CZ421999A3 - Novel process - Google Patents

Abstract

Compounds of formula are obtained by reduction of compounds of formula. Compounds of Formula (I), especially those wherein Z is hydrogen or 3,4-methylenedioxyphenyl are important intermediates also for paroxetine

Description

Technical field

The present invention relates to a novel process for the preparation of pharmaceutically active compounds and intermediates thereof.

BACKGROUND OF THE INVENTION

Pharmaceutical compositions with antidepressant and antiparkinsonian effects are described in US-A-3912743 and US-A-4007196. Of particular interest among these compounds is paroxetine, the (-) trans isomer of 4- (4'-fluorophenyl) -3 ', 4'-methylenedioxyphenoxymethyl) -piperidine. This compound is used in hydrochloride salt therapy for the treatment of, inter alia, depression, obsessive-compulsive disease (OCD) and panic disorder.

The present invention overcomes the disadvantages of existing methods for preparing such compounds and includes an alternative method for their preparation.

The present invention has been developed based on the fact that the compounds of formula (I) below are both valuable chemical intermediates for the production of important medical products, such as paroxetine hydrochloride, and are themselves active compounds as described in U.S. Pat. A-3912743 and US-A-4007196.

According to Example 4 of US 4007196, paroxetine can be prepared from a compound of formula (1) wherein R is methyl and Z is hydrogen, i.e. 4- (4'-fluorophenyl) -3-hydroxymethyl-1-methylpiperidine, by reaction with

3,4-methylenedioxyphenol followed by demethylation. In the same Example 4, 4- (4'-fluorophenyl) -3-hydroxymethyl-10-a-4-methyl-4-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl-10-hydroxymethyl

0 0 · 0 0 0 0 0 0

0 ·

-methylpiperidine prepared by reducing 4- (4'-fluorophenyl) -3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropiridine (II), which is prepared from 4- (4'-fluorophenyl) -1-methyl - 1,2,3, β-tetrahydropiridine (III) by reaction with formaldehyde.

Alternative methods for preparing 4- (4'-fluorophenyl) -3-hydroxymethyl-1-methylpiperidine are disclosed in EP-A-0223334 and include the reduction of a compound of formula (A):

wherein Z is alkyl and R is H, alkyl or aralkyl.

The above methods produce compounds of formula (1) as mixtures of enantiomers. Therefore, the conversion of compounds of formula (1) to useful pharmaceutical agents such as paroxetine, i.e. the (-) trans isomer of 4- (4'-fluorophenyl) -3 ', 4'-methylenedioxy-phenoxymethyl) -piperidine, usually requires a resolution step such as described in EP-A-0223334.

SUMMARY OF THE INVENTION

The invention includes a process for the preparation of 4-aryl-piperidines of formula (1)

F

and

R (D) kde kde kde kde β R R R R R R R R R R R R R where R is hydrogen or a group selected from the group consisting of alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, and Z 'is 3,4-methylenedioxyphenyl, said method comprising reducing a compound of formula (2a) or (2b): FF

wherein Y is oxygen or sulfur, and

R and X are the same as defined above and Z is hydrogen or a group selected from alkyl, aralkyl or aryl, and wherein Z is a group other than 3,4-methylenedioxyphenyl which is then converted to 3,4-methylenedioxyph enyl.

The present invention also includes a process for preparing 4-aryl-piperidines of formula (1): F

OZ

N i

R (1) wherein R is hydrogen or a group selected from alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, and Z 'is a group selected from the group consisting of: Alkyl, aralkyl or aryl, preferably wherein Z is hydrogen or

3,4-methylenedioxyphenyl, wherein said method comprises reducing a compound of formula (2a)

(2a) (2b) wherein Y is oxygen or sulfur, and

R, X and Z are the same as defined above.

When Z contains an aryl group, the aryl group, for example phenyl, may be optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, or may be substituted with two substituents that are joined to form a ring system. For example, a particularly preferred substituent Z is 3,4-methylenedioxyphenyl, as present, for example, in paroxetine. Alkyl groups, including alkyl groups that are part of other groups such as alkoxy or acyl groups are usually C _e, better group.

It is believed that compounds of the formulas (2a) and (2b) are new and form part of the present invention, particularly those wherein X is H, Z is H or 3,4-methylenedioxyphenyl and R is H or C _i _ ₄ alkyl, in particular methyl.

