AU1563002A - Novel process - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANTS: SmithKline Beecham Corporation AND SmithKline Beecham plc ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Novel process" The following statement is a full description of this invention, including the best method of performing it known to us: NOVEL PROCESS This application is a divisional of Australian Patent Application No. 77089/98, the entire contents of which are incorporated herein by reference.

The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.

Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the trans isomer of fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.

This invention aims to overcome disadvantages in the existing processes for 15 preparation of such compounds and so to provide alternative processes for their manufacture.

This invention has been developed on the basis that compounds of structure (1) below are either valuable.chemical intermediates useful for the manufacture of 20 important medicinal products, for example paroxetine hydrochloride, or are themselves active compounds, such as disclosed in US-A-3912743 and US-A- 4007196.

By reference to Example 4 of US 4007196, paroxetine may be prepared from a 25 compound of structure below in which R is methyl, and Z is hydrogen, that is 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine, by reaction with 3,4methylenedioxyphenol followed by demethylation. In the same Example, fluorophenyl)-3-hydroxymethyl- I-methyl piperidine is prepared by reduction of 4-(4'-fluorophenyl)-3-hydroxymethyl- -methyl -1,2,3,6-tetra- hydropyridine (II), which is in turn prepared from 4-(4'-fluorophenyl)-1-methyl-1,2,3,6tetrahydropyridine (III), by reaction with formaldehyde.

Alternative processes for the preparation of 4-(4'-fluorophenyl)-3hydroxymethyl- 1-methylpiperidine are given in EP-A-0223334, by reduction of compounds of structure (A) -1rr-; 7 1 1 I i

(A)

in which Z is alkyl and R is H, alkyl or aralkyl.

5 The above described processes produce compounds of structure as a mixture of enantiomers. Therefore conversion of compounds of structure to useful pharmaceuticals, such as paroxetine i.e. the trans isomer of fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine, will normally require a resolution stage, as described in EP-A-0223334.

This invention provides a process for the preparation of 4-aryl-piperidines of structure (1)

F

OZ'

N

R

(1) in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z' is a 3,4methylenedioxyphenyl group, which comprises reduction of a compound of structure (2a) or (2b) (2a) (2b) a.

a in which Y is oxygen or sulphur, and R and X are as defined above and Z is hydrogen or an alkyl, aralkyl or aryl group, and where Z is other than a 3,4-methylenedioxyphenyl group thereafter converting Z to 3,4-methylenedioxyphenyl.

This invention also provides a process for the preparation of 4-aryl-piperidines of structure (1) 3oz

N

R

(1) in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or an alkyl, aralkyl or aryl group, most suitably where Z is a hydrogen atom or a 3,4methylenedioxyphenyl group, which comprises reduction of a compound of structure (2a) or (2b) NL Y OZ YkN' OZ I

I

R

R

(2a) (2b) in which Y is oxygen or sulphur, and S R, X, and Z are as defined above.

When Z incorporates an aryl group, the aryl group, for example phenyl, may be optionally substituted by one or more groups such as halogen or alkyl or alkoxy, or by two substituents linked to form a fused ring. For example, an especially 10 suitable substituent Z is 3,4-methylenedioxyphenyl, as found in paroxetine. Alkyl groups, including alkyl groups that are part of other moieties such as alkoxy or acyl, are typically C1- 6 especially C1-4 groups.

.4.

Compounds of structure (2a) and (2b) are believed to be novel and form part of this invention, especially compounds in which X is H, Z is H or 3,4methylenedioxyphenyl and R is H or C 1 4alkyl, especially methyl.

In a first aspect of the process of this invention compounds of structure (2a) or (2b) are reduced to give compounds of structure in which Z is H, that is 3hydroxymethyl-4-aryl piperidines. Reduction may be accomplished by hydrogenation at atmospheric or above atmospheric pressure using a variety of known catalysts, or using hydride reagents such as lithium aluminium hydride and sodium borohydride, or by a combination of known methods. A particularly useful aspect of this invention is the transformation of 4-aryl-3-carboxyalkyl-1- (optionally substituted)-piperidines to 4-aryl-3-hydroxymethyl- 1-(optionally substituted)-piperidines.

