WO2002032870A1

WO2002032870A1 - Process of the preparation of 3-substituted-4-aryl piperidine compounds

Info

Publication number: WO2002032870A1
Application number: PCT/GB2000/004071
Authority: WO
Inventors: Neal Ward
Original assignee: Smithkline Beecham P.L.C.
Priority date: 2000-10-20
Filing date: 2000-10-20
Publication date: 2002-04-25
Also published as: AU2001210390A1

Abstract

Compounds of structure (2) are prepared by reaction of an arecoline analogue of structure (4) with an organometallic compound containing an X-substituted phenyl group, such as a compound of structure (3). Suitably the compound of structure (3) is a Grignard reagent, where M is magnesium and Y is a halogen atom, or M may be a Group II metal and Y is a halogen atom or a second X-substituted phenyl group. When structure (3) is a Grignard reagent, the reaction is carried out either in a suitable non-ether solvent, typically a hydrocarbon or a non-reactive chlorinated hydrocarbon, or in a mixture of such a solvent with diethyl ether. Compounds of structure (2) are important intermediates in the preparation of inter alia paroxetine.

Description

PROCESS OF THE PREPARATION OF 3-SUBSTITUTED-4-ARYL PIPERIDINE COMPOUNDS

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.

This invention aims to overcome disadvantages in the existing processes for 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) and (2) below are valuable chemical intermediates useful for the manufacture of important medicinal products, for example paroxetine hydrochloride.

(1) (2)

By reference to Example 4 of US 4007196, paroxetine may be prepared from a compound of structure (1) in which R is methyl and X is 4-fluoro, that is 4-(4'-fluorophenyl)-3- hydroxymethyl-1-methylpiperidine, by replacing the hydroxymethyl group with 3,4- methylenedioxyphenoxymethyl, followed by demethylation, replacing the R=methyl group by hydrogen. In the same Example, 4-(4'-fluorophenyl)-3-hydroxymethyl- 1 -methyl piperidine is prepared by reduction of 4-(4'-fluorophenyl)-3-hydroxymethyl-l- methyl- 1, 2,3, 6-tetrahydropyridine, which is in turn prepared from 4-(4' -fluorophenyl)- 1 - methyl- 1, 2,3, 6-tetrahydropyridine, by reaction with formaldehyde.

US-A-4007196 also discloses that compounds of structure (1) which are 4-(fluorophenyl)-3-hydroxymethyl-l-alkyl piperidines can be obtained by reduction of compounds of structure (2) which are 4-(fluorophenyl)-3-carboxymethoxy-l-alkyl piperidines. The latter are prepared using a literature procedure (J.T. Plati, A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265). Plati et al describe the reaction of the tetrahydropyridine arecoline with phenyl magnesium bromide in diethyl ether to prepare l-methyl-3-carbomethoxy-4-phenyl piperidine (compound (2) where R and R' are methyl groups and X is a hydrogen atom).

EP-A-0219034 discloses an alternative method for the preparation of some 4-(substituted phenyl)-3-carboxyalkoxy-l-alkyl piperidines, and their reduction to 4-(substituted phenyl)-3 -hydroxymethyl- 1 -alkyl piperidines.

Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4^,-methylenedioxy- phenoxymethyl)-piperidine. The above described processes produce compounds of structure (1) as a mixture of enantiomers. Therefore conversion of compounds of structure (1) to useful pharmaceuticals will normally require a resolution stage.

The Plati et al procedure uses diethyl ether, which is a very flammable solvent and its use in large scale production is highly undesirable. However, we have found that other ether solvents conventionally used in Grignard reactions, such as tetrahydrofuran or diisopropyl ether result in little if any of the desired 1,4-conjugate addition product, as the major product arises from attack of the Grignard reagent on the ester grouping (so called 1,2- addition). We have also have found that the Plati procedure generates thick unstirrable gels and is unsuitable for large scale production of compounds of structure (2).