In a first aspect of the process of the present invention, the compounds of formula (2a) or (2b) are reduced to form compounds of formula (2a) or (2b). A compound of formula (1) wherein Z is H, ie 3-hydroxymethyl-4-aryl-piperidines. The reduction can be carried out by hydrogenation at atmospheric or higher pressure using various known catalysts, or using hydride reagents such as lithium aluminum hydride and sodium borohydride, or a combination of known techniques. A particularly useful aspect of the present invention is the transformation of 4-aryl-3-carboxyalkyl-1- (optionally substituted) -piperidines to 4-aryl-3-hydroxymethyl-1- (optionally substituted) -piperidines.

It will be appreciated that the reduction of esters or carboxylic acids of formula (2) may be carried out sequentially and an intermediate, for example a carboxyaldehyde, may be isolated and that reduction of these intermediates to the compound of formula (1) is also included within the scope of the present invention.

It is believed that the carboxaldehyde intermediates are novel and form part of the present invention. A particularly valuable intermediate is 4- (4-fluorophenyl) -5-oxopiperidine-3-carboxaldehyde.

In a second aspect of the process of the present invention, compounds of formula (2a) and (2b) wherein Z is not H are reduced to ethers of formula (1). This can be accomplished using known selective agents such as diborane and DIBAL, or by desulfurizing the thionoester intermediate using Raney nickel. A particularly preferred ether for the production of paroxetine is

3,4-methylenedioxyphenyl ether.

After reduction to give the ether of formula (1), one or both of Z and R may be converted to another of Z and R using conventional means to obtain the desired pharmaceutical agent. For example, the preparation of paroxetine, it may be preferred to convert Z = H to Z = 3,4-methylenedioxyphenyl and / or R = C _i _ ₄ alkyl group at R = H. This aspect is also within the scope of the present • · · · · · * Of the invention.

One advantage of this process is that a single enantiomer of intermediate (2) can be prepared, either by enantioselective synthesis or from a chiral precursor, and therefore the separation of the mixture can be completely eliminated or it can be moved to frequent stages of the process.

Starting materials of formula (2a), wherein Y is oxygen, can be prepared, for example, by carboxylation of a 4-aryl-piperidin-2-one precursor, which can be obtained from the reaction of activated alkyl-3-aryl-5-hydroxyvalerate with an amine. In a particularly preferred embodiment of the present invention, alkyl-3-aryl-5-hydroxyvalerate is prepared as a single enantiomer by selective reduction of 3-arylglutarate monoesters, which is obtained by enzymatic hydrolysis of pro-chiral dialkyl-3-arylglutarate, for example using pig liver esterase to obtain S-enantiomers and chymotrypsin to obtain R-enantiomers. Suitable dialkyl-3-arylglutarates can be obtained, for example, by reaction of 4-fluorobenzaldehyde with methyl acetate.

The ester group in the 3-position or the group convertible to the ester group may already be present on the starting material or may be bound, for example by reacting 2-piperidone of formula (3) first with a strong base such as sodium hydride or lithium hexamethyldisilazide and a carboxylating agent such as a chloroform ester or a thiochloroform ester.

F

 (3)

Compounds of formula (2b) wherein Z is oxygen can be prepared, for example, by reductive cyclization of 2-cyano-3- (4'-fluorophenyl glutarate) esters.

3-ethoxycarbonyl-4- (3'-methoxyphenyl) -2-piperidone (Journal of Organic Chemistry (1977), Volume 42, pp. 1485-1495), but this procedure has been found to be unsuitable for compounds of formula (2b) and yields a complex mixture of compounds. A novel and effective process has now been discovered in which esters of 2-cyano-3- (4'-fluorophenyl glutarate, in particular diethyl 2-cyano-3- (4'-fluorophenyl) glutarate, are hydrogenated in 1,4-dioxane Such compounds can be prepared, for example, by reacting ethyl cyanoacetate and ethyl 4-fluorocinnamate in sodium ethoxide.

Compounds of formula (2a) and (2b) wherein Y is sulfur may be prepared by cyclization of analogous thionoesters or by reaction of piperidones with sulfurizing agents such as Lawesson's reagent or phosphorous pentasulfide as described in Organic Synthesis (1984), Volume 62, 158a Journal of Organbic Chemistry (1981), Volume 46, page 3558. The reduction of thiopiperidones can be carried out sequentially, especially when an agent such as Raney nickel is used in the first step. Resulting

The 4-aryl-3-carboxyalkylpiperidines can then be separated reduced to the compounds of formula (1) by conventional reduction methods, preferably with a hydride reagent such as lithium aluminum hydride.

Suitable starting materials of formula (2) may be prepared as described above or by transesterification of ester intermediates.