-4- It will be appreciated that reduction of esters or carboxylic acids of structure (2) may be carried out stepwise and an intermediate may be isolated, for example a carboxaldehyde, and the reduction of these intermediate compounds to a compound of structure is also included in the scope of this invention.

Intermediate carboxaldehydes are believed to be novel and form part of this invention. A particularly valuable intermediate is 4-(4-fluorophenyl)-5oxopiperidine-3-carboxaldehyde.

In a second aspect of the process of this invention compounds of structure (2a) and where Z is not H, are reduced to ethers of structure This may be accomplished by the use of known selective reagents such as diborane and DIBAL, or by Raney nickel desulphurization of a thionoester intermediate. A particularly advantageous ether for the manufacture of paroxetine is the 3,4- 15 methylenedioxyphenyl ether.

Following the reduction to give an ether of structure either or both the groups Z and R may be subsequently converted to a different group Z or R by S. conventional means, in order to produce the desired pharmaceutical agent. For example, in the preparation of paroxetine, it may be appropriate to convert Z H to Z 3,4-methylenedioxyphenyl and/or R C_4alkyl to R H. This aspect is S. also included in the scope of this invention.

One advantageous aspect of this process is that a single enantiomer of the 25 intermediate may be prepared either by enantioselective synthesis or from a chiral precursor, in which case the resolution noted above may be avoided entirely or transferred to an early stage in the overall process.

Starting materials of structure where Y is oxygen, may be prepared conveniently by carboxyalkylation of a 4-aryl-piperidine-2-one precursor, which may in turn be obtained from the reaction of an activated alkyl hydroxyvalerate with an amine. In a particularly advantageous embodiment of this invention the alkyl 3-aryl-5-hydroxyvalerate is prepared as a single enantiomer by selective reduction of a 3-arylglutarate mono-ester obtained by enzymatic hydrolysis of the pro-chiral dialkyl 3-arylglutarate, for example using pig liver esterase to obtain S-enantiomers and -chymotripsin to obtain Rr; i- :j ;l l-rl:\.i r enantiomers. Suitable dialkyl 3-arylglutarates may be obtained by, for example, reaction of 4-fluorobenzaldehyde with methyl acetoacetate.

The ester group at the 3-position or a group convertible to an ester group may already be present in the starting material or may be introduced for example by reaction of a 2-piperidone of structure firstly with a strong base, such as sodium hydride or lithium hexamethyldisilazide followed by a carboxylating agent, such as a chloroformic ester or thiono chloroformic ester.

F

R

N Compounds with structure (2b) where Y is oxygen may be prepared by, for example, reductive cyclisation of 2-cyano-3-(4'-fluorophenyl)-glutarate esters. A similar preparation has been described for the preparation of 3-ethoxycarbonyl-4- 3 '-methoxyphenyl)-2-piperidone (Journal of Organic Chemistry (1977) volume 42, pages 1485-1495), but this procedure had been found to be unsuitable for the preparation of compounds with structure (2b) and results in a complex mixture of products. A new and efficient process has now been discovered in which 2cyano-3-(4'-fluorophenyl)glutarate esters, especially diethyl 2-cyano-3-(4'fluorophenyl)glutarate, are hydrogenated in 1,4-dioxane. Such compounds may be prepared by reaction of, for example, ethyl cyanoacetate and ethyl 4fluorocinnamate in sodium ethoxide.

Compounds of structure (2a) and (2b) where Y is sulphur can be prepared from the cyclization of analogous thionoesters or by the reaction of piperidones with sulphurizing reagents such as Lawesson's reagent or phosphorus pentasulphide, -6r;.l .II. I 1. i, .Ik: (111C l ii. as described in Organic Syntheses (1984), volume 62, page 158 and the Journal of Organic Chemistry (1981) volume 46, page 3558. Reduction of the thiopiperidones may be accomplished stepwise, particularly if a reagent such as Raney nickel is used for the first stage. The resulting 4-aryl-3carboxyalkylpiperidines may then be separately reduced to compounds of structure by conventional reduction, most suitably with hydride reagents such as lithium aluminium hydride.

