HU220968B1 - Process and diastereomeric salts useful for the optical resolution of racemic alpha-[4-(1,1-dimethylethyl)-phenyl]4-(hydroxydiphenylmethyl)-1-piperidinebutanol and derivative compounds - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of compounds of formula (I) wherein R is methyl, carboxyl or C 1-5 alkyl, such that a) a racemic compound of formula II in which: R is an equimolar amount of optically active di-para-toluoyl tartaric acid or optically active mandelic acid as hereinbefore defined, taken up in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature between 50 ° C and 100 ° C, preferably between 50 ° C and 55 ° C, until the solubilized diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; c) cooling the solution for a time sufficient to precipitate the diastereomeric salt; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the compound. EN 220 968 B1 The scope of the description is 26 pages (including 7 sheets)

Description

State of the art

FIELD OF THE INVENTION The present invention relates to racemic compounds, more particularly to racemic isolation of [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] butanol and certain racemic derivatives thereof.

There are several methods known for separating racemic compounds. For example, the formation of diastereomers followed by crystallization, differential absorption (chromatography) biochemical processes, chiral recognition, direct crystallization, differential reactivity and mechanical separation are well known techniques. In the industrial separation of optical isomers, efficiency and economy together are essential, so these procedures must be practical and thus feasible.

In the optical separation method, a diastereomeric complex is formed between a chiral resolving agent and an enantiomer of the racemic compound, and its crystallization is a well-known and very important technique for optical separation. Fractional crystallization is also well known but too empirical since a large number of solvents and chiral resolving agents have to be examined. This process is further limited by the fact that they can only be applied to solids. Research on other methods, i.e. methods for efficient optical separation, is currently under development. As a result, fractional crystallization has been recognized as a very important optical separation tool, but its potential commercial use has decreased in recent years.

Many chiral resolving agents are readily available and known. However, as mentioned above, the use of chiral resolving agents for crystallization on an industrial scale has particular demands. For example, the process must be relatively inexpensive, thereby achieving a high degree of optical purity. The agent should readily react with the target enantiomer and form a diastereomeric complex whose physical properties must be sufficiently different from other associative complexes present in solution to be relatively exclusive in precipitation and free from other associative complexes in this state. The high degree of relative purity of the precipitation is required in order to achieve the high optical purity of the enantiomeric target compound. From now on, good resolution grains must be traceable to the process, so we need to recover it from the solution in significant yield. These additional practical limitations have made the use of chiral resolving agents for optical separation on an industrial scale less feasible.

The generic name for α- [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidin] butanol is terfenadine and its derivatives well known as antihistamines antiallergic agents and bronchodilators as disclosed in (Carr I) and (Carr II) in U.S. Patent No. 3,878,217 and U.S. Patent No. 4,254,129.

Despite the difficulties, finding a suitable resolving agent for optical resolution on an industrial scale has proved to be successful with a chiral resolving agent which was previously used for the optical separation of terfenadine. The solution described in Carr I was used for the optical separation of terfenadine. Carr I describes a process for separating the right and left pivoting isoforms of terfenadine using (-) - dinaphthylphosphoric acid and (+) - dinaphthylphosphoric acid (-) / (+) - 1,1'- also known as dinaphthyl-2,2'-diyl hydrogen phosphate.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of racemic α- [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidinec] butanol, 4- [4- [4 - (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzene acetic acid and lower 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1 -hydroxybutyl] -α, for optical separation of adimethylbenzene acetates.

The invention also relates to a resolution process which is efficient and economical. Schemes A and B graphically illustrate the process of the present invention wherein the di-para-toluoyl tartaric acid and mandelic acid are separated to separate the (R) - and (S) -terfenadine enantiomers, their acid derivatives and acid ester derivatives thereof. how we implement it. In Schemes A and B, unless otherwise noted, the parentheses refer to the diastereomeric salt, the first being the target molecule and the second being the resolving agent.

The present invention relates to an improved process for the preparation of compounds of formula I wherein R is methyl, carboxyl or lower alkyl ester; a .ni Hl or (Unit · indicates that the binding is backward from the paper plane;

or indicates that the bond is forward of the paper plane;

indicates that the spatial location of the bond is not stoichiometrically indicated (racemic compound); in a way that

a) transferring the racemic compound of formula II, wherein R is and the bonds are represented by an equimolar amount of an optically active resolving agent, (+) - di-para-toluoyl tartaric acid, as defined above, into a suitable organic solvent;

b) raising the temperature of the solution to form a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolyzing the diastereomeric salt to isolate the compound.

The same procedure can be applied if the resolving agent is (-) - mandelic acid, as follows:

a) an equimolar amount of a racemic compound of formula II wherein R is methyl or lower alkyl ester and the bonds are as defined above;

With an optically active resolving agent (-) - mandelic acid in a suitable organic solvent;

b) heating the solution to an elevated temperature to form a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolyzing the diastereomeric salt to isolate the compound.

In a similar manner, the compound of formula (Ia) wherein R is methyl, carboxyl or lower alkyl ester and the bonds are as defined above can be prepared by

a) introducing the racemic compound of formula II, wherein R and the bonds are as defined above, into an appropriate organic solvent with an equimolar amount of an optically active resolving agent, (+) - di-para-toluoyl tartaric acid;

b) heating the solution to an elevated temperature to form a primary solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a time sufficient to precipitate the primary diastereomeric salt;

d) removing the primary diastereomeric salt and discarding the solution as a filtrate;

e) hydrolyzing the compound from the filtrate and separating it;

f) dissolving the compound in an equimolar amount of an optically active resolving agent, (-) - di-para-toluoyl tartaric acid, thereby swallowing the secondary solubilized diastereomeric salt;

g) precipitating the secondary diastereomeric salt;

h) collecting the secondary diastereomeric salt; and

i) hydrolyzing the secondary diastereomeric salt to isolate the compound.

The same procedure is used when (+) - mandelic acid is used as a resolving agent in the process

a) The racemic compound of formula II, wherein R is methyl or lower alkyl ester and the bonds are as defined above, is added with an equimolar amount of an optically active resolving agent, (-) - almonds, in a suitable organic solvent. ;

b) heating the solution to an elevated temperature to form a primary solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a time sufficient to precipitate the primary diastereomeric salt;

d) removing the primary diastereomeric salt and discarding the solution as a filtrate;

e) hydrolyzing the compound from the filtrate and separating it;

f) dissolving the compound in equimolar amounts with an optically active resolving agent (+) - mandelic acid to form a secondary solubilized diastereomeric salt;

g) precipitating the secondary diastereomeric salt;

h) collecting the secondary diastereomeric salt; and

i) hydrolyzing the secondary diastereomeric salt to isolate the compound.

It has further been found that while in Schemes A and B, as detailed above, the (R) -enantiomer crystallizes from solution first with the chiral resolving agent, it remains in the (S) enantiomeric solution until crystallization with the subsequent resolving agent, its order is reversible. That is, the (S) -enantiomer can be crystallized first with the resolving agent, while the (R) -enantiomer remains in solution and can be separated in the next step with the resolving agent.

The present invention also relates to diastereomeric salts of the racemic α- [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] butanol; [4- [4- (Hydroxy-diphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -α, α-dimethyl-benzene-acetic acid and low-carbon 4- [4- [4- (hydroxy-diphenyl) -methyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate.

Detailed Description of the Invention

As used herein, the term "lower alkyl ester group" refers to compounds in which, in compounds (I), (II) or (III), R is substituted with a carboxylic acid ester group and is C 1 -C 5. Examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group. and the like.

As used herein, the term "chiral resolving agent" or "optically active resolving agent" refers to both left and right-rotating optical isomers of the following compounds: di-para-toluoyl tartaric acid and mandelic acid. The term "resolving agent" refers to enantiomers of the same compounds.

As used herein, the term "suitable organic solvent" refers to any polar organic solvent that forms an interactive complex between the chiral resolving agent and piperidine-butanol, which is soluble at elevated temperature but insoluble at room temperature. Suitable organic solvents for the recrystallization of the target enantiomeric compounds are, for example, the aforementioned methanol, ethanol and acetone.

An "elevated temperature" favors the formation of an interactive complex at any temperature at which the complex is soluble, but is typically in the range of about 5 ° C to about 100 ° C. When acetone is used as the organic solvent, it is in the range of 50 ° C to 55 ° C.