It will be appreciated that the reduction of compounds of formula (2) to compounds of formula (1) may occur via, for example, compounds of formula (2c) and (2d).

and the reduction of these intermediates in their production by such a process is also within the scope of the present invention.

Compounds of formula (2c) wherein X is hydrogen, Z is methyl and R is hydrogen or C _i _ ₄ alkyl, are described in US-A-4,007,196, although none of the described method is not suitable for industrial production. These problems have been overcome in the related application GB9700690.2. The preparation of a compound of formula (2c), wherein R and Z are alkyl, by reduction of quaternary pyridinium salts, has also been described in EP-0219934.

Compounds of formula (2c) other than those described in the above patent applications and compounds of formula (2d) are novel and form part of the present invention. Particularly important compounds of formula (2c) are those wherein Z is aryl, in particular 3,4-methylenedioxyphenyl, which may be prepared, for example, by selective reduction of (2a) or (2b) or by transesterification of other compounds (2c). Compounds of formula (2c) and (2d) may be further reduced to compounds of formula (1).

Alternatively, by intermittent or selective reduction of compounds (2a) and (2b), novel alcohol or ether intermediates of formula (4a) or (4b) may be formed, which may be isolated aa · aa aa · aa aa These also form part of the present invention.

In a preferred process for preparing compounds of formula (4a) and (4b), compounds of formula (2a) and (2b) are first converted to thioesters which are desulfurized, for example, with Raney nickel. Thionoester intermediates are also novel and form part of the present invention.

Compounds of formula (4a) and (4b) may also be separately prepared by reactions analogous to those described above for the preparation of compounds of formulas (2a) and (2b) and may be used in the methods of the present invention. For example, the carbinol of formula (4a) can be prepared by hydroxymethylation of compound (3) and the ether group can be attached by reaction (3) with chloromethyl ether.

Particularly important compounds of formula (4a) and (4b) are those wherein Z is 3,4-methylenedioxyphenyl and especially those wherein X and R are both hydrogen. Compounds of formula (4) may be further reduced to compounds of formula (1).

The novel compounds of formula (4) can also be prepared by other methods such as etherification (4) wherein Z is hydrogen, or reductive alkylation of aldehydes.

Many of the intermediates in the methods of the present invention are novel and these intermediates form part of the present invention.

In another aspect of the invention, a compound of formula (1), wherein Z is a hydrogen atom obtained by the process of the present invention, can be converted to the active compound described in US-A-3912743 and US-A-4007196 using conventional procedures described herein. .

In particular, a compound of formula (1) wherein Z is hydrogen may be used to prepare paroxetine. Paroxetine is preferably prepared in the form of the hydrochloride salt, and most preferably is prepared as the hemihydrate of such a salt as described in EP-A-0223403. The present invention includes the compound paroxetine, in particular the paroxetine hydrochloride salt, especially in the form of hemihydrate, and any novel intermediates formed by the processes described above.

The paroxetine obtained by the process of the present invention can be prepared for therapy in the dosage forms described in EP-A-0223403 or WO 96/24595, either in solid dosage forms or in solutions for parenteral or oral use.

The therapeutic use of paroxetine, in particular the paroxetine hydrochloride salt obtained by the method of the present invention includes the treatment of: alcoholism, anxiety, depression, obsessive-compulsive disease, panic disorder, chronic pain, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance dependence, collectively referred to as disease.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Accordingly, the present invention also includes:

a pharmaceutical composition for the treatment or prophylaxis of a disease comprising paroxetine or paroxetine hydrochloride obtained by the method of the present invention and a pharmaceutically acceptable carrier;

the use of paroxetine or paroxetine hydrochloride salt obtained by the process of the present invention for the manufacture of a medicament in solid or liquid form for the treatment or prophylaxis of a disease; and a method of treating a disease comprising administering an effective or prophylactic amount of paroxetine or paroxetine hydrochloride obtained by the method of the present invention to an individual suffering from one or more of the diseases.

The invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1: Dimethyl-3- ⁽¹ 4-fluorophenyl) glutarate

4-Fluorobenzaldehyde (75 mL), methyl acetate (150 mL), piperidine (10 mL) and methanol (235 mL) were stirred for 8 hours at ambient temperature. The precipitate was filtered, washed twice with cold methanol (2 x 75 mL), resuspended in methanol (150 mL), treated with a mixture of 25% sodium methoxide in methanol (650 mL) and water (54 mL) and heated at temperature reflux for 7 hours. After cooling, the solvent (500 ml) was removed by distillation in vacuo, water (1 liter) was added and another volume of solvent was removed by distillation (100 ml). The mixture was extracted with t-butyl methyl ether (400 mL), acidified to pH <3 with concentrated hydrochloric acid and extracted with ethyl acetate.