Suitable starting materials of structure can be prepared by the manner described above or by transesterification of intermediate esters.

It will be appreciated that the reduction of compounds of structure to give compounds of structure may take place stepwise via, inter alia, compounds of structure (2c) and (2d) F F

S.X

CHO

Oz N N R R (2c) (2d) and the reduction of these intermediate compounds, when produced by this process is also included in the scope of this invention.

Compounds of structure (2c) where X is hydrogen, Z is methyl, and R is hydrogen or C -4alkyl, were described in US-A-4007196, though no procedure was described which is satisfactory for large scale manufacture. These problems have been overcome in the pending application GB9700690.2. The preparation of compounds of structure where R and Z are alkyl, by reduction of quaternary pyridinium salts have also been described in EP 0219934.

:1 Compounds of structure (2c) other than those described in the above mentioned patent applications and compounds of structure (2d) are novel and form part of this invention. Particularly important compounds of structure (2c) are those where Z is aryl, especially 3 4 -methylenedioxyphenyl, which may inter alia be prepared by selective reduction of compounds (2a) or (2b) or by transesterification of other compounds Compounds of structure (2c) and (2d) may be reduced further to compounds of structure Alternatively, interrupted or selective reduction of compounds (2a) and (2b) may give rise to novel intermediate alcohols or ethers of structure (4a) or (4b) which may be isolated, and which also form part of this invention.

*F

F

X X

I

R R (4a) (4b) In a preferred method for the preparation of compounds of structure (4a) and compounds of structure (2a) and (2b) are first converted into thioesters which are desulphurised with, for example, Raney nickel. The intermediate thiono esters are also novel and form part of this invention.

Compounds of structure (4a) and (4b) may also be separately prepared by reactions analogous to those described above for the preparation of compounds of structure (2a) and (2b) and employed in the processes of this invention. For example a carbinol of structure (4a) may be prepared by hydroxymethylation of compound and an ether group may be introduced by reaction of with a chloromethyl ether.

!ti;r r- -r Tr.: 1 m- i. I: Particularly important compounds of structure (4a) and (4b) are those where Z is 3,4-methylenedioxyphenyl, and especially where X and R are both hydrogen.

Compounds of structure may be reduced further to compounds of structure The novel compounds of structure may also be prepared by other methods such as etherification of where Z is hydrogen, or reductive alkylation of aldehydes.

Many of the intermediate compounds in the processes of this invention are novel, and such intermediates form another aspect of this invention.

In a further aspect of the invention, a compound of structure in which Z is a hydrogen atom obtained by processes of this invention may be converted to an 15 active compound disclosed in US-A-3912743 and US-A-4007196 using conventional procedures disclosed therein.

In particular the compound of structure in which in which Z is a hydrogen atom may be used to prepare paroxetine. The paroxetine is preferably obtained as 20 the hydrochloride salt and most preferably as the hemihydrate of that salt, as described in EP-A-0223403. The present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.

Paroxetine obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or W096/24595, either as solid formulations or as solutions for oral or parenteral use.

Therapeutic uses of paroxetine, especially paroxetine hydrochloride, obtained using this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders".

-9c L.1. I :1:1.1 Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier, the use of paroxetine or paroxetine hydrochloride obtained using the process of this invention to manufacture a medicament in solid or liquid form for the treatment or prophylaxis of the Disorders; and a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine hydrochloride obtained using the S* process of this invention to a person suffering from one or more of the Disorders.