As used herein, the term "salt" or "diastereomeric salt" is used to mean a term generally known in the art. For example, this term may refer to association complexes in which the anionic moiety of the acidic chiral resolving agent is formed by the basic racemic target compound (associated with its cationic moiety), thereby forming one or more interaction points with one or more weak attractive forces.

HU 220 968 Bl

By "solubilized diastereomeric salt" is meant the diastereomeric salts formed in solution. A solubilized diastereomeric salt may exhibit different physical properties in solution from other associative complexes. These physical differences (e.g., association equilibrium, crystallization energy, etc.) may occur such that the diastereomeric salt precipitates between the target enantiomer and the chiral resolving agent, while the other association complex with the chiral resolving agent, the target enantiomer, impurities, and the like. remains in solution. The forces between the chiral resolving agent which forms the racemic target compound and the enantiomers are different; In this way, the precipitation of the desired salt can be influenced, which process is also influenced by the choice of the organic solvent.

The temperature at which the solution is cooled may be any temperature lower than the value at which the interactive complex begins to precipitate, typically between -20 ° C and + 40 ° C. Preferably, this value is -10 ° C to + 30 ° C, especially 4 ° C to 25 ° C.

The time required for cooling to allow enough time for the diastereomeric salt to precipitate may vary greatly from temperature to stirring during the crystallization period, but typically from 0.5 days to 10 days, preferably 0.3 days to 3 days, most preferably 1 day. day-2 days.

The following examples illustrate the invention in more detail, without, however, limiting it.

Unless otherwise noted, physical analyzes were performed using the following apparatus. The microscopic (hot stage) melting point was measured with a YANAGIMOTO® melting point meter (Model MP) and not calibrated, while the capillary melting points were determined with a YAMATO® melting point meter (Model MP-21) and was not calibrated; NMR spectra were recorded on a HITACHI® R-90H Fourier transform NMR spectrometer with chemical shifts and unless otherwise noted, the δ-unit refers to the internal tetramethylsilane; IR spectra were recorded on a HITACHI® 260-10 infrared spectrophotometer. Specific rotation was measured with a JASCO® DIP-370 digital polarimeter. HPLC was measured using a WATERS® liquid chromatograph with a 510 pump model, a U6K injector and a 990J photodiode array detector. Chemical yields of diastereomeric salts (interactive complexes) and enantiomers were calculated based on half of the amount of racemic compound used.

In the following examples, optical purity was determined by chiral HPLC. Unless otherwise noted, terfenadine [both (+) - and (-) - enantiomers] were analyzed with the following parameters:

Column: Size, 4.6 χ 150 mm stationary phase, ULTRON®ES-OVM (5 pm) (SHINWA CHEMICAL INDUSTRIES)

Wavelength: 210 nm

Mobile Phase: CH ₃ CN-0.05M Sodium Phosphate Buffer pH 6.0 (20:80)

Flow rate: 1.0ml / min

Sample: 5 μΐ (in 0,05% methanol solution).

Unless otherwise noted, the ethyl 4-a, a-dimethylbenzoacetate derivative was converted to a 4-α, α-dimethylbenzoacetic acid derivative prior to HPLC analysis. The following parameters were used for acid analysis: Column: size, 4.6 χ 150 mm stationary phase, ULTRON®ES-OVM (5 pm) (SHINWA CHEMICAL INDUSTRIES) Wavelength: 210 nm

Mobile Phase: CH ₃ CN-0.05M Sodium Phosphate Buffer pH 4.5 (6:94)

Flow rate: 1.0ml / min

Sample: Dissolve about 5 mg of the sample in about 2 ml of ethanol and add 1 ml of 2N sodium hydroxide. The solution was placed in ampoules. The vial was sealed at one end by melting, melting the flame and placed in a water bath at 80 ° C for 2 hours. After neutralization with 1 ml of 2N hydrochloric acid, the solution was diluted with 10 ml of ethyl alcohol. 5 µl of solution was injected for analysis.

Separation of Terfenadine Example 1A Preparation of (R) - (+) - Terfenadine

10.0 g (21.2 mmol) of racemic α- [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] butanol (terfenadine) and 8.60 g (21.3 mmol) of (2S, 3S) (+) -di-para-toluoyl tartaric acid monohydrate [(+) DPTTA] are dissolved in 90 ml of acetone at 55 ° C. The resulting solution was cooled to room temperature (15-30 ° C) for 1 day and then placed in a refrigerator for an additional 1 day. The resulting crystals were collected by filtration and the precipitated diastereomeric salt contained (+) - terfenadine and (+) - DPTTA (98%, 90% chemical yield, diastereomer (% de)).

The salt was recrystallized twice from 8 ml of acetone and dried at 80 ° C under reduced pressure for 1 day to give 7.54 g of purified diastereomeric salt (83, about 100% de). Melting point about 125-134 ° C (melting point)

IR (KBr): 2800-2200,1720,1610,1265,1105 cm -1. [a] ^{2 "4} + 20 ° (c = 1.0, CHC1 ₃₎

Elemental analysis for C52H5 ₉ NO _10. (0,5) H2O:

Calculated: C, 72.03; H, 6.97; N: 1.62; Found: C, 72.11; H, 6.99; N: 1.60.

The diastereomeric salt (7.04 g) was then dissolved in ethanol (45 ml). To the solution was added 16.5 mL of 1N sodium hydroxide followed by 30 mL of water. The resulting crystals were collected and ethanol / H ₂ O (1: 1) system for simultaneously recrystallized optically pure (ca. 100% ee) of (R) - (+) - terfenadine obtained 3.81 g weight. Yield 81%. Melting point 145-146 ° C.

[a] ² D ⁴ + 50 ° (c = 4.0, CHC1 ₃₎

GB 220 968 Bl • Η NMR [CDC1 _3] δ: 7.1-7.6 (14H, m, aromatic H), 4.5-4.7 (1H, m, CH-OH), about 3, 05 (2H, bd. Trip, J = 13Hz, axial H in the N-CH ₂ x 2 piperidine ring), 1.4-2.5 (14H, m, H remaining), 2.25 (1H, s, OH), 1.29 (9H, s, t-but.-H).

Elemental analysis for C ₃₂ H ₄₁ NO ₂ :

Calculated: C, 81.49; H, 8.76; N: 2.97; Found: C, 81.43; H, 8.72; N, 2.84.

Experimental results and certain parameters of crystallization are shown in Table 1 in comparison with other resolving agents and other organic solvents.

Example IB Preparation of (S) - (-) - Terfenadine To a mother liquor obtained by crystallization of (R) - (+) - terfenadine and (2S, 3S) - (+) - di-paratoluoyltartaric acid from diastereomeric salt 22 ml of IN sodium hydroxide, followed by 80 ml of water. The resulting crystals were collected and recrystallized once in ethanol / water to give partially separated (S) - (-) - terfenadine in 96% chemical yield (4.81 g).

The crystals are then mixed with an equimolar amount of (2R, 3R) - (-) - di-para-toluoyl tartaric acid (3.94 g, 10.2 mmol) in 75 mL of acetone and kept at room temperature (15-30 ° C) for 1 day. and the mixture was refrigerated for another 1 day. The crystals formed are collected by filtration to give the diastereomeric salt of (S) - (-) - terfenadine and (-) - di-paratoluoyltartaric acid. The salt was recrystallized from a charcoal system of about 8 ml of acetone / 1 g of salt and dried at 80 ° C under reduced pressure. After drying for 1 day, 7.03 g of purified diastereomeric crystals were obtained in 77% chemical yield with an optical purity of about 100% diastereomer. Melting point about 125-134 ° C (melting point)

IR (KBr): 2800-2200,1720,1610,1265,1105 cm -1. [α] D 20 -21 ° (c = 1.0, CHCl ₃ )

Elemental analysis for C ₅₂ H ₅₉ NO _10. (0,5) H ₂ O:

Calculated: C, 72.03; H, 6.97; N: 1.62;

Found: C, 72.10; H, 6.95; N: 1.62.

Then, 6.53 g of the diastereomeric crystal is dissolved in 45 ml of ethanol, to which is added 15.5 ml of 1N sodium hydroxide and 30 ml of water. The resulting crystals were collected and recrystallized simultaneously in ethanol / water (1: 1) to give (S) (-) - terfenadine (3.53 g, 100% enantiomeric purity) in 75% chemical yield. Melting point 145-146 ° C.