• ·

T-butyl methyl ether (3 x 300 mL). The extracts were evaporated and the t-butyl methyl ether was replaced with methanol (800 mL). Concentrated hydrochloric acid (10 ml) was added and the mixture was heated at reflux for 12 hours and the solvent was partially removed by evaporation. Dilution with water gives dimethyl 3- (4'-fluorophenyl) glutarate crystals. The yield after drying was 124.1 g (71%).

Example 2: S-3- (4'-Fluorophenyl) glutaric acid monomethyl ester The pH of a solution of dimethylformamide in water (20%, 7 liters) is adjusted to pH 7.0 with 1.0 M phosphate buffer and dimethyl-3- (4'-Fluorophenylglutarate (160 g). Heat the mixture at 37 ° C, add pig liver esterase (46 mL, 96000 U) and continue the reaction for 24 hours at constant temperature and pH. The extracts were washed with dilute hydrochloric acid (2 x 1 liter), reduced to approximately 1 liter by evaporation, treated with hexane (100 ml) and cooled. The crystalline (S-enantiomer) mono-ester yielded 118.8 g (78%) of the title compound after drying to 0 ° C to crystallize the resultant material, decanting, evaporating to 200 mL and reacting with hexane (50 mL) to give additional crystals. %).

The R-enantiomer was obtained by an analogous procedure using -chymotrypsin (Can. J. Chem. 1994, 72 (11), 2312).

Example 3: R-1-Benzyl-3- (4'-fluorophenyl) -piperidin-2-one

A solution of S-3- (4'-fluorophenyl) glutaric acid monomethyl ester in tetrahydrofuran (800 mL) was treated with lithium hydride (2.65 g) and heated to reflux for both hours. After cooling, lithium borohydride solution (108 ml, 2 ml) is slowly added. The mixture was heated at reflux for 12 hours and then cooled to ambient temperature. Dimethylformamide (400 ml) and methyl sulphate (56.6 ml) were added and the mixture was heated at reflux for 5 hours, cooled, quenched with methanol (80 ml) and after 30 minutes diluted with toluene (1500 ml). ) and washed with 10% ammonium chloride solution (3 x 800 mL). The toluene phase is evaporated to approximately 400 ml, diluted with toluene (1 liter) and again evaporated to 400 ml; too repeats two or more times.

Toluene (600 mL) and triethylamine (96 mL) were added to crude methyl 3- (4'-fluorophenyl) -5-hydroxyvalerate, cooled to 0 ° C and then methanesulfonyl chloride (32 mL) was added slowly. The mixture was stirred for 45 min at 0 ° C, filtered through silica and the cake washed with toluene (100 mL). To the filtrate was added triethylamine (100 mL), benzylamine (40 mL) and sodium iodide (2 g), and the mixture was heated at reflux for 20 hours, then cooled and washed with 2 molar hydrochloric acid (3 x 600 mL). ) and saturated sodium bicarbonate solution (2 x 500 mL). The resulting solution of crude R-1-benzyl-3- (4'-fluorophenyl) -piperidin-2-one was evaporated to a volume of approximately 300 mL and diluted with heptane (50 mL) to induce crystallization.

The yield of dried material was 52.6 g (56%, > 99% ee).

Example 4: S-1-Benzyl-3- (4 &apos; -fluorophenyl) -piperidin-2-one

S-1-benzyl-3- (4'-fluorophenyl) -piperidin-2-one is prepared from S-3- (4'-fluorophenyl) glutaric acid monomethyl ester in an analogous manner in which the initial reduction is carried out with borane. Similarly, R-1-benzyl-3- (4'-fluorophenyl) -piperidin-2-one can be prepared from R-3- (4'-fluorophenyl) glutaric acid monomethyl ester.

Example 5: trans- (4R) -1-Benzyl-3-carboxymethyl-4- (4'-fluorophenyl) -piperidin-2-one

A solution of R1-benzyl-4- (4'-fluorophenyl) -piperidin-2-one (2.0 g) in toluene (40 mL) is treated with sodium hydride (0.704 g, 60% dispersion in oil) and dimethyl carbonate (3, 0 ml) and the mixture was heated at reflux for 14 hours. After cooling, the reaction was quenched with ice, treated with methanol (15 mL) and potassium carbonate (0.5 g), and stirred for 1 hour. Toluene (100 mL) was added and the phases were separated. The organic phase was washed with 1 molar hydrochloric acid (2 x 50 ml) and saturated sodium bicarbonate solution (2 x 50 ml) and water (50 ml). The organic phases are evaporated and the crude trans- (4R) -1-benzyl-3-carboxymethyl-4- (4'-fluorophenyl) -piperidin-2-one is crystallized from t-butyl methyl ether and hexane. Yield 1.56 g (65%).