15 This invention is illustrated by the following Examples.

Example 1 Dimethyl 3 -(4'-fluorophenyl)glutarate 4-Fluorobenzaldehyde (75 ml), methyl acetoacetate (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 a 25% solution of sodium methoxide in methanol (650 ml) and water (54 ml), and heated at reflux for 7 hours. After cooling, solvent (500 ml) was removed by vacuum distillation, "25 water (1 litre) was added, and a further quantity of solvent removed by distillation (100 ml). The mixture was extracted with tert-butyl methyl ether (400 ml), acidified to pH less than 3 with concentrated hydrochloric acid, and extracted with tert-butyl methyl ether (3 x 300 ml). The extracts were evaporated and the tert-butyl methyl ether replaced by methanol (800 ml). Concentrated hydrochloric acid (10 ml) was added, the mixture heated at reflux for 12 hours, and the solvent partially removed by evaporation. Dilution with water (75 ml) gave crystals of dimethyl 3 -(4'-fluorophenyl)glutarate. Yield after drying 124.1 g Example 2 S-3-(4'-fluorophenyl)glutaric acid monomethyl ester A solution of dimethylformamide in water 7 litres) was adjusted to pH with 1.0 M phosphate buffer, and dimethyl 3-(4'-fluorophenyl)glutarate (160 g) added. The mixture was held at 37 0 C, pig liver esterase (46 ml, 96,000 U) added, and the reaction continued for 24 hours at constant temperature and pH. The mixture was cooled, acidified to below pH 3 with hydrochloric acid, and extracted with tert-butyl methyl ether (3 x 1500 ml). The extracts were washed with dilute hydrochloric acid (2 x 1 litre), reduced to about I litre by evaporation, treated with hexane (100 ml), and cooled to 0°C to crystallize the product. The supernatant liquors were decanted, evaporated to 200 ml, and treated with hexane (50 ml) to give further crystals. The yield of crystalline (S-enantiomer) monoester after drying was 118.8 g 15 The R-enantiomer is obtained by an analogous procedure using -chymotrypsin (Can. J. Chem., 1994, 72(11), 2312).

Example 3 R-l-benzyl-3-(4'-fluorophenyl)-piperidine-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 at reflux for 1 hour. After cooling, a lithium borohydride solution (108 ml, 2 molar) was added slowly and the mixture heated at reflux for 12 hours, then cooled to ambient temperature. Dimethylformamide (400 ml) and methyl sulphate (56.6 25 ml) were added and the mixture 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 was evaporated to about 400 ml, diluted with toluene (1 litre) and evaporated again to 400 ml; this was repeated twice more.

Toluene (600 ml) and triethylamine (96 ml) were added to the crude methyl the mixture cooled to 0°C, then slowly treated with methanesulphonyl chloride (32 ml). The mixture was stirred for 45 minutes at 0°C, filtered through silica, and the cake washed with toluene (100 ml).

Triethylamine (100 ml), benzylamine (40 ml), and sodium iodide (2 g) were added to the filtrate and the mixture heated at reflux for 20 hours, then cooled and 11 washed with 2 molar hydrochloric acid (3 x 600 mnl) and saturated sodium hydrogen carbonate (2 x 500 ml). The resulting solution of crude R-l-benzyl-3- (4'-fluorophenyl)-piperid-2-one was evaporated to about 300 mrl and diluted with heptane (50 mnl) to induce crystallization.

Yield of dried product 52.6 g >99% ee).

Example 4 S-1-benzyl-3-(4'-fluorophenyl)-piperidine-2-one S-1-benzyl-3-(4'-fluorophenyl)-piperidine-2-one is prepared from fluorophenyl)glutaric acid monomethyl ester by an analogous procedure in which the initial reduction is carried out with borane. Similarly R-l-benzyl-3-(4'fluorophenyl)-piperidine-2-one may be prepared from fluorophenyl)glutaric acid monomethyl ester.

Example trans-( 4 R)-1-benzyl-3-carboxymethyl4..(4'.fluorophenyl)..piperidine.2-one A solution of R-1-benzyl-4-(4'-fluorophenyl)-piperidine-2-one (2.0 g) in toluene (40 ml) was treated with sodium hydride (0.704 g, 60% dispersion in oil) and dimethyl carbonate (3.0 and heated at reflux for 14 hours. After cooling the reaction mixture was quenched with ice, treated with methanol (15 ml), and .:potassium carbonate (0.5 g) and stirred for I hour. Toluene (100 ml]) was added and the phases were separated. The organic phase was washed with I molar hydrochloric acid (2 x 50 mld), saturated sodium hydrogen carbonate solution (2 x 50 ml), and water (50 ml). The organic phase was evaporated and the crude trans-(4R)- 1 -benzyl-3-carboxymethyl-4-(4'-fluorophenyl)piperidine2one crystallised from tert-butyl methyl ether and hexane. Yield 1.56 g -12- Example 6 Preparation of trans-(4R)-l-benzyl-4-(4'-fluorophenyl)-3-hydroxymethyl piperidine A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4'-fluorophenyl)piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with boranetetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours.

