanol to obtain the compound of formula (X) c) reacting the compound of formula X with phenyl magnesium bromide to obtain the terfenadine. This process has the disadvantage that the yields in the final products the terfenadine are rather low (24%), furthermore the reducing step (b) requires selective conditions in order to avoid the hydrolysis of the ester substituent present on the piperidinic ring such as operating at low temperatures in the presence of anhydrous solvents. CA vol.106, 1987 67123t discloses the same process as that disclosed in ES 522.610 with the only difference that in place of the Grignard reactant Aryl magnesium halide Aryl lithium is used in the final step. This process presents hence the same drawbacks as those pointed out for the previous process. In fact as it results also from US-A-3.000.896 the use of Aryl lithium or Aryl magnesium halide for preparing secondary diphenyl piperidinyl compounds from piperidincarboxylic esters is equivalent. The Applicant has unexpectedly found a process for preparing terfenadine in higher yields which does not require many steps. The process for preparing the compound of formula (I) according to the present invention comprises a) reacting the isonipecotate of formula (II): in which R' is a C₁-C₅ alkyl or an arylalkyl selected from benzyl, with 1-(alkylphenyl)-4-chloro-butanol (III) in which R' is a C₁-C₅ alkyl radical to obtain the compound of formula (IV) b) reacting the compound (IV) with phenyl magnesium halide to obtain the compound of formula (I). The process according to the present invention is much simpler and more economical than known processes and also leads to the formation of purer products. The step (a) of the process according to the present invention is carried out by boiling under reflux in a reaction medium consisting of an organic solvent in the presence of an inorganic base. The preferred solvent is acetonitrile, but dimethylformamide, dimethylacetamide, ethylacetate, dioxane, tetrahydrofuran, acetone, methylethylketone, toluene or their mixtures can be used. The inorganic base used can be either a carbonate or bicarbonate of an alkaline earth metal, such as Na₂CO₃, CaCO₃, or Li₂CO₃. The molar ratio of (II) to (III) used in the reaction is stoichiometric. The step (b) is conducted in an organic solvent at temperatures ranging from 40 to 50°C. The preferred organic solvent for this reaction is tetrahydrofuran, but other solvents can be used such as ethylether, isopropylether or butylether. The phenyl magnesium halide is preferably phenyl magnesium bromide, or phenyl magnesium chloride. The molar ratio of (IV) to phenylmagnesium halide is stoichiometric. The following example of the preparation of the compound of formula (I) is given by way of illustration of the present invention. EXAMPLE 1 The following are fed into a flask fitted with a reflux condenser, a stirrer and a thermometer: 300 g (1.25 mol) of 1-(p-tert.butyl phenyl)-4-chlorobutanol 1 l of acetonitrile 160 g (1.02 mol) of ethyl-isonipecotate 200 g of potassium carboante and the mixture is heated under reflux for 24 hours. The reaction mixture is then poured into a mixture of 5 l of water with 1 l of methylene chloride. The mixture obtained is then stirred and the methylene chloride containing the product is separated and evaporated to dryness under vacuum. The residue is treated with 500 ml of tetrahydrofuran and heated to 40-50°C until completely dissolved. To this solution at 40°C, 1420 g are slowly added of a 25% solution of phenyl magnesium chloride in tetrahydrofuran, and on completion of the addition the mixture is heated to 50°C for 5 hours. The reaction mixture is then cooled to 20°C and poured into 1 l of water, the mixture acidified with hydrochloric acid to acid pH and alkalified with a diluted caustic soda solution to basic pH in the presence of methylene chloride. The organic phase is separated, dried with anhydrous sodium sulphate, filtered and then concentrated to dryness. The residue is then crystallized from acetone to obtain 350 g (0.74 mol) of the required product having the following characteristics. Title: 99.95% M.P. 150-152°C Elementary Analysis for C₃₂H₄₁NO₂ M.W. = 471.69 C(%) H(%) N(%) O(%) Calculated : 81.48 8.76 2.97 6.78 Found : 81.42 8.71 2.94 6.78

Claims: A process for preparing alpha-(alkylphenyl)-4-(hydroxydiphenylmethyl)-1-piperidine butanol of formula (I) in which R is a C₁-C₅ alkyl, comprising: a) reaction an alkyl isonipecotate of formula (II) in which R' is a C₁-C₅ or an arylalkyl selected from benzyl, with 1-(alkylphenyl)-4-chloro-butanol (III) wherein R has the above mentioned meanings, in stoichiometric amount, in an organic solvent at the boiling solvent temperature under reflux conditions in the presence of an inorganic base to obtain the compound of formula (IV) b) reacting the compound (IV) with phenyl magnesium halide in stoichiometric amounts in the presence of an organic solvent at temperatures ranging from 40 to 50°C, to obtain the compound of formula (I). The process according to claim 1 wherein the organic solvent used in step (a) is selected from the class consisting of acetonitrile, dioxane, dimethylacetamide, dimethylformamide, ethylacetate, tetrahydrofuran, acetone, methylethylketone, toluene or their mixtures. The process according to claim 2 wherein the organic base is selected from the class consisting of: carbonate or bicarbonate of an alkaline or an earth alkaline metal. The process according to claim 1 wherein in step (b) the phenylmagnesium halide is selected from the class consisting of phenylmagnesium bromide or phenyl magnesium chloride. The process according to claim 1, wherein the organic solvent used in step (b) is selected from the group consisting of tetrahydrofuran, ethylether, isopropylether or butylether.

Inventors: MOLINARI, EGIDIO
Applicants: ERREGIERRE INDUSTRIA CHIMICA SPA
Application year: 1988
Main classification: C07D211
IPC codes: C07D211, B01J27