Example 6: Preparation of trans- (4R) -1-benzyl-4- (4'-fluorophenyl) -3-hydroxymethyl-piperidine

A solution of trans- (4R) -1-benzyl-3-carboxymethyl-4- (4'-fluorophenyl) -piperidin-2-one (1.97 g) in tetrahydrofuran (20 mL) is treated with borane-tetrahydrofuran complex (19, 6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid and then the mixture was stirred and refluxed for an additional 1 hour. The mixture was cooled to ambient temperature, adjusted to pH 9 with 1M sodium hydroxide, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans- (4R) -l-benzyl-4- (4-fluorophenyl ¹⁾ -3-hydroxymethyl-piperidine (1.59 g, 92%).

· · · · · · · · · «· · · · · · · · ···················

Example 7: Preparation of Paroxetine Hydrochloride Salt

a) Trans- (4R) -1-benzyl-4- (4'-fluorophenyl) -3-hydroxymethylpiperidine (9.65 g), p-toluenesulfonyl chloride (6.18 g), dimethylaminopyridine (0.1 g) and triethylamine (5.0 mL) in toluene (150 mL) was stirred for 42 hours at ambient temperature. The mixture was diluted with toluene (100 mL), washed with saturated sodium bicarbonate solution (3 x 150 mL) and water (100 mL). Evaporate the organic layer to a minimum volume and dilute with toluene (100 mL). A solution of sesamol (4.28 g) in dimethylformamide (150 mL) was treated with table hydride (1.26 g), added to the activated carbinol solution, and the mixture was heated at 60 ° C for 16 hours. The mixture was cooled, diluted with toluene (200 mL), washed with 1 M sodium hydroxide (2 x 100 mL) and water (2 x 100 mL) and evaporated to an oil. Yield 9.83 g (79%).

b) The oil of Example 7 (a) (4.0 g) was dissolved in isopropanol (40 ml) and acetic acid (4 ml) and hydrogenated with 5% palladium on carbon catalyst (2.0 g) at 70 psi; and 50 ° C for 2 hours. The cold mixture was filtered through celite, the celite was washed with isopropanol (40 mL) and the filtrate was diluted with toluene (100 mL). The solution was washed with saturated sodium bicarbonate solution (2 x 100 mL), 1 molar sodium hydroxide solution (100 mL) and then with water (100 mL) and finally with saturated sodium chloride solution (100 mL). The organic phase was evaporated to a small volume (15 mL), treated with concentrated hydrochloric acid (2 mL) and isopropanol (15 mL). The crystalline paroxetine hydrochloride salt is isolated, washed and dried. Yield 2.1 g.

Example 8: Diethyl 2-cyano-3- (4-fluorophenyl) glutarate

A mixture of ethyl cyanoacetate (13.56 g), and ethyl 4-fluorocinnamate (19.4 g) was added to a solution of sodium ethoxide (2.3 g of sodium in 50 ml of ethanol) at 60 ° C for 2-3 minutes and the mixture was Heat at reflux temperature for 1 hour and then heat to room temperature. cooled to 5 ° C. Glacial acetic acid (6 mL) was added slowly to the reaction mixture at less than 5 ° C. Most of the ethanol was removed by distillation under reduced pressure, the residue was diluted with water (40 mL), extracted with toluene (3 x 30 mL), and the combined organic phases were dried over anhydrous magnesium sulfate. The solution was filtered, evaporated to an oil (28.6 g) and distilled at 166-168 ° C at 3.5 mbar to give diethyl 2-cyano-3- (4-fluorophenyl) -glutarate (23 g, 74 % yield, 98% purity).

Example 9: 3-Carboxyethyl-4- (4'-fluorophenyl) -piperidin-6-one

Diethyl 2-cyano-3- (4-fluorophenyl) -glutarate (15.3 g), platinum oxide (0.57 g) and hydrogen chloride in dioxane (0.1 mol in 50 ml) are hydrogenated at 185 psi and 60 ° C for 6.5 hours. The resulting material was cooled, filtered and evaporated and the residue was dissolved in chloroform (130 mL) and washed with saturated sodium bicarbonate solution (200 mL). The solution was dried and passed through activated carbon (Darco G40) to remove colloidal platinum and evaporated to give crude 3-carboxyethyl-4- (4'-fluorophenyl) -piperidin-6-one. This material was repeatedly treated in a solution of ethyl acetate on activated carbon to give the purified material as a mixture of isomers (9.3 g, 70%, 95.6% purity).