After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar 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)-1benzyl-4-(4'-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%).

*o Example 7 Preparation of paroxetine hydrochloride a) trans-(4R)-l-benzyl-4-(4'-fluorophenyl)-3-hydroxymethylpiperidine (9.65 p-toluenesulphonyl chloride (6.18 dimethylaminopyridine (0.1 and triethylamine (5.0 ml) in toluene (150 ml) were stirred for 42 hours at ambient 'temperature. The mixture was diluted with toluene (100 ml), washed with saturated sodium hydrogen carbonate (3 x 150 ml) and water (100 ml). The organic layer was evaporated to minimum volume, and diluted with toluene (100 ml). A solution of sesamol (4.28 g) in dimethyl formamide (150 ml) was reacted with sodium hydride (1.26 added to the activated carbinol solution, and the mixture heated at 60 0 C for 16 hours. The mixture was cooled, diluted with 25 toluene (200 ml), washed with 1 molar sodium hydroxide (2 x 100 ml) and water (2 x 100 ml), and evaporated to an oil. Yield 9.83 g b) The oil from Example 7 (4.0 g) was dissolved ith isopropanol (40 ml) and acetic acid (4 ml) and hydrogenated with 5% palladium on charcoal catalyst g) at 70 psi and 50 0 C for 2 hours. The cooled mixture was filtered through celite, the celite washed with isopropanol (40 ml) and the filtrate diluted with toluene (100 ml). The solution was washed with saturated sodium hydrogen carbonate (2 x 100 ml), 1 molar sodium hydroxide (100 ml), then water (100 ml), and finally withsaturated sodium chloride (100 ml). The organic phase was evaporated to low volume (15 ml), treated with concentrated hydrochloric acid (2 ml) and isopropanol (15 ml). The crystalline paroxetine hydrochloride was isolated, washed and dried. Yield 2.1 g.

13- ,17: r LT.r- I- I :i :Li li ii V^I 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 sodium in 50 ml ethanol) at 60°C over 2-3 minutes and the mixture heated under reflux for 1 hour then cooled to 5 0 C. Glacial acetic acid (6 ml) was added slowly to the reaction mixture at below 5 0 C. The bulk of the ethanol was removed by distillation at reduced pressure the residue diluted with water (40 ml), extracted with toluene (3 x ml), and the combined organic phases dried over anhydrous magnesium sulphate.

The solution was filtered, evaporated to an oil (28.6 and distilled at 166- 180 0 C at 3.5 mbar to produce diethyl 2-cyano-3-(4-fluorophenyl)-glutarate (23 g, 74% yield, 98% purity).

Example 9 15 3 -Carboxyethyl-4-(4'-fluorophenyl)-piperidine-6-one.

Diethyl 2 -cyano-3-(4-fluorophenyl)-glutarate (15.3 platinum oxide (0.57 g), and hydrogen chloride gas in dioxane (0.1 mole in 50 ml) were hydrogenated at 185 psi and 60°C for 6.5 hours. The product was cooled, filtered, and evaporated, and the residue was dissolved in chloroform (130 ml) and washed 20 with saturated sodium bicarbonate (200 ml). The solution was dried and passed through activated carbon (Darco G-40) to remove colloidal platinum and evaporated to give crude 3-carboxyethyl-4-(4'-fluorophenyl)-piperidine-6-one.

This product was repeatedly treated in ethyl acetate solution with activated carbon to give a purified product as a mixture of isomers (9.3 g, 70%, 95.6% 25 purity).

Example 3 -Carboxyethyl-4-(4'-fluorophenyl)-piperidine-6-one.