1 H-NMR (CDCl ₃ ) δ: 7.1-7.6 (14H, m, aromatic H), 4.5-4.7 (1H, m, CH-OH), about 3.05 (2H, bd) .trip-, J = 13 Hz, axial H in N-CH ₂ x 2 in the piperidine ring), 1.4-2.5 (14H, m, H remaining), 2.25 (1H, s, -OH), 1 , 29 (9H, s, t-butyl-H).

[a] ^{2 4} D -50 ° (c = 4.0, CHC1 ₃₎

Elemental analysis for C ₃₂ H ₄₁ NO ₂ :

Calculated: C, 81.49; H, 8.76; N: 2.97; Found: C, 81.48; H, 8.74; N, 2.84.

Example 2A Preparation of (R) - (+) - Terfenadine G (42.4 mmol) of racemic terfenadine and 6.45 g (42.4 mmol) of (R) - (-) - mandelic acid are dissolved in 180 ml of methanol. The resulting solution was cooled to room temperature (15-30 ° C) and kept at this temperature, and the mixture was kept in a refrigerator for an additional 1 day. The precipitated crystals were collected by filtration and a crystalline diastereomeric salt was obtained under vacuum containing the resole and the (+) - enantiomer (101% chemical yield, 78% de). The crystals were then recrystallized twice from 9 ml of methanol (containing 1 g of salt) and dried at 80 ° C for 1 day under reduced pressure to give 9.70 g of purified diastereomeric crystals in 73% yield (99% de). 112-118 ° C (m.p.)

IR (KBr): 2800-2200,1720,1610,1360cm -1.

[α] D 25 -5.9 ° (c = 2.0; CHCl ₃ )

Elemental analysis for C ₄₀ H ₄₉ NO ₅ :

Calculated: C, 77.01; H, 7.92; N, 2.25; Found: C, 77.14; H, 8.03; N: 2.29.

9.1 g of the purified diastereomeric crystal are dissolved in 60 ml of ethanol. To the solution was added 15 ml of 1N sodium hydroxide and 45 ml of water. The crystals formed are then collected and simultaneously crystallized from a 1: 1 ethanol / water system to give 6.40 g of the (R) - (+) enantiomer in 68% chemical yield with 99% optical purity for the enantiomer. Melting point 145-146 ° C.

^[3 αβ + 51 ° (c = 4.0, CHC1 ₃₎

Elemental analysis for C ₃₂ H ₄₁ NO ₂ :

Calculated: C, 81.49; H, 8.76; N: 2.97; Found: C, 81.68; H, 8.81; N: 2.85.

The crystallization of (R) - (+) - terfenadine with (R) - (-) - mandelic acid and certain experimental parameters are shown graphically in Table 1. Table 1 also illustrates the comparison between the efficiency of different resolving agents and organic solvents.

Example 2B Preparation of (S) - (-) - Terfenadine

To the mother liquor obtained during the crystallization of (R) - (+) - terfenadine and (R) - (-) - mandelic acid was added 23 ml of IN sodium hydroxide followed by 150 ml of water. The resulting crystals were collected and recrystallized once from a 1: 1 ethanol / water system to give 9.80 g of partially resolved (S) - (-) - terfenadine in 98% chemical yield. The crude crystals were mixed with an equimolar amount of (S) - (+) - mandelic acid (20.8 mmol, 3.16 g) in methanol (120 mL) and kept at room temperature (15-30 ° C) for 1 day and then at 4 ° C. and refrigerated for another day. The crystals were collected by filtration to give the crude diastereomeric salt of (S) - (-) - terfenadine and (S) - (+) - mandelic acid. This crude diastereomeric salt has 9 ml of meta5 per gram

Recrystallize simultaneously using a female U 220 968 B1 and drying at 80 ° C under reduced pressure for 1 day to give a 76% purified diastereomeric salt (10.0 g, 98% de). 112-119 ° C (melting point)

IR (KBr): 2800-2100, 1610, 1360 cm -1.

[α] 25 D + 5.5 ° (c = 2.0, CHCl ₃ )

Elemental analysis for C40H49NO5:

Calculated: C, 77.01; H, 7.92; N, 2.25; Found: C, 76.75; H, 8.04; N, 2.22.

The purified salt (9.5 g) was dissolved in ethanol (60 mL), and solution 10 was treated with IN sodium hydroxide (15.5 mL) and treated with water (45 mL). The resulting crystals were collected and recrystallized simultaneously in a 1: 1 ethanol / water system to give optically pure (S) - (-) - terfenadine (6.61 g) in 70% yield. M.p. 144-145 ° C.

[α] D -49 ° (c = 4.0, CHCl ₃ )

Optical purity assays revealed the presence of 98% enantiomer.

Elemental analysis for C ₃₂ H ₄₁ NO ₂ :

Calculated: C, 81.49; H, 8.76; N: 2.97; Found: C, 81.47; H, 8.76; N: 2.94.

Comparative Example 1 Preparation of (R) - (+) - Terfenadine Following the optical separation method described in U.S. Patent 3,878,217, 40.8 g (86.5 mmol) of racemic terfenadine, i.e., α- [4- (l) 1,1-dimethylethylphenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidin] butanol and (R) - (-) - 1,1.0 g (30.0 g, 86.1 mmol). '-dinaphthyl-2,2'-diyl hydrogen phosphate was stirred in 50 ml of ethanol and a solution was obtained at a temperature close to reflux.

The solution was then cooled to room temperature (15-30 ° C) for 5 hours. The reaction vessel was then cooled to 5 ° C for 20 hours and the crystals formed were collected. The crystals are then crystallized seven times from methanol by placing 3-7 ml / g of crystal in the solution and adjusting the final crystallization temperature to -5 ° C for 40 days (15-20 hours) and thus crystallizing. the diastereomeric salt of 8.5 g of (R) (-) - 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and (R) - (+) - [4- (l) is obtained. , 1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] butanol. Chemical yield 24%. The resulting salt was dissolved in 80 ml of acetone, treated with 8 ml of 10% aqueous sodium hydroxide solution and water was added until the solution became cloudy. The solution was then cooled to room temperature (15-30 ° C) and held at this temperature for 1 day (20 hours) and filtered. The crystals were recrystallized twice by dissolving them in 80 mL of warm acetone and adding water until the solution became cloudy, yielding 4.28 g of the title compound in 21.0% yield. Melting point 145-146 ° C.

[α] D + 49 ° (c = 4.10 CHCl ₃ )

Elemental analysis for the formula C3 ₂ H ₄₁ NO ₂ :

Calculated: C, 81.49; H, 8.76; N: 2.97; Found: C, 81.40; H, 8.92; N: 2.99.

The enantiomeric purity was determined to be 98% using a chiral HPLC method with the following parameters.

Column: Size, 4.6 χ 150 mm stationary phase, ULTRON®ES-OVM (5 pm) (SHINWA CHEMICAL INDUSTRIES, LTD.)

Wavelength: 210 nm 20 Mobile Phase: CH ₃ CN-0.05M Sodium Phosphate pH 6.0 (20:80)

Flow rate: 1.0 ml / min

Sample: 10 μΐ (in 0,02% methanol solution).

Example 3 Preparation of (R) - (+) - Terfenadine 500 mg (1.1 mmol) of racemic α- [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenyl) methyl ) -1-piperidinyl] -butanol and an equimolar amount of the resolving agent are simultaneously dissolved in an organic solvent at about reflux. After the dissolution is complete and a clear solution is obtained, the reaction mixture is cooled to room temperature (15-30 ° C) and maintained at this temperature for 3 to 8 days, eliminating interfering conditions for the diastereomeric salt to crystallize. The crystals were dried under reduced pressure.

Table 1 illustrates the comparison between Examples ΙΑ, 2A and 3A-M, showing the results obtained for different combinations of resolving agents and organic solvents.

Comparative Table 1 from Comparative Example vizsgálat, 2A and 3A-M shows that the use of (+) - di-para-toluoyl tartaric acid and (R) - (-) mandelic acid resolving agent results in higher chemical yields (less labor intensive). , see recrystallization 2 versus 7 recrystallization) and the process results in a higher optical purity of the (+) - terfenadine enantiomer due to the use of (-) - 1,1'-binaphthyl-2,2'-diylhydrogen phosphate.

