Background Art Several methods of preparation of compounds of general formula I wherein R'= methyl, ethyl, protected hydroxymethyl, hydroxymethyl, protected carboxyl, or carboxyl ; and R2 = hydrogen, or an OH protecting group; and of their pharmaceutical acceptable salts have been known. The compounds of formula I are used as antihistamines.

Terfenadine (formula I wherein R1 is the methyl group and R2 is hydrogen) is a non-sedative antihistamine, e. g. Carr et al., US 4,254, 129. A primary active metabolite is a compound known as terfenadine carboxylate or fexofenadine, which is described in e. g. US 4,254, 129.

In patent literature there are described three basic procedures of preparation of compounds of general formula 1. One of the procedures is represented by patent documents, e. g.: US 3,941, 795; US 3,806, 526; US 3,878, 217; US 3,941, 759; US 3,965, 257; US 4,254, 130; US 4,285, 957; US 4,285, 958; WO 9321156 A1 ; US 5,618, 940; US 5,631, 375; US 5,644, 061; US 5,650, 516; US 5,652, 370; US 5,654, 433. The essence of this patent protection is alkylation of a piperidine derivative with, m-halogenbutyro phenones"and subsequent reduction of the chain ketone group.

A second used method is a preparation method according to patents: US 5,578, 610; US 5,581, 011; US 5,589, 487; US 5,633, 412; US 5,750, 703; US 5,994, 549; US 6,153, 754; EP 0 723 958 A1.

In this method an intermediate of a cyclopropylphenone type is used for alkylation of the piperidine derivative, or said intermediate is subsequently transferred in a convenient way to the corresponding, m-halogenbutyrophenone", which is used for alkylation.

There are several options for preparation of a pure regioisomer of the cyclopropylphenone type. It can be prepared by stereoselective reaction, or by separation from the reaction mixture (separation of the p-and m-isomers). A method has been worked out for separation by crystallization of the p-isomer of "butyrophenone"from the useless, but in the preparation of the intermediate in the Friedel-Crafts alkylation originating, ortho derivative. This method is used e. g. in US patent 6,147, 216 or in patent WO 0001671 A2.

A method of preparation of fexofenadine derivatives with use of Grignard salts is based on preparation of intermediate (I) Intermediate I which is coupled with a piperidine derivative to give unsaturated compounds, which are transferred by catalytic reduction into the desired compound. This method is patented in US patent 5,925, 761. The method is also patented in US patent 6,147, 217.

Opening of the dioxolane ring with H2SO4 provides the desired aldehyde, which is in balance with the corresponding lactone.

Other preparation methods which can be used for the chosen range of aimed derivatives are listed in US patents 3,806, 526 and 3,931, 197.

Disclosure of Invention According to this invention, a method of preparation of terfenadine and its derivatives of general formula I wherein R = methyl, ethyl, protected hydroxymethyl, hydroxymethyl, protected carboxyl, or carboxyl ; and R2= hydrogen, or an OH protecting group; and of their salts is based on reaction of compounds of general formula 11 wherein R'= methyl, ethyl, protected hydroxymethyl, or protected carboxyl ; and Xi = CHO, with a Grignard compound of formula 111, wherein X and X1 represent independently an atom of bromine or chlorine and subsequently the resulting compound of general formula IV wherein R1 = methyl, ethyl, protected hydroxymethyl, or protected carboxyl ; is reacted with a piperidine derivative of general formula V V, wherein R1 and R2-independently represent hydrogen, methyl, hydroxy, methoxy, or a double bond; in the presence of methanesulphonic, p-toluenesulphonic or benzenesulphonic acid chloride and of organic bases, thus giving rise to the compound of formula 1.

The starting compounds of general formula 11 are well known and in many cases commercially available or their preparation method is widely documented.

Similarly, if structures of general formula 11 are phenethyl alcohol derivatives, these can be prepared by Friedel-Crafts reaction of suitable benzene derivatives with suitably protected 2-methyl-2-propenyl alcohols. The choice of protective groups for compounds of formula 11 wherein R'is protected hydroxymethyl, or protected carboxyl, is well known and described in, e. g.,"Protective Groups in Organic Syntheses", T. W. Greene, Wiley (1981). Correspondingly, the removing of <BR> <BR> protective groups e. g. , with mineral acids, strong inorganic hydroxides and the like, is described in the literature. The preparation of Grignard compounds of formula III is also well known, e. g. , by reaction of the respective halogenpropanol in an inert solvent.