Diethyl 2 -cyano-3-(4-fluorophenyl)-glutarate (85.0 g, 0.22 mol), platinum oxide (2.1 and 4 molar hydrogen chloride gas in dioxane (112 ml, 0.45 mol) were stirred in a Parr apparatus under hydrogen (90-195 psi) at 60 0 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 through activated carbon (Darco G-40) to remove colloidal platinum, and evaporated to give the title compound (72.1 g, 84%) as an oil which crystallised 14on standing. Recrystallisation from hexane-dichloromethane gave a product with a cis/trans ratio 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 20 hours in 3 stages (in 3.6 mmol portions) at a rate of 7 ml/hour by means of a syringe pump to a solution of 4-(4-fluorophenyl)-3carboxyethylpiperidin-6-one (0.53 g, 2 mmol, trans/cis-1:1) in tetrahydrofuran (3 ml) at 260C. The reaction mixture was stirred for 1 hour after addition of the last portion of the borane solution, then quenched with 3.5 ml 30% aqueous potassium carbonate solution. The phases were separated and the aqueous phase extracted with diethyl ether (25 ml). The organic phases were combined and evaporated to yield 0.43 g of the title compound. Yield Example 12 4 4 -Fluorophenyl)-3-hydroxymethylpiperidine Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran, 0.75 ml, 0.75 mmol) was added gradually to a solution of trans-4-(4-fluorophenyl)-3- 20 carboxyethylpiperidin-6-one (0.25g, 0.836 mmol) in tetrahydrofuran (3 ml) keeping the temperature below 25 0 C. The reaction mixture was stirred for 1 hour at 25°C, then quenched with 1 drop of water, followed by 2 drops 15% sodium hydroxide solution, and finally with 5 drops of water. Extraction with dichloromethane (35 ml) followed by exaporation of the dichloromethane phase gave 0.21 g of the title compound. Yield 76%.

Example 13 4 4 -Fluorophenyl)-3-carboxyethylpiperidine 4 4 -fluorophenyl)-3-carboxyethylpiperidin-6-one (12.0 g, 0.045 mol, trans/cisratio was added in one portion to a solution of trimethyloxonium fluoroborate (12.0 g, 0.081 mol) in dichloromethane (80 ml) and the resulting solution 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 I. i~ ~3 ii:C :!Yi (100 ml), heated to 45°C and treated with sodium borohydride (10.0 g, 0.26 mol) in 1.0 g portions, allowing the mixture to boil under reflux. Most of the solvent was evaporated and the residue quenched with water (60 ml) followed by concentrated hydrochloric acid. After neutralization with 10% sodium bicarbonate solution the products were extracted with dichloromethane (150 and ml). The extracts were dried with anhydrous sodium sulphate, filtered, and evaporated to afford the title compound as a cis/trans mixture Yield A portion of the product was purified by column chromatography (silica gel, eluted with ethyl acetate-triethylamine, 98:2).

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

00 Example 14 0 0 15 3 -Carboxy-4-(4-fluorophenyl)piperidine-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 solution of sodium hydroxide (0.4 g, 0.01 mol) in 95% ethanol and the mixture brought to reflux and stirred for 2.5 hours.

The solvent was then removed by evaporation at reduced pressure, and the residue neutralized with 10% aqueous hydrochloric acid (25 ml) and extracted with ethyl acetate (3 x 20 ml). After separation, the combined organic phases were dried with anhydrous sodium sulphate, filtered, and evaporated to give only 0.1 g of a white solid. The aqueous phase was therefore lyophilized and the .:residue extracted with hot methanol. The residue, consisting of inorganic salts, 25 was discarded while the methanol extracts were combined and evaporated at reduced pressure to give the title compound (1.34 g, Example 4 4 -Fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxycarbonyl]-piperidine- 6-one.

A solution of 4 4 -fluorophenyl)-3-carboxyethylpiperidin-6-one (0.5 g, 1.88 mmol, trans/cis ratio 56:44) in ethanol (10 ml) was added to a solution of sodium hydroxide (0.08 g, 2 mmol) in 95% ethanol (5 ml) and the mixture heated for 4 hours at 60 0 C. The solvent was removed at reduced pressure and the residue of water removed by distillation with toluene. The residue was suspended in dichloromethane (5 ml), treated with a solution of thionyl chloride (0.24 g, 2 16- I 1 s r r mmol), and the mixture was brought to reflux. After 1 hour evolution of sulphur dioxide ceased, so the mixture was cooled to room temperature and treated with pyridine (0.16 g, 2 mmol) followed by a solution of sesamol (0.24 g, 1.75 mmol) in chloroform (2.5 ml). The resulting mixture was brought to reflux, heated for 4 hours, and stirred at ambient temperature for 2 days. The solvent was then removed at reduced pressure and the residue 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 sulphate, filtered and evaporated to give the title compound (0.32 g).