Table 1

Optical separation of terfenadine with different resolving agents in different solvents

Example resolving Organic solvent formed diastereomer Yield (%) ^a Optical purity (% de, ee) ^b 1 Krist. (X) rekrist. 1 Krist. (X) rekrist. 1A (+) - DPTTA.H ₂ ° acetone (+) - isomer / (+) - DPTTA 98 (Lx) 81 90 (Lx) 100

HU 220 968 Bl

Table 1 (continued)

Example resolving Organic solvent formed diastereomer Yield (%) ^a Optical purity (% de, ee) ^b 1 Krist. (X) rekrist. Krist. (X) rekrist. 2A (-)-TODAY. methanol (+) - isomer / (-)-TODAY. 101 (Ix) 68 78 (Ix) 99 3A abiet connect ethanol no - - - 3B (+) - camphor sulfonic acid ethanol no - - - - 3C (-)-camphor- sulfonic acid ethanol no - - - - 3D (+) - DPTTA H ₂ O ethanol (+) - isomer / (+) - DPTTA 96 - 24 - 3E L-malic sav ethanol no - - - - 3F (-)-TODAY. ethanol (+) - isomer / ()-TODAY. 93 - 74 - 3G (-)-TODAY. acetone no - - - - 3H (-)-TODAY. CH ₂ CHOEt no - - - (-) - TODAY. ³¹ (-)-TODAY. 2-butanone no - - - - 3J (-)-TODAY. CH ₂ CN no - - - - 3K (-)-TODAY. dioxane no - - - - 3L L-PCA ethanol no - - - - 3M L-tartaric acid ethanol no - - - - Comparative Example 1 ^c (-) - BNDHP methanol (+) - isomer / (-) - BNDHP 102 (2x) 21 18 (2x) 98

Explanation of Labeling: ^b Optical purity was measured by chiral HPLC analysis.

DPTTA = di-para-toluoyl tartaric acid The first column shows the% optical purity of the diastereomer

TODAY. = mandelic acid in diastereomeric excess after initial crystallization of the diastereomeric compound L-PCA = L-2-pyrrolidone-5-carboxylic acid lex. The second column is

The optical purity of the enantiomeric excess ^of BNDHP = 1,1'-dinaphthyl-2,2'-diyl hydrogen phosphate is shown ⁱⁿ the first column in% yield of diastereomeric salt after recrystallization of the separated enantiomer (x). This is the type of racemic compound used. Second column ^c Comparative example, U.S. Pat. No. 3,878,287 shows the recrystallization yield of the enantiomer (x) from optical resolved first separation. .

Table 2

Experimental parameters for terfenadine release

Example Rezorválószer Organic solvent reaction Conditions Type Amount (Mg) Type ml Temperature ³ Time (Sun) ^13A both of them 320 ethanol 2 r.t. 3 3B (+) - camphoric 212 ethanol 2 r.t. 3 3C (-)-camphor- sulfonic acid 246 ethanol 2 r.t. 3 3D (+) - DPTTA.H ₂ O 430 ethanol 3 r.t. 8 3E L-malic acid 142 ethanol 2 r.t. 3 (-)-TODAY. 170 ethanol 8 r.t. 6

HU 220 968 Bl

Table 2 (continued)

Example Rezorválószer Organic solvent reaction Conditions Type Amount (Mg) Type ml Temperature ³ Time (Sun) 3G (-)-TODAY. 170 acetone 2 r.t. 8 3H (-)-TODAY. 170 ethyl acetate 2 r.t. 8 31 (-)-TODAY. 170 2-butanone 2 r.t. 8 3J (-)-TODAY. 170 CH ₃ CN 2 r.t. 8 3K (-)-TODAY. 170 dioxane 2 r.t. 8 3L L-PCA 136 ethanol 2 r.t. 3 ^13M L-tartaric acid 160 ethanol 3 r.t. 3

DDTTA = Di-para-toluoyl-tartaric acid TODAY. Mandelic = L-PCA = L-2-pyrrolidone-5-carboxylic acid ^a rt = room temperature = 15-30 ° C

Separation of 4-? X,? -Dimethylbenzene-acetic acid derivatives

In the following Examples 4A and 4B, the NMR spectra were recorded on a HITACHI® R-1900 Fourier Transform NMR Spectrometer and the parameters for the determination of optical purity are as follows:

Column: size, 4.6 χ 150 mm stationary phase. ULTRON®ES-OVM (5 µm)

SHINWA CHEMICAL INDUSTRIES Wavelength: 210 nm

Mobile phase: _CH3 CN-O, O5M sodium phosphate buffer (pH 4.5 (6: 4)

Flow rate: 1.0ml / min

Sample: 5-7 µl (in 0.05% methanol solution).

Example 4A Preparation of (R) - (+) - 4- [4- [4- (Hydroxy-diphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -α, α-dimethyl-benzoacetic acid

8.00 g (15.9 mmol) of well-dried racemic 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] α, α-dimethylbenzene acetic acid and 6 , (+) - di-para-toluoyl-tartaric acid monohydrate (45 g, 16.0 mmol) was dissolved in acetone (55 mL) at 55 ° C. The solution was then cooled in a refrigerator for 3 days at 4 ° C, and the precipitated crystals were collected by filtration and the diastereomeric salt (+) -4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] thus obtained was collected. -1-hydroxybutyl] -α, α-dimethylbenzene acetic acid and (2S, 3S) - (+) - di-para-toluoyl tartaric acid. Weight 7.53 g. Chemical yield 110% (74% de). The crystals were recrystallized twice from a methanol / acetone (1:99) solvent system (9 mL volume) such that 9 mL of the solvent system contained 1 g of salt and dried at 80 ° C for 1 day at 6.00 g (85%). mass crystalline material (96% chemical yield).

IR (KBr): 2800-2200,1720,1610,1265,1105 cm -1.

Melting point about 133 ° C (shrinks),

145-148 ° C (dec.) [Α] ²⁵ D + 26 ° (c = 1.0 CHCl ₃ )

Elemental analysis for C ₅₂ H ₅₇ NO ₁₂ .H ₂ O:

Calculated: C, 68.93; H, 6.56; N, 1.55. Found: C, 69.12; H, 6.37; N: 1.63.

Purified crystals (5.50 g) were dissolved in ethanol (20 ml) and treated with normal sodium hydroxide (12.3 ml) and water (ml). The resulting crystals were collected and recrystallized simultaneously in a 2: 1 chloroform-ethanol system to give (R) - (+) - enantiomer (2.90 g, 79% chemical yield) in an optical purity of 96% ee, theoretically anhydrous. The dried sample is highly hygroscopic, equilibrated at atmospheric pressure and room temperature until constant weight is reached and then analyzed. Melting point 211-213 ° C.

IR (KBr): 1570 cm -1.

[α] D + 33 ° (c = 0.40 CHCl ₃ ) • 1 H-NMR [DMSO-d ⁶ ] δ; 7.50 (4H, d, J = 6Hz; oH monosubstituted benzenes), 7.25 (4H, s, disubstituted aromatic H), 7.0-7.4 (6H, m, p, mH monosubstituted benzenes), 5.1-5.3 (IH, m, OH or COOH), 3.0 to 5.0 (m, OH and / or COOH, overlapping with _H2 O), 4.3-4.6 (H , m, CH-OH), about 2.80 (2H, bd. d, J = 9Hz, equatorial in H / N-CH ₂ χ 2 piperidine ring), 1.44 (6H, s, CH ₃ x 2), 1 0-2.4 (13H, m, H remaining).

Elemental analysis for C ₃₂ H ₃₉ NO ₄ .1,2H ₂ O:

Calculated: C, 73.45; H, 7.97; N: 2.68; Found: C, 73.52; H, 7.99; N: 2.65.

Example 4B Preparation of (S) - (-) - 4- [4- [4- (Hydroxy-diphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -α, α-dimethyl-benzoacetic acid

To the mother liquor obtained by crystallization of the (+) - enantiomer and (+) - di-para-toluoyl tartaric acid was added 15 ml of 1N sodium hydroxide and 100 ml of water. The resulting crystals were collected by simultaneous recrystallization from partially resolved (S) - (-) - 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] in a chloroform-2: 1 system. a, a-dimethyl-benzol8

Acetic acid (HU 220 968 B1) was obtained in a yield of 3.11 g (79%).

The crude (-) - enantiomeric crystals were combined with 2.42 g (6.26 mmol) of (2R, 3R) - (-) - di-p-toluoyl tartaric acid in 45 ml of acetone and the mixture was cooled in a refrigerator for 3 days at -4 ° C. we. The resulting crystals were collected and the crude diastereomeric salt, i.e. the (S) - (-) - enantiomer, obtained after filtration, was obtained with the resolving agent (4.81 g, 68% chemical yield). The salt was recrystallized once in a 1:99 methanol / acetone solvent system, the portions of 9 ml / l salt were mixed and dried at 80 ° C for 1 day to give purified crystals weighing 4.56 g. 65% chemical yield, 99% de. Melting point about 133 ° C (shrinks), 146-149 ° C (decomposed).