Example 10: 3-Carboxyethyl-4- (4'-fluorophenyl) -piperidin-6-one

Diethyl 2-cyano-3- (4-fluorophenyl) glutarate (85.0 g, 0.22 mol), platinum oxide (2.1 g) and 4 molar hydrogen chloride in dioxane (112 mL, 0.45 mol) was mixed in a Parr apparatus under hydrogen (90-195 psi) at 60 ° C for 18 hours. The residue was filtered and evaporated and then dissolved in chloroform (300 mL), washed with saturated sodium bicarbonate solution (250 mL), dried, filtered. · Charge through activated carbon (Darco G40) to remove colloidal platinum and evaporate to give the title compound (72.1 g, 84%) as an oil which crystallizes on standing. Recrystallization from hexane-dichloromethane gave the title compound with a cis / trans ratio of 88:12, m.p. 139-141 ° C.

Example 11: 4- (4-Fluorophenyl) -3-hydroxymethylpiperidine

Borane-tetrahydrofuran complex (1.0 molar solution in tetrahydrofuran (10.8 mL, 10.8 mmol)) was added over 3 hours in 3 steps (3.6 mL each) at a rate of 7 mL / hr. by syringe into a solution of 4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (0.53 g, 2 mmol, trans / cis 1: 1) in tetrahydrofuran (3 mL) at 26 ° C. The reaction mixture was stirred for 1 hour after the last portion of the borane solution was added, and then quenched with 3.5 mL of a 30% aqueous potassium carbonate solution. The phases were separated and the aqueous phase was extracted with diethyl ether (25 mL). The organic phases were combined and evaporated to give 0.43 g of the title compound. Yield 80%.

Example 12: 4- (4-fluorophenyl) -3-hydroxymethylpiperidine

Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran, 0.75 mL, 0.75 mmol) was gradually added to a solution of trans-4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (0.25 g, 0.836 mmol) in tetrahydrofuran (3 mL), maintaining the temperature below 25 ° C. The reaction mixture was stirred for 1 hour at 25 ° C, quenched with 1 drop of water followed by 2 drops of 15% sodium hydroxide solution and finally 5 drops of water. Extraction with dichloromethane (35 mL) followed by evaporation of the dichloromethane phase gave 0.21 g of the title compound. Yield 76%.

· · E e e e e e e e e e e e e e e e e e e e e e e e e

Example 13: 4- (4-fluorophenyl) -3-carboxyethylpiperidine

4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (12.0 g, 0.045 mol, trans / cis ratio 1: 1) is added in one portion to a solution of trimethyloxonium fluoroborate (12.0 g, 0.081 mol) in dichloromethane ( 80 ml) and the resulting solution was stirred at 14-18 ° C for 60 hours under an argon atmosphere. The solvent was removed in vacuo and then the residue was dissolved in absolute ethanol (100 mL), heated to 45 ° C and treated with sodium borohydride (10.0 g), 0.26 mol) in a 1.0 g portion allowing achieving a boiling mixture at reflux. Most of the solvent was evaporated and the residue was quenched with water (60 mL) and then concentrated hydrochloric acid. After neutralization with 10% sodium bicarbonate solution, the materials were extracted with dichloromethane (150 and 50 mL). The extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound as a cis / trans (1: 1) mixture. Yield 75%. A portion of the material was purified by column chromatography (silica gel eluted with ethyl acetate-triethylamine, 98: 2).

Under the same conditions, trans-4- (4-fluorophenyl) -3-carboxyethylpiperidine is prepared from trans-enriched 4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one.

Example 14: 3-Carboxy-4- (4-fluorophenyl) piperidin-6-one

A solution of 4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (2.0 g, 0.0075 mol) in ethanol (10 ml) was added to a sodium hydroxide solution (0.4 g, 0.01 mol). in 95% ethanol, and the mixture was stirred and refluxed for 2.5 hours. The solvent was then removed by evaporation under reduced pressure and the residue was neutralized with 10% aqueous hydrochloric acid (25 ml) and extracted with ethyl acetate (3 x 20 ml). After separation, the combined organic phases are dried over anhydrous sodium sulfate,

9 »*« - · · 9 9 9 9 9 9 9 9

Filter and evaporate to give only 0.1 g of a white solid. The aqueous phase is therefore lyophilized and the residue is extracted with hot methanol. The residue, consisting of inorganic salts, was removed and the methanolic extracts were combined and evaporated under reduced pressure to give the title compound (1.34 g, 75%).