Example 16 "4-(4-Fluorophenyl)-3-formylpiperidine-6-one.

DIBAL-H (4.03 ml, 6 mmol) was added gradually at a rate of 5.6 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)- 15 piperidine-6-one (0.53g, 2 mmol) in 4 ml tetrahydrofuran at -70 0 C under an 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 0

C,

followed by 0.12 ml water at 0°C. After 30 minutes stirring at ambient temperature, the gel which formed was destroyed by the addition of 1.5 ml brine 20 and the reaction mixture was extracted with diethyl ether (50 ml). The organic phase was separated, dried with anhydrous sodium sulphate, filtered and S.i evaporated to yield 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). A further 0.08 g product was isolated from the :i 25 dichloromethane extract.

Example 17 4-( 4 -Fluorophenyl)-3-hydroxymethylpiperidine-6-one.

DIBAL-H (15.1 ml, 0.0225 mol) was added at a rate of 50 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6one (1.99 g, 0.0075 mol) in tetrahydrofuran (15 ml) at -70 0 C under an argon atmosphere keeping the temperature below 0°C. The mixture was allowed to warm to 23 0 C and stirred for 45 minutes, then a solution of methanol (0.9 ml) in toluene (7.5 ml) was added to destroy the excess DIBAL-H, followed by potassium carbonate solution (8.5 ml), all below 30 0 C. The organic phase was separated, dried with anhydrous sodium sulphate, filtered, and evaporated to -17afford 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 a product with >96% purity, m.p.188.8-191.6 0

C.

Example 18 4-(4-Fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine-6one.

To a solution of 4-(4-fluorophenyl)-3-hydroxymethylpiperidine-6-one (0.36 g, trans/cis ratio 95:5) and dimethylethylamine (0.25 g) in dichloromethane (6 ml) was added a solution of benzenesulphonyl chloride (0.34 g, 0.25 ml, 1.94 mmol) in dichloromethane (4 ml). The mixture was homogenised with N,Ndimethylformamide (1 ml) and stirred at ambient temperature for 5 hours during which time more dimethylethylamine was added in aliquots (2.5 ml over 15 hours making a total of 0.5 ml). The mixture was then quenched with water ml), the phases separated, and the aqueous phase extracted with dichloromethane ml). The combined organic phases were washed with brine (10 ml) and evaporated to give 0.56 g of the O-benzenesulphonate intermediate.

This product was dissolved in N,N-dimethylformamide (6 ml), mixed with a solution of sesamol (0.25 g, 1.81 mmol) in N,N-dimethylformamide (4 ml), and treated with 1 drop of water. Sodium methoxide (0.28 g, 5.14 mmol) was added slowly to the solution, keeping the temperature at approximately 20°C, 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 diethylether (3 x 50 ml). The combined organic extracts were washed with a 15% sodium hydroxide solution (2 x 35 ml) and brine (50 ml), dried with anhydrous sodium sulphate, filtered, and evaporated to give crude 4- (4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine-6-one (0.24 This product was purified by column chromatography (silica gel eluted with ethyl acetate/methanol gradient with 2% triethylamine).

-18i l ;r i: ^I i Example 19 4 4 -Fluorophenyl)- 3 3 4 -methylenedioxyphenyl)oxymethyl]piperidine.

A solution of lithium aluminium hydride in tetrahydrofuran (1.OM solution, 2 ml, mmol) was added over ten minutes to a well stirred solution of 4-(4fluorophenyl)-3-[(3, 4 -methylenedioxyphenyl)oxymethyl]piperidine-6-one (0.41 g, 0.96 mmol) in tetrahydrofuran (7 ml), maintaining the temperature below The reaction solution was stirred for 2 hours and then quenched first of all with water (0.16 ml), then with 15% aqueous sodium hydroxide solution (0.1 ml), and finally with water again (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 product with a trans/cis ratio 72:28. Yield Column chromatography on silica gel 60 (elution with a mixture of ethyl acetate methanol triethylamine 80:20:5) yielded a pure product as the transisomer.