IR (KBr): 2800-2200,1720,1610,1265, 1107 cm -1. [α] Β -26 ° (c = 0 CHC1 ₃₎

Elemental analysis for C ₅₂ H ₅₇ NO ₁₂ .H ₂ O:

Calculated: C, 68.93; H, 6.56; N, 1.55. Found: C, 69.28; H, 6.34; N: 1.61.

3.70 g of the purified crystal are dissolved in 15 ml of ethanol and treated with 8.3 ml of 1N sodium hydroxide and 20 ml of water. The resulting crystals were collected and recrystallized from a 2: 1 chloroform-ethanol system to give the optically pure (99% ee) 1.93% (S) - (-) enantiomer in 60% chemical yield, which was theoretically anhydrous. The sample is equilibrated for analysis. Melting point 211-213 ° C. IR (KBr): 1570 cm -1 [α] D -33 ° (c = 0.41 CHCl ₃ ) • 1 H-NMR [DMSO-d ⁶ ] δ; 7.50 (4H, d, J = 6Hz, OH monosubstituted benzenes), 7.25 (4H, s, disubstituted aromatic H), 7.0-7.4 (6H, p, mH monosubstituted benzenes), δ, 1 to 5.3 (1H, m, OH or COOH), 3.0 to 5.0 (m, OH and / or COOH, overlapping with _H2 O), 4.3-4.6 (1H, m , CH-OH), about 2.80 (2H, bd. D, J = 9 H, equatorial H / N-CH ₂ x 2 in the piperidine ring), 1.44 (6H, s, CH ₃ x 2), 1.0 -2.4 (13H, m, residual protons).

Calcd for C ₃₂ H ₃₉ NO ₄ .1.2H ₂ O: C, 73.45; H, 7.97; N: 2.68;

Found: C, 73.38; H, 7.99; N: 2.64.

Example 5 Preparation of (R) - (+) - 4- [4- [4- (Hydroxy-diphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -?,? - dimethylbenzene acetic acid

4- [4- [4- (Hydroxy-diphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene-acetic acid (500 mg, 1.0 mmol) and an equimolar amount of the resolving agent are dissolved in an organic solvent. near reflux temperature. Crystals precipitate out of the solution upon cooling, either at room temperature or at 4 ° C in the refrigerator. The crystals were collected by filtration. Test results are shown in Table 3 and experimental conditions are shown in Table 4.

After examination of Table 3, it appears that (+) - di-para-toluoyl tartaric acid is the only resolving agent tested which is demonstrably applicable to the terfenadine 4-a, a-dimethylbenzene acetic acid derivative (R) - ( +) - to separate its enantiomer. It also appears that acetone is the most effective organic solvent.

Table 3

Optical separation of the terfenadine derivative of α, α-dimethylbenzene-acetic acid with different resolving agents in different solvents

Example resolving Organic solvent formed diastereomer Yield: (%) " Optical purity (% de, ee) ^b % de ^b % ee ^c 1 Krist. (X) rckrist. 1 Krist. (X) rekrist. (X) rekrist. 4A (+) - DPTTA-H ₂ O acetone (+) - isomer / (+) - DPTTA 107 (Ix) 79 74 (2x) 96 (Ix) 96 5A (+) - DPTTA.H ₂ O ethanol (+) - isomer / (+) - DPTTA 14 - 46 - - 5B (+) - DPTTA.H ₂ O 2-butanone (+) - isomer / (+) - DPTTA 17 - 86 - - 5C (-) - BNDHP ethanol no - - - - - 5D (-)-camphor- sulfonic acid ethanol no - - - - - 5E L-malic acid ethanol no - - - - - 5F (-)-TODAY. ethanol / H ₂ O 1: 2 racemic crystals ⁰ - - 0 - -

HU 220 968 Bl

Table 3 (continued)

Example resolving Organic solvent formed diastereomer Yield: (%) Optical purity (% de, ee) ^b % de ^b % ee ^c 1 Krist. (X) rekrist. 1 Krist. (X) rekrist. (X) rekrist. 15G (-)-TODAY. acetone racemic crystals ⁰ - - 0 - - 5H (-) - l-phenylethylamine MeOH / EtOH, 1: 1 racemic crystals ⁰ - - 0 - - 51 L-tartaric acid ethanol no - - - - -

DDTTA = di-para-toluoyl tartaric acid

TODAY. Mandelic =

BNDHP = 1,1 '-binaphthyl-2,2'-diylhydrogen phosphate ^a The first column shows the chemical yield of the crude diastereomeric complex after the first isolation. The second column shows the chemical yield of the final purified enantiomer after separation and x-recrystallization.

^b Optical purity measured by chiral HPLC analysis. The diastereomeric complexes on the first column were measured together after the initial separation of the diastereomeric salt and the second after the x-recrystallization. ^c Optical purity was measured by chiral HPLC analysis. It was determined after separation of the enantiomers from the first diastereomeric salt and x-recrystallization. ^d Crystallization of both enantiomers.

Table 4

Experimental conditions for resolution of the terfenadine derivative of 4-a, a-dimethylbenzene-acetic acid

Example resolving Organic solvent reaction Conditions Type Amount (Mg) Type ml Temperature ³ Time (Sun) 5A (+) - DPTTA.H ₂ O 404 ethanol 4 4 10 5B (+) - DPTTA.H ₂ O 404 2-butanone 2 4 10 5C (-) - BNDHP 348 ethanol 4 rt ^a 9 5D (-) - camphorsulfonic acid 232 ethanol 2 rt ^a 3 5E L-malic acid 134 ethanol 2 rt ^a 3 ^15F (-)-TODAY. 152 ethanol / H ₂ O ₂ : 12 rt ^a 4 5G (-)-TODAY. 152 acetone 2 4 10 5H (-) - 1-Phenylethylamine 121 MeOH / EtOH, 1: 1 8 4 4 51 L-tartaric acid 150 ethanol 2 rt ^a 3

DDTTA = di-para-toluoyl tartaric acid

TODAY. Mandelic =

BNDHP = 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate ^rt = room temperature (15-30 ° C).

Evaluating Table 3, it is found that the use of (+) DPTTA resolving agent and organic solvent acetone results in higher chemical yields and higher optical purities than any of the other resolved solvents and organic solvents tested.

Isolation of the ethyl 4-a .alpha.-dimethylbenzene acetate derivative

Example 6A Preparation of (R) - (+) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate g. 18.9 mmol) of racemic ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate and 7.64 g (2S). , 3S) - (+) - di-para-toluoyl-borkő10

Acid monohydrate is dissolved in 80 ml of acetone at 55 ° C. The resulting solution was cooled to room temperature for 1 day and then placed in a refrigerator at 4 ° C for 1 additional day. The crystals were collected by filtration to give the crude diastereomeric salt (8.48 g, 98%). The optical purity of the material was 92% diastereomer. The crude salt was recrystallized from twice 6 ml of acetone per gram of salt, dried at 80 ° C under reduced pressure for 1 day to give 7.45 g (86%) of the purified diastereomeric salt. The diastereomeric purity was determined to be 99% by optical purity. IR (KBr): 2800-2200, 1720, 1607, 1265, 1105 cm -1. Melting point about 113-120 ° C (melting point) [α] 20 D + 20 ° (c = 1.0 CHCl ₃ )

Analysis calculated for C ₅₄ H ₆₁ NO ₁₂ (0.5) H ₂ O: C, 70.11; H, 6.76; N, 1.51;

Found: C, 70.00; H, 6.63; N: 1.50.

Purified diastereomeric salt (6.95 g) was redissolved in ethanol (40 mL) and treated with IN sodium hydroxide (15.5 mL) followed by water (25 mL). The resulting crystals were collected and recrystallized in 2: 1 ethanol / water to give the (R) (+) - enantiomer of 99% ee optical purity. Weight 3.93 g, chemical yield 84%. 141-142 ° C.

IR (KBr): 1727, 1707 cm -1.