The new compounds of general formula IV are, for the purposes of this invention, prepared by reaction of a Grignard reagent III and compounds 11 in anhydrous organic solvents. The reaction is carried out in a solvent with 1 to 2.5 molar equivalents of Grignard reagent Ill. The solvents are chosen from the group of ether solvents such as diethylether, tetrahydrofuran, dioxane, dimethoxyethane or their mixtures. Apparently, reaction of the Grignard reagent with compounds 11 can run in an alternative way; nevertheless the preferred product is that resulting from reaction with the reactive aldehydic group. These reactions are carried out at temperatures from-15 °C to the boiling point of the solvent, preferably at 0 °C, and the reaction time ranges from 2 to 8 hours. Preferred are those temperatures that enable control of generation of the undesired product.

In the next step the compounds IV are subjected to reaction with compounds of general formula V, in the presence of the chloride of methanesulphonic acid, p- toluenesulphonic acid or benzenesulphonic acid and of organic bases. Preparation of intermediate mesylates or tosylates for the substitution reaction is generally known. The use of substances of general formula V, wherein R1 is hydroxyl and R2 is hydrogen, is preferred for the purposes of this invention.

As the organic bases for the purposes of this invention, aliphatic tertiary amines such as triethylamine, N-methylmorpholine or pyridine are used. In the reaction are used equivalent molar ratios of the corresponding base and of the acid chloride, or, preferably, an excess of the organic base is used. Suitable solvents for the substitution reaction are chlorinated solvents such as e. g. dichloromethane, dichloroethane, or methylchloroform. This way of running of the reaction enables to isolate and purify the intermediate. Alternatively, it is possible to carry out the reaction directly with isolation of the corresponding eliminated hydrochloride of the base in solvents such as diethylether, tetrahydrofuran, or dioxane. It is obvious that it is not necessary to isolate the prepared reactive intermediate of compound IV for the subsequent substitution reaction with derivatives of formula V.

For the piperidine derivatives, wherein R is hydroxy, use of appropriate protective groups is documented. The choice of the protective groups for compounds of formula V is well known and described e. g. in"Protective Groups in Organic Syntheses", T. W. Greene, Wiley (1981). Correspondingly, the removing of protective groups e. g. , with mineral acids, strong inorganic hydroxides and the like, is described in the literature.

The piperidine derivatives of general formula V are well known and in many cases commercially available, or their preparation method is widely documented. For example, compound V wherein R1 and R2 create a double bond between carbons can be prepared by simple dehydration of compound V wherein R'is hydroxy.

Advantages of this invention over the prior art are simplicity of execution, high purity of the intermediates and of the product (regiospecificity of the method) with a content of antihistaminically active substance over 98%, which is sufficient for preparation of the therapeutic substance having corresponding quality declared in pharmacopoeiae, and easy industrial implementation (possibility of process control, automation and the like).

This invention is below described in examples, without being limited to these exclusively.

Examples Example 1 Step A Methyl 2- (4-formylphenyl)-2-methylpropionate Into a 250-ml three-necked flask there were placed 2.5 g of 2-phenyl-2-methyl propionic acid methyl ester and 2.4 g of zinc cyanide and 100 ml of tetrachloroethane. A strong flow of hydrogen chloride was introduced into the flask with intense stirring during 4 hours. The flask was cooled down with an ice bath and 4.8 g of finely divided aluminium chloride were added in one dose with continued intense stirring. The stirring continued for another thirty minutes and the flask was placed onto an oil bath where it was gradually heated up to the temperature of 70 °C. Further on, the mixture was kept at the given temperature for three hours. After cooling with running water, the contents of the flask were poured onto crushed ice/15m1 conc. HCI. The reaction mixture was left to stand overnight. Then it was transferred to the flask where it was refluxed for three hours and after cooling, it was divided in a separatory funnel. The organic layer was separated; the aqueous layer was extracted with 15 mi of tetrachloroethane. The combined organic extracts were washed with water, with 10% sodium carbonate and dried over sodium sulphate.

The solvent was distilled off until 1/3 of the volume and the product was filtered through a short column of silica gel. 2. 1 g of the product were obtained having 92.6% GC purity.