Example 15: 4- (4-fluorophenyl) -3 - [(3,4-methylenedioxyphenyl) oxycarbonyl] -piperidin-6-one

A solution of 4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (0.5 g, 1.88 mmol, cis / trans ratio 56:44) in ethanol (10 mL) was added to a sodium hydroxide solution (0, 08 g (2.00 mmol) in 95% ethanol (5 mL) was added and the mixture was stirred and heated at 60 ° C for 4 hours. The solvent was then removed by evaporation under reduced pressure and the remainder of the water was removed by distillation with toluene. The residue was suspended in dichloromethane (5 mL), treated with a solution of thionyl chloride (0.24 g, 2 mmol) and the mixture was heated to reflux. After 1 hour as sulfur dioxide evolution ceased, the mixture was cooled to ambient temperature and pyridine (0.16 g, 2 mmol) was added followed by a solution of sesamol (0.24 g, 1.75 mmol) in chloroform (2.5 mL). ml). The resulting mixture was heated at reflux for 4 hours and then stirred at ambient temperature for 2 days. Then the solvent was removed under reduced pressure and the residue was treated with water (5 mL), then extracted with ethyl acetate (20 and 10 mL). The organic extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.32 g).

Example 16: 4- (4-Fluorophenyl) -3-formylpiperidin-6-one

DIBAL-H (4.03 mL, 6 mmol) was gradually added at a rate of 5.6 mL / hr. via a syringe pump to a solution of 3-carbxyethyl-4- (4-fluorophenyl) -piperidin-6-one (0.53 g, 2 mmol) in 4 mL of tetrahydrofuran at -70 ° C below argon atmosphere. The reaction mixture was stirred for 1 hour at -70 ° C, then quenched with a solution of methanol (0.24 mL) in toluene (2 mL) at -70 ° C, followed by the addition of 0.12 mL of water at 0 ° C. After stirring at ambient temperature for 30 minutes, the gel formed was quenched by the addition of 1.5 ml of brine and then extracted with diethyl ether (50 ml). The organic phases were separated, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.2 g) as a yellow oil. The aqueous layer was basified with 10% aqueous sodium hydroxide and extracted with dichloromethane (20 mL). An additional 0.08 g of the title compound was isolated from the dichloromethane extract.

Example 17: 4- (4-Fluorophenyl) -3-hydroxymethylpiperidin-6-one

DIBAL-H (15.1 mL, 0.0225 mol) was gradually added at a rate of 50 mL / hr. by injection pump into a solution of 3-carbxyethyl-4- (4-fluorophenyl) -piperidin-6-one (1.99 g, 0.0075 mol) in tetrahydrofuran (15 mL) at -70 ° C under argon, under keeping the temperature below 0 ° C. The mixture was allowed to warm to 23 ° C and stirred for 45 minutes and then a solution of methanol (0.9 mL) in toluene (7.5 mL) was added to remove excess DIBAL-H, followed by a potassium carbonate solution ( 8.5 ml), all below 30 ° C. The organic phases were separated, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (1.54 g) as a slightly colored oil, which was crystallized by trituration with ether. Yield 67%.

Recrystallization from ether-ethyl acetate gave the title compound of greater than 96% purity, m.p. 188.8-191.6 ° C.

Example 18: 4- (4-Fluorophenyl) -3 - [(3,4-methylenedioxyphenyl) oxymethyl] -piperidin-6-one

To a solution of 4- (4-fluorophenyl) -3-carboxyethylpiperidin-6-one (0.36 g, cis / trans ratio> 95: 5) and dimethylethylamine (0.25 g) in dichloromethane (6 mL) was added a solution of benzenesulfonyl chloride. (0.34 g, 0.25 mL, 1.94 mmol) in dichloromethane (4 mL). The mixture is homogenized with Ν, Ν-dimethylformamide (1 ml) and stirred at ambient temperature for 5 hours, during which more dimethylethylamine (2.5 ml over 2.5 hours is added in aliquots, totaling 0.5). ml). The mixture was then quenched with water (15 mL), the phases separated and the aqueous phase extracted with dichloromethane (20 mL). The combined organic phases were washed with brine (10 mL) and evaporated to give 0.56 g of the O-benzenesulfonate intermediate. This material was dissolved in Ν, Ν-dimethylformamide (6 mL), treated with a solution of sesamol (0.25 g, 1.81 mmol) in Ν, Ν-dimethylformamide (4 mL), and 1 drop of water was added. Sodium methoxide (0.28 g, 5.14 mmol) was added slowly to the solution, maintaining the temperature at about 20 ° C, and then the temperature was raised to 50 ° C and maintained for 6.5 hours. The mixture was then quenched with water (30 mL), the phases separated and the aqueous phase extracted with diethyl ether (3 x 50 mL). The combined organic extracts were washed with 15% sodium hydroxide solution (2 x 35 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give crude 4- (4-fluorophenyl) -3 - [( 3,4-methylenedioxyphenyl) oxymethyl] -piperidin-6-one (0.24 g). This material was purified by column chromatography (solica gel eluted with ethyl acetate / methanol with 2% triethylamine).