1 H-NMR (CDCl 3), δ; 7.1-7.6 (14H, m, aromatic H), 4.5-4.7 (1H, m, CH-OH), 4.09 (2H, quart., J = 7.0 Hz, CH ₂ CH ₃ ), about 3.06 (2H, bd. Trip., J = 13 Hz, axial H N-CH ₂ x 2 in the piperidine ring), 1.4-2.6 (14H, m, H remaining), 2 , 23 (1H, s, OH); 1.54 (6H, s, _CH3 x2), 1.15 j (3H, triplet. J = 7.0 Hz, _CH2 CH ₃₎ [i]) + 49 ° (c = 0 CHC1 ₃ )

Elemental analysis using the formula C ₃₄ H ₄₃ NO ₄ :

Calculated: C, 77.09; H, 8.18; N: 2.64; Found: C, 76.88; H, 8.29; N, 2.55.

Table 5 graphically illustrates the experimental results with certain reaction parameters and comparing them with other resolving agents and organic solvents.

Example 6B Preparation of (S) - (-) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -?,? - dimethylbenzene acetate

To the residue obtained by crystallization of the (R) - (+) - enantiomer and (+) - di-para-toluoyl tartaric acid are added 20 ml of 1N sodium hydroxide and 70 ml of water. The resulting crystals were collected and recrystallized once in 2: 1 ethanol / water to give (S) - (-) - ethyl-4- [4- [4- (hydroxydiphenylmethyl) 4.96 g partially resolved]. -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate is obtained. Chemical yield 99%.

The crude crystalline material and 3.62 g (9.37 mmol) of (2R, 3R) - (-) - di-para-toluoyl tartaric acid were dissolved in 50 ml of acetone and the mixture was stirred at room temperature (15-30 ° C) for 1 day. ) and placed in a refrigerator for another 1 day at 4 ° C. The resulting crystals were collected by filtration to give the crude diastereomeric salt of (S) - (-? - enantiomer and (-) - DPTTA) (7.65 g, 88% yield). It was dried over 1 day to give the purified diastereomeric salt, 2.25 g, 84% yield, 99% optical purity, m.p. 113-120 ° C (m.p.).

IR (KBr) cm 2800-2200,1720,1607,1265,1105 [a] ² J-21 ° (c = 0 CHC1 ₃₎

Analysis calculated for C ₅₄ H ₆₁ NO ₁₂ (0.5) H ₂ O: C, 70.11; H, 6.76; N, 1.51;

Found: C, 70.19; H, 6.69; N, 1.52.

To a solution of 6.75 g of purified diastereomeric salt in 40 ml of ethanol is added 15.0 ml of 1N sodium hydroxide followed by 25 ml of water. The resulting crystals were collected once by recrystallization in 2: 1 ethanol / water to give (S) - (-) - ethyl-4- [4- [4- (hydroxydiphenylmethyl) 3.82 g (99% ee) of optical purity. -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzoacetate is obtained. Chemical yield 82%. Optical purity 99% ee. 141-142 ° C. IR (KBr): 1727.1707 cm -1.

[a] ^{2 4} D -48 ° (c = 0 CHC1 ₃₎

1 H-NMR (CDCl ₃ ), δ; 7.1-7.6 (14H; m, aromatic H), 4.5-4.7 (1H, m, CH-OH), 4.09 (2H, quart., J = 7.0 Hz, CH ₂ CH ₃ ), about 3.06 (2H, bd., Trip., J = 13 Hz, axial H N-CH ₂ x 2 in the piperidine ring), 1.4-2.6 (14H, m, H remaining), 2.23 (1H, s, OH); 1.54 (6H, s, CH ₃ x 2), 1.15 (3H, trip., J = 7.0 Hz, CH ₂ CH ₃ ).

Elemental analysis using the formula C ₃₄ H ₄₃ NO ₄ :

Calculated: C, 77.09; H, 8.18; N: 2.64; Found: C, 76.86; H, 8.47; N: 2.61.

Example 7A Preparation of (R) - (+) - ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, a-dimethylbenzene acetate g , 8 mmol) racemic ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, adimethylbenzene acetate and 5.75 g (37.8 mmol) (R) - (-) - Mandelic acid is dissolved in 110 ml of methanol at about 60 ° C. The resulting solution was kept at room temperature (15-30 ° C) for 1 day and then placed in a refrigerator for a further 1 day at 4 ° C. The precipitated crystals were collected by filtration to give 12.3 g of crystalline diastereomeric salt in 95% yield, 82% de optical purity, containing (R) (+) enantiomer and (R) - (-) - mandelic acid. The crystals were recrystallized from methanol (6 ml) containing 1 g of the diastereomeric salt and dried at 50 ° C under reduced pressure for 1 day to give 8.90 g of the diastereomeric salt. Yield 69%, optical purity 99% but. Melting point about 73 ° C (sintered) 78-83 ° C (melting point)

IR (KBr): 2800-2100, 1727, 1607, 1360 cm -1.

[a] J ² -4.9 ° (c = 2.0, CHC1 ₃₎

Analysis calculated for C ₄₂ H ₅₁ NO ₇ (0.25) H ₂ O: C, 73.50; H, 7.56; N, 2.04; Found: C, 73.38; H, 7.62; N, 2.06.

HU 220 968 Β1

The purified diastereomeric salt (8.40 g) was dissolved in ethanol (50 mL) and treated with IN sodium hydroxide (12.5 mL) and water (40 mL). The crystals were collected and recrystallized once in 2: 1 ethanol / water to give (R) - (+) - ethyl-4- [4- [4- (hydroxydiphenylmethyl) 6.08 g (99% ee) of optical purity. -1-piperidinyl] -1-hydroxybutyl] -α, adimethylbenzene acetate is obtained. Yield 64%. Melting point 140-141 ° C.

[?] ² D ² + 48 ° (c = 1.0 CHCl ₃ )

IR (KBr): 1727.1707 cm -1.

Elemental analysis for C ₃₄ H ₄₃ NO ₄ :

Calculated: C, 77.09; H, 8.18; N: 2.64; Found: C, 76.93; H, 8.31; N, 2.56.

Table 5 graphically shows experimental results with some reaction parameters and comparisons with other resolving agents and organic solvents.

Example 7B Preparation of (S) - (-) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate

The filtrate formed by crystallization of the crude diastereomeric salt formed between the (R) - (+) - enantiomer and (R) - (-? - mandelic acid) was treated with 20 ml of 1N sodium hydroxide and 50 ml of water. Recrystallize once from water to give the partially resolved (S) - (-) - enantiomer, 10.4 g (100.4%).

A solution of (S) - (-) - enantiomer (19.6 mmol) and (S) - (+) - mandelic acid (2.99 g, 19.7 mmol) in methanol (75 mL) was kept at room temperature (15-30 ° C) for 1 day, then place the solution in a refrigerator at 4 ° C for another day. The crystalline material is then collected by filtration to give a crystalline diastereomeric salt consisting of the (S) - (-) enantiomer and (S) - (+) - mandelic acid. Yield: 10.2 g (79%). The crystals were recrystallized once from 1 g of a salt / methanol solution and dried at 50 ° C under reduced pressure for 1 day to give 9.07 g of purified diastereomeric salt. Melting point about 72 ° C (shrink), about 77-83 ° C (melt) [α] ² D ² + 4.8 ° (c = 2.0 in CHCl ₃ )

IR (KBr): 2800-2100, 1727, 1707, 1607, 1360 cm @ -1. Elemental analysis for C ₄₂ H ₅₁ NO ₇ :

Calculated: C, 73.98; H, 7.54; N, 2.05; Found: C, 73.84; H, 7.58; N, 2.09.

The purified salt (8.50 g) was dissolved in ethanol (50 ml) and treated with IN sodium hydroxide (12.7 ml) and water (40 ml). The crystals were collected and recrystallized from 2: 1 ethanol / water to give (S) - (-) - ethyl-4- [4- [4- (hydroxydiphenylmethyl) - 6.11 g (98% ee) of optical purity. 1-piperidinyl] -1-hydroxybutyl] α, α-dimethylbenzene acetate is obtained. Yield 64%. M.p. 141-142 ° C.

[a] D ^{2 2} -48 ° (c = 0 CHC1 ₃₎

IR (KBr) cm 1727.1707 ^first

Elemental analysis for C ₃₄ H ₄₃ NO ₄ :

Calculated: C, 77.09; H, 8.18; N: 2.64;

Found: C, 77.33; H, 8.41; N: 2.64.