Step B Methyl 2- (4- (1, 4-dihydroxybutyl) phenyl)-2-methylpropionate A Grignard reagent was prepared under nitrogen atmosphere from 0.36g magnesium and 1.6g ethylbromide in 20moi THF. The reaction mixture was cooled down to 0 to-5 °C and into the slurry-like mixture a solution of 1.3g of 3-chloro-1- propanol in 15 ml THF was added with intensive stirring; the stirring was continued for another thirty minutes at laboratory temperature. Subsequently, 0.36g of magnesium were added and stirred at the temperature of 55 °C until it almost dissolved for ca two hours. The reaction mixture was cooled down to a temperature of 0 to-5 °C and a solution of 2. 1g methyl 2- (4-formylphenyl)-2-methylpropionate in 20 ml THF was added at once with cooling. After short stirring the magnesium salt precipitated and the reaction mixture got thick. The reaction mixture was stirred at given temperature for one hour; subsequently it was heated up and stirred at laboratory temperature for one hour. After re-cooling to 5-10 °C the precipitated magnesium salt was filtered off, washed with 15 mi THF and after being thoroughly sucked off it was decomposed in ca 50 ml of 15 % ammonium chloride. The product was extracted into 4 x 50 ml ethylacetate. The organic layer was dried over sodium sulphate, the solvent was distilled off under reduced pressure and ca 35moi of cyclohexane were added. After staying in a refrigerator overnight the precipitated product was filtered off, washed with 2x 10ml cooled cyclohexane and dried. 2. 1 g of light yellow solidifying oil were obtained.

0. 1 g of a second fraction was obtained by concentrating of the tetrahydrofuran filtrates, analogous decomposition and processing of the extracts.

The product was purified by chromatography on a silica gel column by elution with cyclohexane-ethyl acetate 4: 1, whereas a second fraction of 1. 1 g of the product was obtained.

Step C 2- [4- (1-Hydroxy-4- (4-hydroxydiphenylmethyl-piperidyl) butyl) phenyl]-2-methyl propionic acid hydrochloride Into a flask equipped with a stirrer 0.57g methane sulphonylchloride, 30 ml dichloromethane and 0.97g of dried pyridine were placed. Then, 1. 1g of the product from step B in 25ml of dichloromethane was added with intense stirring and the temperature was kept at 30 to 35 °C for seven hours. After cooling the reaction mixture was quickly washed with 20ml of iced water, 2x 20ml 10% HCI and 20ml water. The organic layer was separated, dried over sodium sulphate and the solvent was distilled off under reduced pressure of about 13 kPa and at the aqueous bath temperature of 40 °C. To the oily residue 25 ml of toluene and 1. 1g azacyclonole were added and the reaction mixture was refluxed for three hours. After cooling, the reaction mixture was washed with 2 x 20ml water and dried over sodium sulphate with the addition of activated carbon. It was concentrated to about 1/3 of volume at 13 kPa and water bath temperature up to 60 °C. The solution was purified by filtration through a short column of silica gel and subsequently concentrated until dry at about 13 kPa and water bath temperature up to 60 °C. 1.4g of 2- [4- (1-hydroxy-4- (4-hydroxydiphenylmethyl-piperidyl) butyl) phenyl]-2-methyl propionic acid methyl ester were obtained having the melting temperature 140 to 144 °C.

The methyl ester was dissolved in 20ml of methanol and 4. 5m1 of a 20 % solution of KOH were added. The reaction mixture was refluxed under nitrogen atmosphere for five hours, and subsequently the organic solvent was distilled off.

The cloudy aqueous layer was overlaid with 45moi ethyl acetate, acidified with 15% hydrochloric acid until pH 5.6 to 4.5 and the separated organic layer was dried over sodium sulphate. It was concentrated to about 1/4 volume at 13 kPa and water bath temperature up to 60 °C and subsequently 10 ml of diethyl ether saturated with hydrogen chloride were added with intensive stirring. The cloudy mixture was left to stand in the refrigerator overnight. The precipitated light yellow honey-like product crystallised in the course of time; it was filtered off through an S 2 frit, washed with ether and dried at 40 °C in a vacuum drier under a vacuum of 3 kPa for 6 hours.