0 15 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

-19-

Claims (17)

1. A process for the preparation of 4-aryl-piperidines of structure (1) F oz' in which R is hydrogen or an alkyl, aralkyl, aryl. acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z' is a 3,4- methylenedioxyphenyl group, which comprises reduction of a compound of structure (2a) or (2b) (2a) (2b) in which Y is oxygen or sulphur, and R and X are as defined above and Z is hydrogen or an alkyl, aralkyl or aryl group, and where Z is other than a 3,4-methylenedioxyphenyl group thereafter converting Z to 3 ,4-methylenedioxyphenyl. 20

2. A process for the preparation of 4-aryl-piperidines of structure (1) F Oz N R (1) in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or an alkyl, aralkyl or aryl group, most suitably where Z is a hydrogen atom or a 3,4- methylenedioxyphenyl group, 10 which comprises reduction of a compound of structure (2a) or (2b) (2a) (2b) in which Y is oxygen or sulphur, and R, X, and Z are as defined above.

3. A process according to claim 1, in which the reduction is carried out by catalytic hydrogenation at atmospheric or above atmospheric pressure or using hydride reagents. -21- -c i~ -i:a:

4. A process according to claim 1, in which a compound of structure in which Z is alkyl, aralkyl or aryl is prepared by selective reduction of the ester group in a compound of structure (2a) or (2b) in which Z is alkyl, aralkyl or aryl.

5. A process for the preparation of 4-aryl-piperidines of structure (1) F OZ N I R (1) in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or an alkyl, aralkyl or aryl group, especially a hydrogen atom or a 3,4-methylenedioxyphenyl group, which comprises reduction of a compound of structure (4a) or (4b) F F x x I I R R (4a) (4b) where X is one or more of hydrogen or a readily reducible group such as chlorine, bromine or iodine, and R and Z are as defined above. -22- ;I il i: i;r j :s :r :rl ,i i ;i

6. A process according to claim 1, in which the reduction is accomplished by catalytic hydrogenation at atmospheric or above atmospheric pressure or using hydride reagents.

7. A compound of structure (2a) or (2b) (2b) 10 in which Y is oxygen or sulphur, and R, X, and Z are as defined in claim 1.

8. A compound of structure (4a) or (4b) (4a) (4b) in which R, X, and Z are as defined in Claim I -23- :7 1 i')

9. A compound of structure (4c) or (4d) .CHO (4c) (4d) in which R and X are as defined in Claim 1

10. A compound of structure (1) in which R is hydrogen and Z is 3 ,4-methylenedioxyphenyl, whenever obtained by a process according to Claim 1, or condensing a compound in which Z is hydrogen obtained by a process according to claim 1 with 3 4 -methylenedioxyphenol, and where necessary removing a group R that is other than hydrogen. -24- P:\OPER\Kbm\2503915 div.doc-14A2/02

11. A compound according to claim 9, in the form of a hydrochloride salt.

12. A method of treating the Disorders which comprises administering an effective or prophylactic amount of a compound as claimed in claim 9 to a person suffering from one or more of the Disorders.

13. A process for the preparation of 4-aryl-piperidines of structure according to claim 1, substantially as hereinbefore described with reference to the Examples.

14. A compound of structure (2a) or (2b) according to claim 7, substantially as hereinbefore described with reference to the Examples.

A compound of structure (4a) or (4b) according to claim 8, substantially as hereinbefore described with reference to the Examples.

16. A compound of structure (4c) or (4d) according to claim 9, substantially as hereinbefore described with reference to the Examples.

17. A compound of structure according to claim 10, substantially as hereinbefore described with reference to the Examples. DATED this 14th day of February, 2002 SmithKline Beecham Corporation AND SmithKline Beecham plc By DAVIES COLLISON CAVE Patent Attorneys for the Applicants .i