Example 8 Preparation of (R) - (+) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, o-dimethylbenzene acetate

Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate (500 mg, 0.94 mmol) was added with an equimolar amount of the resolving agent to an organic solvent and the dissolution is performed at a temperature close to reflux. The resulting solution was either cooled to room temperature or to 4 ° C and placed in a refrigerator for a period of time. The crystals formed are dried by filtration. The results are shown in Table 5 and individual experimental conditions are shown in Table 6.

Comparative Example 2A Preparation of (S) - (-) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate

45.0 g (85.0 mmol) of racemic ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, adimethylbenzene acetate and (R) - (-) - 1,1'-Binaphthyl-2,2'-diyl hydrogen phosphate ((R) - (-) - BNDHP) is dissolved in 300 ml of 2-butanone and heated to form a solution. The resulting solution was left at room temperature (15-30 ° C) for 3 days and the precipitated crystals were collected by filtration. The crystals were then dissolved in about 100 mL of warm methanol and evaporated. The oily residue was dissolved in about 100 ml of 2-butanone and evaporated. Finally, the oily residue was dissolved in 100 ml of hot 2-butanone and then cooled to room temperature (15-30 ° C) for 20 hours. The hot methanol / 2-butanone process was repeated 7 more times to give 21.6 g of (S) - (-) - enantiomer and (R) - (-) - 1,1'-bm-methyl-2,2'-diyl Purified diastereomeric salt of hydrogen phosphate.

The salt is suspended in 60 ml of ethanol and treated with 30 ml of 1N sodium hydroxide and allowed to stand at room temperature for 20 hours. The resulting crystals were recrystallized by filtration and recrystallized from 2: 1 ethanol / water to give 12.4 g (55%) of the title compound. 139-140 ° C.

[α] ²⁰ D ³ -48 ° (c = 1.05 CHCl ₃ )

Elemental analysis for C ₃₄ H ₄₃ NO ₄ :

Calculated: C, 77.09; H, 8.18; N: 2.64; Found: C, 77.15; H, 8.20; N: 2.63.

Table 5 graphically illustrates the experimental results with certain reaction parameters, illustrating the comparison with other resolving agents and organic solvents.

HU 220 968 Bl

Comparative Example 2B Preparation of (R) - (+) - Ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate

The filtrate obtained by crystallization of the (S) - (-) - enantiomer and (R) - (-) - BNDHP is combined with the washing water and evaporated. The oily residue was dissolved in a mixture of 140 ml of ethanol and 70 ml of 1N sodium hydroxide and the solution was kept at 15-30 ° C, i.e. room temperature. The crude crystalline product was recrystallized from 2: 1 ethanol / water to give 24.3 g of product.

[α] D + 25 ° (c = 1.07 CHCl ₃ )

The crude crystalline product is taken up in 200 ml of 2-butanone with (S) - (+) - 1,1'-dinaphthyl2,2'-diyl hydrogen phosphate [(S) - (+) - BNDHP] and the solution is heat until formation. The solution was maintained at 15-30 ° C, i.e. room temperature, for 4 days, after which the resulting crystals were redissolved in hot methanol and evaporated. The residual oily residue was concentrated and dissolved in about 100 mg of 2-butanone and evaporated again. Finally, the oily residue was redissolved in 100 ml of hot 2-butanone and kept at 15-30 ° C, i.e. room temperature, for 20 hours. The methanol / 2-butanone recrystallization was repeated 2 more times to give the (R) (+) - enantiomer and (S) - (+) - BNDHP diastereomeric salt (18.7 g).

The diastereomeric salt is suspended in 60 ml of ethanol, treated with 30 ml of 1N sodium hydroxide and allowed to stand at 15-30 ° C, i.e. room temperature, for 20 hours. The precipitated crystals were recrystallized from 2: 1 ethanol / water to give 10.2 g (45%) of the title compound. 139-140 ° C.

[α] D + 48 ° (c = 1.06 in CHCl ₃ )

Elemental analysis for C ₃₄ H ₄₃ NO ₃ :

Calculated: C, 77.09; H, 8.18; N: 2.64; Found: C, 77.00; H, 8.20; N: 2.64.

Table 5

Optical separation of ethyl 4-a, a-dimethylbenzoacetate terfenadine

Example Rezorválószer Organic solvent formed diastereomer Yield (%) ^a Optical purity (% de, cc) ^b 1 Krist. (X) rekrist. 1 Krist. (X) rekrist. 6A (+) - dptta.h ₂ o acetone (+) - isomer / (+) - DPTTA 98 (Lx) 84 92 (Lx) 99 ^7A (-)-TODAY. methanol (+) - isomer / (-)-TODAY. 95 (Lx) 64 82 (Lx) 99 I ^8A abiet connect ethanol no - - - - 18 ^8B (-) - BNDHP methanol no - - - - 8C (-) - BNDHP EtOH / H ₂ O ₂ no - - - - 8D (+) - camphoric ethanol no - - - - 8E (-)-camphor- sulfonic acid ethanol no - - - - 8F (+) - DPTTA.H ₂ O ethanol (+) - isomer / (+) - DPTTA 71 - 54 - 8G L-malic acid ethanol no - - - - 8H (-)-TODAY. ethanol (+) - isomer / (-)-TODAY. 91 - 79 - 81 (-)-TODAY. acetone no - - - - 8J (-)-TODAY. CH ₃ CO ₂ Et no - - - - 8K (-)-TODAY. 2-butanone no - - - - 8L (-)-TODAY. CH ₃ CN no - - - - 8M (-)-TODAY. dioxane no - - - - 8N L-PCA ethanol no - - - - 80 L-tartaric acid ethanol no - - - - Compound 2A (-) - BNDHP MeOH / 2-butanone (-) - isomer / (-) - BNDHP 131 (Lx) 55 30 (Lx) 98

HU 220 968 BI

DPTTA = di-para-toluoyl tartaric acid

TODAY. Mandelic =

BNDHP = 1,1 '-binaphthyl-2,2'-diyl hydrogen phosphate ^a The first column shows the chemical yield after the first separation of the diastereomeric salt. The second column shows the chemical yield after recrystallization of the separated purified enantiomer (x).

^b The first column shows the optical purity of the diastereomer after the first separation of the diastereomeric complex. The second column shows the optical purity of the enantiomer after isolation of the isolated enantiomer (x).

Table 6

Experimental conditions for the resorption of the ethyl a, a-dimethylbenzoacetate terfenadine derivative

Example Resorual condom Organic solvent reaction Conditions Type Amount (Mg) Type ml Temperature ² Time (Sun) 8A abietik conn 284 ethanol 2 r.t. 3 8B (-) - BNDHP 327 methanol 3 r.t. 2 8C (-) - BNDHP 327 EtOH / H ₂ O 2.1 6 r.t. 2 8D (+) - camphoric 190 ethanol 2 r.t. 3 8E (-) - camphorsulfonic acid 218 ethanol 2 r.t. 3 8F (+) - DPTTA.H ₂ O 388 ethanol 4 4 4 8G L-malic acid 126 ethanol 2 r.t. 3 8H (-)-TODAY. 150 ethanol 5 r.t. 2 ⁸¹ (-)-TODAY. 150 ethanol 3 r.t. 10 8J (-)-TODAY. 150 ethyl acetate 2 r.t. 8 8K (-)-TODAY. 150 2-butanone 2 r.t. 8 8L (-)-TODAY. 150 MeCN 2 r.t. 8 8M (-)-TODAY. 150 dioxane 2 r.t. 8 18N L-PCA 121 ethanol 2 r.t. 8 1 80 L-tartaric acid 140 ethanol 2 r.t. 8

TODAY. Mandelic =

L-PCA = L-2-pyrrolidone-5-carboxylic acid

BNDHP = 1,1'-Rbinaphthyl-2,2'-diyl hydrogen phosphate 40

DPTTA = di-para-toluoyl tartaric acid ^a rt = room temperature = 15-30 ° C

Table 5 has shown that the use of (+) - DPTTA and (-) - mandelic acid resolving agents in optical separation results in higher chemical yields and higher optical purities and requires less recrystallization than other resolved resolved agents.