As a result, we have discovered that the Plati et al procedure used in US 4007196 can be improved by use of other organometallic compounds in place of the Grignard reagent, or by varying the conditions under which a Grignard reagent is used, enabling the stirring problems to be overcome and the use of diethyl ether eliminated or significantly reduced.

Accordingly a first aspect of this invention provides a process for the preparation of a compound of structure (2)

(2)

in which R and R' are independently an alkyl, aryl, or arylalkyl group, most suitably lower alkyl, and X is one or more of hydrogen, halogen (especially fluoro), hydroxy, aikoxy, nitro, nitrile, amino (optionally protected or substituted), trifluoromethyl, acyl, formyl, carboxyl or carboxyalkyl, which comprises reacting a compound of structure (4)

(4) with an organometallic compound having one or more X-substituted phenyl groups, in a suitable organic solvent, provided that the solvent is not wholly diethyl ether when the organometallic compound is a Grignard reagent.

The organometallic compound may be any X-substituted phenyl derivative capable of undergoing a 1,4-conjugate to a compound of structure (4), such as a Grignard reagent, and X-substituted phenyl derivatives of Group II metals. For example, the organometallic compound may be a compound of structure (3)

(3) in which M is a Group II metal and Y is a halogen or an X-substituted phenyl group. Suitable compounds of structure (3) include Grignard reagents, in which case M is magnesium and Y is conveniently chlorine or bromine. The compound of structure (3) may also be a symmetrical molecule, where M represents for example a zinc atom and Y is a second X-substituted phenyl group.

When structure (3) represents a Grignard reagent the reaction is carried out either in a suitable non-ether solvent, or in a mixture of such a solvent with diethyl ether. Suitable non-ether solvents are those which are compatible with the reaction conditions, for example those which do not react with Grignard reagents. Such solvents include hydrocarbons such as hexane or toluene, and unreactive chlorinated hydrocarbons such as dichloromethane.

Where it is desired to carry out the reaction in a non-ether solvent, the Grignard reagent of formula (3) may either be prepared in the chosen solvent, or prepared in an ether solvent and the ether subsequently removed by distillation and replaced by the chosen solvent. When employed in a non-ether solvent, a Grignard reagent of formula (3) may be partially or completely insoluble, but the resulting suspension is stirrable and compatible with large scale operation. When a mixture of diethyl ether and a suitable non-ether solvent is employed, a completely clear solution may be obtained, rendering the process particularly suitable for industrial scale operation.

By using the processes of this invention the reaction has been found to be more efficient, and the large excess of Grignard reagent specified by Plati (2 molar equivalents) can be -significantly reduced without loss in yield. We have also found that the reaction is equally efficient if the order of addition of the reagents is reversed, i.e. the Grignard reagent is added to the tetrahydropyridine ester.

Compounds of structure (3) may be prepared by conventional procedures for Grignard reagents and the other organometallic compounds, starting from an appropriately X- substituted aromatic compound. Where the desired end product is paroxetine, an appropriately X-substituted aromatic compound would be l-bromo-4-fluorobenzene.

Compounds of formula (4) may be prepared from the natural products guvacine, arecaidine or arecoline, by conventional methods, or by synthesis from other materials. A particularly convenient synthetic procedure involves the esterifϊcation, quaternisation and partial reduction of nicotinic acid [see for example Journal of Organic Chemistry (1955), volume 20, pages 1761-1765; Journal of Chemical Research (1983), volume 10, pages 2326 - 2342; Journal of Pharmaceutical Sciences (1992), volume 81, pages 1015 -1019; and references quoted therein].

Other methods for the preparation of compounds of structure (4) are given in Tetrahedron (1989) volume 45 pages 239-258, and Heterocycles (1990) volume 30 pages 885 - 896.

The compounds of structure (2) may be reduced to compounds of structure (1) by the general procedures disclosed in EP-A-0219934.