Example 19: 4- (4-fluorophenyl) -3 - [(3,4-methylenedioxyphenyl) oxymethyl] -piperidine

A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M solution, 2 mL, 2.0 mmol) was added over 10 minutes to a well-mixed solution.

And a 4- (4-fluorophenyl) -3 - [(3,4-methylenedioxyphenyl) oxymethyl] -piperidine-6 solution. -one (0.41 g, 0.96 mmol) in tetrahydrofuran (7 mL), maintaining the temperature below 25 ° C. The reaction mixture was stirred for 2 hours and then quenched first with water (0.16 mL), then with 15% aqueous sodium hydroxide solution (0.1 mL), and finally again with water (0.4 mL). The reaction mixture was stirred for 0.5 hours to complete the precipitation, diluted with dichloromethane (30 mL) and filtered. The filtrate was evaporated in vacuo to give the title compound with a trans / cis ratio = 72:28. Yield 90%.

Column chromatography on silica gel 60 (eluting with ethyl acetate: methanol: triethylamine = 80: 20: 5) gave pure material as a transisomer.

Claims (10)

AND? t θ ra fc ο λχ ^- ee η Μ. x? ο 3c ~ y A process for preparing 4-aryl-piperidines of formula (1): F (Ό wherein R is hydrogen or a group selected from the group consisting of alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryl oxycarbonyl, and Z 'is 3,4- methylenedioxyphenyl comprising a reduction of a compound of formula (2a) or (2b): wherein Y is oxygen or sulfur, and R and X are as defined above and Z is hydrogen or a group selected from alkyl, aralkyl or aryl, and wherein Z is a group other than 3,4-methylenedioxyphenyl which is then converted to 3,4-methylenedioxyphenyl. • «· · A process for preparing 4-aryl-piperidines of formula (1): F OZ (D wherein R is hydrogen or a group selected from alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, and Z is a group selected from alkyl, aralkyl or aryl, preferably wherein 3,4-methylenedioxyphenyl, characterized by wherein the compounds of formula (2a) or (2b): Z is hydrogen or that it comprises a reduction (2b) (2a) wherein Y is oxygen or sulfur, and R, as defined above. X and Z are the same as they are 3. A process according to claim 1 wherein the reduction is carried out by catalytic hydrogenation at atmospheric or above atmospheric pressure or by using hydride reagents. • 9 9 The process of claim 1, wherein the compound of formula (1) wherein Z is alkyl, aralkyl or aryl is prepared by selectively reducing an ester group in a compound of formula (2a) or (2b) wherein Z is alkyl, aralkyl or aryl . A process for preparing 4-aryl-piperidines of formula (1): F OZ N i R m wherein R is hydrogen or a group selected from alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, and Z is a group selected from hydrogen, alkyl, aralkyl or aryl, preferably wherein Z is hydrogen or 3,4-methylenedioxyphenyl, characterized by the compound of formula (4a) or (4b): wherein X is one or more hydrogen or an easily reducible group such as chlorine, bromine or iodine and R and Z are as defined above. 6. The process of claim 1 wherein the reduction is accomplished by catalytic hydrogenation at atmospheric or above atmospheric pressure or by use of hydride reagents. (2a) (2b) wherein Y is oxygen or sulfur, and R, X and Z are the same as defined in claim 1. • · · Compound of formula (4c) or (4d) (4c) (4d) R and X are as defined in claim 1 10. Compound of formula (1) OZ N i R (D wherein R is hydrogen and Z is 3,4-methylenedioxyphenyl when obtained by (a) the process of claim 1; or (b) condensing a compound wherein Z is hydrogen obtained by the process of claim 1 with 3 With 4-methylenedioxyphenol and, if necessary, removal of the group R other than hydrogen. A compound according to claim 9, which is in the form of the hydrochloride salt. • 9 • 9 • 4 »4 · ··············· 12. A method of treating a disease comprising administering an effective or prophylactic amount of a compound of claim 9 to an individual suffering from one or more of the diseases.