Claims (36)

PATENT CLAIMS A process for the preparation of a compound of formula I wherein R is methyl, carboxyl or C 1 -C 5 alkyl ester, characterized in that: a) introducing a racemic compound of formula II wherein R is an equimolar amount of (+) - di-para-toluoyl tartaric acid as defined above in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature in the range of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a soluble biliary diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and E) hydrolyzing the diastereomeric salt to isolate the resulting compound. Process for the preparation of a compound of formula (III) according to claim 1, characterized in that HU 220 968 Bl a) introducing an equimolar amount of the (+) - di-para-toluoyl tartaric acid into a polar organic solvent, such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the compound. The process for the preparation of a compound of formula (V) according to claim 1, characterized in that: a) introducing an equimolar amount of the (+) - di-para-toluoyl tartaric acid racemic compound of formula VI into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (VII) according to claim 1, characterized in that: a) introducing an equimolar amount of the racemic compound of formula VIII with (+) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. 5. A process for the preparation of a compound of formula I wherein R is methyl or C 1 -C 5 alkyl ester. a) introducing a racemic compound of formula II wherein R is an equimolar amount of (-) - mandelic acid as defined above in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (III) according to claim 5, characterized in that a) introducing an equimolar amount of a (-) - mandelic acid racemic compound of formula (IV) into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (V) according to claim 5, characterized in that a) introducing a racemic compound of formula VI into an equimolar amount of (-) - mandelic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (Ia) wherein R is methyl, carboxyl or lower C 1 -C 5 alkyl ester, characterized in that a) transferring the racemic compound of formula II wherein R is as defined above with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (IIIa) according to claim 8, characterized in that: a) transferring the racemic compound of formula IV with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; HU 220 968 BI c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. The process for the preparation of a compound of formula (Va) according to claim 8, characterized in that: a) transferring the racemic compound of formula VI with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (VHa) according to claim 8, characterized in that: a) transferring the racemic compound of formula VIII with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. 12. A process for the preparation of a compound of formula I wherein R is methyl or C 1 -C 5 alkyl ester, characterized in that: a) introducing an equimolar amount of the (+) - almond acid into a polar organic solvent such as methanol, ethanol or acetone to form a racemic compound of formula (U) wherein R is as defined above; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. 13. A process according to claim 12 for the preparation of a compound of formula (IIIa), characterized in that: a) introducing an equimolar amount of (+) - mandelic acid into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. A process for the preparation of a compound of formula (Va) according to claim 12, characterized in that: a) introducing an equimolar amount of a (+) - mandelic acid racemic compound of formula (VIa) into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until the diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the interactive complex precipitates as a diastereomeric salt; d) collecting the diastereomeric salt; and e) hydrolyzing the diastereomeric salt to isolate the resulting compound. 15. A process for the preparation of a compound of formula I wherein R is methyl, carboxyl or C1-5 alkyl ester, characterized in that: a) introducing a racemic compound of formula II wherein R is as defined above with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the diastereomeric salt precipitates; d) removing the first diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (+) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (III) according to claim 15, characterized in that a) introducing an equimolar amount of a racemic compound of formula IV into (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until the primary solubilized diastereomeric salt is formed; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; HU 220 968 Bl f) dissolving the compound in equimolar amounts with (+) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (V) according to claim 15, characterized in that a) introducing an equimolar amount of the racemic compound of formula II into (-) - di-para-toluoylboronic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; 18. A process for the preparation of a compound of formula VII according to claim 15, characterized in that a) transferring the racemic compound of formula VIII with an equimolar amount of (-) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of from 50 ° C to 100 ° C, preferably from 50 ° C to 55 ° C, to form the primary diastereomeric salt; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (+) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 19. A process for the preparation of a compound of formula I wherein R is methyl or C 1 -C 5 alkyl ester, characterized in that: a) transferring the racemic compound of formula II wherein R is as defined above with an equimolar amount of (+) - mandelic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of from 50 ° C to 100 ° C, preferably from 50 ° C to 55 ° C, to form the primary diastereomeric salt; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (+) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (III) according to claim 19, characterized in that: a) transferring the racemic compound of formula (IV) with an equimolar amount of an optically active resolving agent (+) mandelic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of from 50 ° C to 100 ° C, preferably from 50 ° C to 55 ° C, to form the primary diastereomeric salt; c) cooling the solution for between half a day and 10 days, preferably between half a day and 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - mandelic acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (V) according to claim 19, characterized in that: a) transferring the racemic compound of formula V with an equimolar amount of an optically active resolving agent (+) - mandelic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of from 50 ° C to 100 ° C, preferably from 50 ° C to 55 ° C, until the primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - mandelic acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 22. A process for the preparation of a compound of formula Ia wherein R is methyl, carboxyl or C1-5 alkyl ester, characterized in that: a) introducing a racemic compound of formula II wherein R is as defined above with an equimolar amount of (+) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; HU 220 968 Bl c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (IIa) according to claim 22, characterized in that: a) transferring the racemic compound of formula IV with an equimolar amount of (+) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (Va) according to claim 22, characterized in that: a) transferring the racemic compound of formula (V) with an equimolar amount of (+) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 25. A process for the preparation of a compound of formula (VIIa) according to claim 22, wherein: a) transferring the racemic compound of formula VIII with an equimolar amount of (+) - di-para-toluoyl tartaric acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - di-para-toluoyl tartaric acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 26. A process for the preparation of a compound of formula Ia wherein R is methyl or C 1-5 alkyl ester, characterized in that: a) introducing an equimolar amount of a racemic compound of formula II, wherein R is as defined above, into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (-) - mandelic acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. A process for the preparation of a compound of formula (IIa) according to claim 26, characterized in that: a) introducing an equimolar amount of (-) - mandelic acid into a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (+) - mandelic acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; HU 220 968 Bl h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 28. A process for the preparation of a compound of formula (Va) according to claim 26 wherein: a a) transferring a compound of Formula VI into an equimolar amount of (-) - mandelic acid in a polar organic solvent such as methanol, ethanol or acetone; b) heating the solution to a temperature of 50 ° C to 100 ° C, preferably 50 ° C to 55 ° C, until a solubilized primary diastereomeric salt is formed; c) cooling the solution for half a day to 10 days, preferably half a day to 3 days, until the primary diastereomeric salt precipitates; d) removing the primary diastereomeric salt and discarding the solution as a filtrate; e) hydrolyzing the compound from the filtrate and separating it; f) dissolving the compound in equimolar amounts with (+) - mandelic acid to form a solubilized secondary diastereomeric salt; g) precipitating the resulting secondary diastereomeric salt; h) collecting the secondary diastereomeric salt; and i) hydrolyzing the secondary diastereomeric salt to isolate the compound. 29. A compound which is substantially (R) - (+) -? - [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] -butanol (2S, 3S) ) is a diastereomeric salt of (+) - di-para-toluoyl tartaric acid or (R) - (-) - mandelic acid. 30. A compound which is substantially (S) - (-) -? - [4- (1,1-dimethylethyl) phenyl] -4- [4- (hydroxydiphenylmethyl) -1-piperidine] -butanol (2R, 3R). ) is a diastereomeric salt of (-) - di-para-toluoyl tartaric acid or (S) - (+) - mandelic acid. 31. A compound which is (R) - (+) - 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidin-1] -1-hydroxybutyl] -α, adimethylbenzene acetic acid and (2S). , 3S) - (+) - di-para-toluoyl tartaric acid diastereomeric salt. 32. A compound which is substantially (S) - (-) - 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] α, α-dimethylbenzene acetic acid, and It consists of the diastereomeric salt of (2R, 3R) - (-) - di-paratoluoyltartaric acid. 33. A compound which is essentially a compound of formula (I) wherein R is a C 1 -C 5 alkyl ester, with (2S, 3S) - (+) - dipara-toluoyl tartaric acid or (R) - (- ) diastereomeric salt thereof. 34. A compound according to claim 33 which is substantially (R) - (+) - ethyl-4- [4- [4- (hydroxyphenylmethyl) -1-piperidinyl] -1-hydroxy butyl] α, α-dimethylbenzene acetate, a diastereomeric salt of (2S, 3S) - (+) - di-paratoluoyl tartaric acid or (R) - (-) - mandelic acid. 35. A compound having a compound of formula (Ia) wherein R is a (C1-C5) alkyl ester group with (2R, 3R) - (-) - dipara-toluoyl tartaric acid or (S) - It consists of the diastereomeric salt of (+) - mandelic acid. 36. The compound of claim 35, which is essentially (S) - (-) - ethyl-4- [4- [4- (hydroxyphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -, Dimethylbenzene acetate is a diastereomeric salt of (2R, 3R) - (-) - di-para-toluoyl tartaric acid or (S) - (+) - mandelic acid.