Compounds of structure (1) may be converted to an active compound disclosed in US-A- 3912743 or US-A-4007196 using conventional procedures disclosed therein. Where appropriate or necessary, compounds of structure (1) may be resolved to obtain the (- )trans isomer using conventional reagents such a nitro tartranilic acid, as described in EP- A-0223334 - see Example 5. In particular, the compound of structure (1) in which X is 4-fluoro may be used to prepare paroxetine. The paroxetine is preferably obtained as 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.

The invention is illustrated by the following Examples:

Example 1 l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine

A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was diluted with toluene (5 ml) and heated under nitrogen until the ether had been removed. The resulting suspension was cooled to ca. -5 °C and treated with a solution of arecoline (0.78 g) in toluene (4.5 ml) over 15 minutes. The mixture was stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 880 mg (70 %).

Example 2 l-methyl-3-carbomethoxy-4-(4-fluorophenyI)-piperidme

A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was stirred at -5 to -10 °C under nitrogen, and a solution of arecoline (0.78 g) in toluene (5.0 ml) added^'over 15 minutes at -5 °C. The clear solution was stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 905 mg (72 %).

Example 3 l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine

A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was stirred at -5 to -10 °C under nitrogen, and a solution of arecoline (0.78 g) in dichloromethane (4.0 ml) added over 15 minutes at -5 °C. The clear solution was stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 950 mg (76 %).

Example 4 l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine

A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (3.5 ml, 1.4 molar equivalents) was stirred at -5 to -10 °C under nitrogen, and a solution of arecoline (0.78 g) in dichloromethane (4.0 ml) added over 15 minutes at -5 °C. The clear solution was stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 965 mg (77 %).

Example 5 l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine - reverse addition A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (3.5 ml, 1.4 molar equivalents) was added over 15 minutes to a stirred solution of arecoline (0.78 g) in dichloromethane (4.0 ml) at -5 to -10 °C under nitrogen. The clear solution was stirred at -5 °C for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 970 mg (77 %).

Example 6 Preparation of (±) trans l-methyl-3-carbomethoxy-4-(4'-fiuorophenyl)-piperidine

i) A solution of arecoline (25.0 g) in dichloromethane (160 ml) was added to a stirred solution of 4-fluorophenylmagnesium bromide in diethyl ether (97 ml, 2.0 molar, 1.2 equivalents) over 45 minutes at -5 to -10 °C under nitrogen. The clear solution was stirred at about -5°C for 1 hour, then quenched by the rapid addition of a mixture of water (800 ml) and concentrated hydrochloric acid (96 ml). The temperature of the mixture rose to 36°C. The phases were separated and the dichloromethane layer discarded. The aqueous phase was washed twice more with dichloromethane (150 ml) then brought to about pH 10 by the cautious addition of solid potassium carbonate. The mixture was extracted with dichloromethane (3 x 250 ml) and the combined extracts washed with saturated sodium chloride (50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the crude cis/trans ester dried in vacuo. HPLC analysis of the product showed that the cis/trans ratio was 2.22 : 1.

Yield 32.62 g (81%).

ii) A solution of arecoline (15.54 g) in toluene (82 ml) was added to a stirred solution of 4-fluorophenylmagnesium bromide in diethyl ether (60 ml, 2.0 molar, 1.2 equivalents) over 35 minutes at -5°C under nitrogen. The mixture was stirred at about -5 °C for 1.5 hours, then quenched by the rapid addition of a mixture of water (500 ml) and concentrated hydrochloric acid (60 ml). The phases were separated and the toluene layer discarded. The aqueous phase was washed twice with dichloromethane (150 ml) then brought to about pH 10 by the cautious addition of solid potassium carbonate. The mixture was extracted with dichloromethane (3 x 250 ml) and the combined extracts washed with saturated sodium chloride (60 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the crude cis/trans ester dried in vacuo. HPLC analysis of the product showed that the cis/trans ratio was 2.90 : 1.