0.9g of crude product were obtained. By crystallisation from a mixture 2-propanol- diethylether the product having a melting temperature of 196 to 198 °C was obtained; the product purity is controlled by HPLC, contents 98 area %.

Example 2 Step A a- (p-tert-Butylphenyl)-1, 4-butanediol A Grignard reagent was prepared under nitrogen atmosphere from 0.36g magnesium and 1. 6g of ethyl bromide in 20ml THF. The reaction mixture was cooled down to 0 to-5 °C and a solution of 1.3 g 3-chloro-1-propanol (0.014 mol) in 15 ml THF was added to the slurry-like mixture with intense stirring and the stirring was continued at laboratory temperature for another 30 minutes. Subsequently, 0.36g of magnesium were added and stirred at the temperature of 55 °C until it dissolved for ca 2 hours. The reaction mixture was cooled to the temperature of 0 °C and a solution of 2.4g 4-tert-butyl-benzaldehyde in 30 ml THF was added at once with cooling. After short mixing the magnesium salt precipitated and the reaction mixture got thick. The reaction mixture was processed analogously as in Example 1.2. 7g of light yellow solidifying oil were obtained.

Step B a-(p-tert-Butylphenyl)-4-(diphenylmethylene)-1-piperidinobut anol Into a flask with a stirrer 30mi THF, 2.6 g of p-toluenesulphonic acid chloride and 1,4 g of dried pyridine were gradually added. Subsequently, 2.7g of the product from Step A in 25ml THF was added with intense stirring and the temperature was kept at 30 to 35 °C for 7 hours. After cooling, the reaction mixture was concentrated, dissolved in 25 mi of toluene, washed with 20mut iced water, 2x 20mut 10% HO and 20ml water. The organic layer was separated, dried over sodium sulphate and the solvent was distilled off under reduced pressure of about 13 kPa and water bath temperature up to 40 °C. To the oily residue, 25 ml DMF and 3.3g dehydrated azacyclonole were added and the reaction mixture was heated at 110 °C for 3 hours.

After distilling off the solvent 1.9 g of a-(p-tert-butylphenyl)-4-(diphenylmethylene)-1- piperidinobutanol were obtained by analogous procedure as in Example 1.3. 5g of the product, m. p. 122 to 124 °C, are obtained by crystallisation from ethanol.

Example 3 Step A 4- (1, 4-Dihydroxybutyl)-2, 2-dimethylphenethyl benzyl ether A Grignard reagent was prepared under nitrogen atmosphere from 0.26g magnesium and 1.2g of ethyl bromide in 20ml THF. The reaction mixture was cooled down to 0 to-5 °C and a solution of 1.39 g of 3-bromo-1-propanol in 15 ml THF was added to the slurry-like mixture with intense stirring and the stirring was continued at laboratory temperature for another 30 minutes. Subsequently, 0.26g of magnesium was added and stirring was continued at the temperature of 55 °C until it dissolved for ca 2 hours. The reaction mixture was cooled to the temperature of-10 °C and a solution of 2. 6g of 4-formyl-2, 2-dimethylphenethyl benzyl ether was added at once with cooling. After short mixing the magnesium salt precipitated and the reaction mixture got thick. The reaction mixture was processed analogously as in Example 1.

2.8g of solidifying oil were obtained.

Step B 4- [4- [4- (Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-2, 2-dimethylphenethyl alcohol By a procedure analogous to Example 1, starting from the product of Step A, 3.8g of 4- (4- [4- (hydroxydiphenylmethyl)-l-piperidinyll-I-hydroxybutyl]-2, 2- dimethylphenethyl benzyl ether were obtained.

The product was dissolved in 25ml acetic acid and 5ml of hydrobromic acid were added and the mixture was refluxed for eight hours. The reaction mixture was concentrated and overlaid with 45ml of ethyl acetate, the pH was adjusted to 6.5-7 and the separated organic layer was dried over sodium sulphate. By distilling off the solvent and subsequent crystallisation from toluene 2.9 g of the product were obtained. By crystallisation from a toluene-cyclohexane mixture the product having the melting temperature of 135 to 137 °C was obtained; the product purity is controlled by HPLC, contents 97.5 area %.

Industrial Applicabilitv The invention can be used in the pharmaceutical industry for the preparation of derivatives of butylphenyl acetic acids as active substances in the production of non-sedative antihistamines.