Yield 21.95 g (87.5%).

iii) Freshly prepared sodium methoxide (8.03 g) was added to a solution of the cis/trans ester (115 g) in toluene (1000 ml) and the mixture refluxed with stirring for 3 hours, by which time HPLC analysis indicated that the epimerisation was essentially complete. The mixture was cooled to room temperature, washed twice with water (200 ml) and the toluene removed by distillation under reduced pressure to give (±) trans 1 - methyl-3-carbomethoxy-4-(4'-fiuorophenyl) piperidine as an oil (107.4 g, 93%).

Example 7 Preparation of (±) trans-4-(4'-fluorophenyl)-3-hydroxymethyH-methylpiperidine

A solution of (±) trans-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (47.3g) in toluene (400 ml) was added dropwise over about 20 minutes to a 1 molar solution of lithium uminium hydride in tetrahydrofuran (200 ml) under nitrogen, maintaining a temperature of less than 10°C throughout the addition. The mixture was stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% sodium hydroxide solution (10 ml). The mixture was filtered through celite and the solids washed with toluene (2 x 100 ml). The combined toluene solutions were evaporated under reduced pressure and the solid residue dried in vacuo.

Yield 38.73g. (92.2%) Example 8

Preparation of (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine.

i) (±)trans-4-(4^,-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine (10.0 g) was heated and stirred in acetone (100 ml) until the solid dissolved. The solution was mixed with a solution of L(-)-di-p-toluoyl tartaric acid (22.5 g) in acetone (100 ml) and stirred at ambient temperature for 1 hour then at 0°C for 1 hour. The crystals of (-) trans 4-(4'- fluorophenyl)-3-hydroxymethyl-l-methylpiperidine L(-)-di-p-toluoyl tartrate were collected by filtration, washed with acetone and dried in vacuo.

Yield 12.57g

ii) (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine L(-)-di-p-toluyl tartrate (12.0 g) was stirred in dichloromethane (240ml) and water (120g) and 10% sodium hydroxide (25 ml) was added to dissolve the salt. The phases were separated and the organic phase dried over magnesium sulphate and evaporated under reduced pressure to give (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine as a white crystalline solid.

Yield 3.83g

Example 9 Preparation of (-) trans 4-(4'-fluorophenyl)-3-(3'4^,-methylenedioxy-phenoxymethyl)- 1-methylpiperidine.

i) N,N-dimethylethylamine (4.0 ml) was added to a solution of (-) trans 4-(4'- fluorophenyl)-3-hydroxymethyl-l-methylpiperidine (5.57g) in dichloromethane (50 ml) under nitrogen, and the mixture cooled to 0-5 °C. A solution of benzene sulphonyl chloride (3.5 ml) in dichloromethane (12.5 ml) was added slowly with stirring maintaining a temperature of less than 5°C. The mixture was stirred at 0-5 °C for 1 hour, then water (50 ml) was added and stirring continued for a further 1 hour at ambient temperature. The dichloromethane layer was separated and the aqueous layer was extracted again with dichloromethane (25 ml). The combined organic solutions were filtered and the solvent evaporated under reduced pressure to give the benzene sulphonate as an oil which readily solidified.

ii) The benzene sulphonate was dissolved in N,N-dimethylformamide (30 ml), then sesamol (3.5 g) was added followed by sodium methoxide (2.0g), which was added in portions over about 20 minutes, maintaining a temperature of not more than 20°C. The mixture was then heated to 50°C, stirred at this temperature for 2 hours and diluted with water (100 ml). On cooling to room temperature, the product was precipitated as a solid which was isolated by filtration, washed with water and dried in vacuo.

Yield 4.12g

Example 10

Preparation of (-) trans-4-(4'-fluorophenyl)-3-(3'4'-methylenedioxyphenoxymethyl)-

1-phenoxycarbonylpiperidine.

(-) trans 4-(4'-fluorophenyl)-3 -(3 '4'-methylenedioxyphenoxymethyl)-l -methyl piperidine (3.43g) was dissolved in toluene (100 ml) and about half the toluene removed by distillation to remove any traces of water. The solution was then held at 60 °C and a solution of phenyl chloroformate (1.40 ml) in toluene (10 ml) was added dropwise with stirring under nitrogen, over about 25 minutes. The mixture was then stirred at 60°C for 1 hour and cooled to ambient temperature. 5% sulphuric acid (10 ml) was added, the mixture was stirred well and the phases separated. The toluene phase was washed with water (10 ml) and the combined aqueous phases further extracted with toluene (10 ml). The combined toluene phases were washed with water (10 ml) and evaporated down to give an oil. The addition of isopropanol gave (-) trans 4-(4'-fluorophenyl)-3-(3'4'- methylenedioxy phenoxymethyl)-l-phenoxycarbonyl piperidine as a white solid which was dried in vacuo.

Yield 3.98 g

Example 11

Preparation of (-) trans 4-(4'-fluorophenyι)-3-(3'4'-met!ιylenedioxy - phenoxymethyl) piperidine (paroxetine free base).

Powdered potassium hydroxide (3.0g) was added to a solution of (-) trans 4-(4'- fluoropheny l)-3 -(3 '4'-methylenedioxyphenoxymethyl)- 1 -phenoxy carbony 1 piperidine (3.6g) in toluene (100 ml) and the well stirred mixture was refluxed for 2 hours. The mixture was cooled to ambient temperature, treated with water (100 ml), stirred well and the phases separated. The toluene phase was washed with water (50 ml), then evaporated under reduced pressure to give paroxetine free base as an oil.

Yield 2.50 g

Example 12 Preparation of paroxetine hydrochloride hemihydrate.

The free base prepared in Example 11 (2.50 g) was dissolved in isopropanol (25 ml) at room temperature and concentrated hydrochloric acid (1.0 ml) added with stirring. White crystals began to separate after a few minutes and the mixture was cooled in ice/water and stirred for another 30 minutes. The product was collected by filtration, washed with isopropanol (10 ml) and dried in vacuo.

Yield 1.82 g

The infra-red spectrum of the product conformed to that of a standard sample of paroxetine hydrochloride hemihydrate.

Claims

A process for the preparation of a compound of structure (2)

(2) in which R and R are independently selected from an alkyl, aryl, or arylalkyl group, X is one or more of hydrogen, halogen, hydroxy, aikoxy, nitro, nitrile, amino (optionally protected or substituted), trifluoromethyl, acyl, formyl, carboxyl or carboxyalkyl, which comprises reacting a compound of structure (4)

2. A process according to claim 1, in which the organometallic compound is a compound of structure (3)

(3) in which M is a Group II metal and Y is a halogen or an X-substituted phenyl group.

3. A process according to claim 2, in which M is Zn and Y is a second X-substituted phenyl group.

4. A process according to claim 2, in which structure (3) is a Grignard reagent and the organic solvent is a non-ether solvent or a mixture of a non-ether solvent with diethyl ether.

5. A process according to claim 4, in which M is Mg and Y is Cl or Br.

6. A process according to any one of claims 1 to 5, in which the solvent is a hydrocarbon or a non-reactive chlorinated hydrocarbon.

A process for the preparation of a 4-aryl-3-hydroxymethyl-piperidine of structure (1)

(1) comprising reducing a compound of structure (2) obtained by the process of claims 1 to 6.

8. A process for preparing paroxetine comprising obtaining a compound of structure (1) in which X is 4-fluoro by a process as claimed in claim 7, replacing the 3-hydroxymethyl group by a 3-(3,4-methylenedioxyphenyloxymethyl) group, and replacing the substituent R with a hydrogen atom.

9. A process according to claim 8, in which paroxetine is obtained as, or converted to, a hydrochloride salt.

10. A process according to claim 9, in which the paroxetine hydrochloride salt is obtained as the hemihydrate.