NOVEL PROCESS

Abstract: The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor. The (-) <i>trans</i> isomer of 4-(4'-fluorophenyl)-3-(3'',4''-methylenedioxyphenoxymethyl)piperidine(paroxetine) is an important compound having antidepressant and anti-Parkinson properties. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic. There is described herein an improved process for its preparation which avoids several isolation and purification steps required in the prior art.

Description: NOVEL PROCESS 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 4-(4'-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. Previously published processes to paroxetine utilise as a key intermediate the carbinol in which the piperidine nitrogen is protected by a group R, usually an alkyl (typically methyl) or arylalkyl group. The N-substituted piperidine must be coupled with sesamol to make an N-substituted paroxetine analogue which is converted to paroxetine by removal of the nitrogen protecting group. US 4,007,196 Example 1 provides a detailed description of a laboratory scale preparation of trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine, according to which a solution in chloroform of trans-(-)-4-(4-fluorophenyl)-3- hydroxymethyl-1-methylpiperidine is treated with thionyl chloride and the intermediate trans-(-)-4-(4-fluorophenyl)-3-chloromethyl- 1-methylpiperidine is isolated. The chloro compound is reacted with sodium methoxide and sesamol in methanol to produce trans- (-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine, which is isolated as the crystalline hydrochloride salt by extraction into diethyl ether, followed by evaporation, acidification, and crystallisation from ethanol. Example 2 discloses a procedure for the deprotection of this product to prepare paroxetine, by which trans-(-)-4-(4 -fluorophenyl)-3-(3 " ,4 " -methylenedioxyphenoxymethyl)- 1 -methyl piperidine is treated with phenyl chloroformate in dichloromethane, the solvent evaporated, and the intermediate carbamate recrystallised from benzene. The carbamate is hydrolysed by refluxing with KOH in methyl cellusolve, and paroxetine is isolated by adding water and extracting into benzene, which is finally evaporated. US 4,902,801 refers to a process whereby trans-(-)-4-(4-fluorophenyl)-3-hydroxymethyl- 1-methylpiperidine is reacted with thionyl chloride or benzenesulphonyl chloride and then with 3,4-methylenedioxyphenoxide. Subsequently the N-methyl group is replaced by reaction with phenyl chloroformate followed by de-acylation with KOH to obtain paroxetine. No details of solvents or procedure are supplied. Example 1 of EP 0223 403 describes the hydrolysis of trans-(-)4-(4'-fluorophenyl)-3- (3 ',4 -methylenedioxy-phenoxymethyl)-N-phenoxycarbonylpiperidine with potassium hydroxide in refluxing toluene. The resulting solution of paroxetine is treated with concentrated hydrochloric acid to give paroxetine hydrochloride hemihydrate. We have developed a manufacturing process which overcomes the disadvantages in yield, purity, and the use of undesirable solvents inherent in the disclosure of US 4,007,196, by which trans-(-)-4-(4'-fluorophenyl)-3-hydroxymethyl- 1-methylpiperidine is reacted with benzenesulphonyl chloride in dichloromethane and the intermediate sulphonate ester is isolated as a crystalline solid. This ester is then reacted with sesamol and sodium methoxide in N,N -dimethylformamide as a solvent, and the resulting trans-(-)-4-(4 - fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine is isolated as a crystalline solid. This intermediate is demethylated by reaction with phenyl chloroformate in toluene, and the intermediate carbamate is isolated by crystallisation from propan-2-ol. Finally, the carbamate is hydrolysed with KOH in toluene. This process, with its choice of solvents and isolation steps, was developed for robustness in manufacture, high yield, and good purity. In the process of this invention, trans-(-)-4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxy)-l-phenoxycarbonylpiperidine is prepared by a route which surprisingly avoids the need for isolation of the intermediate sulphonyl ester and trans-(-)- 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine. Furthermore, the use of chlorinated solvents is avoided, with benefits to safety and the environment, and a product with an improved impurity profile is obtained. In its broadest aspect, the present invention provides a process for the preparation of a compound of formula (1): where X is an optionally substituted C(i_g) alkyl, aryalkyl, allyl, or alkynyl group, preferably a methyl, ethyl, tertiary butyl, or benzyl group, which comprises preparing a compound of formula (2), in which Y is an optionally substituted alkyl, aryl or arylalkyl sulphonate group, preferably benzenesulphonyloxy, toluenesulphonyloxy, or methylsulphonyloxy, and without isolating compound (2), reacting it with sesamol or a sesamol derivative of sesamol to produce compound (1). Compound (1) may at this stage be isolated and used as an intermediate in the manufacture of paroxetine, for example by converting it by known means into a compound of formula (3), in which R is an optionally substituted C(i _6)alkyl, aryl, allyl, or arylalkyl group. Preferably R is a phenyl, methyl, ethyl, tertiary butyl or benzyl group. In a particularly advantageous aspect of this invention, however, compound (1) is not isolated, but the solution is used directly for the formation of compound (3). Compounds (1) and (3) may be further converted by conventional methods to paroxetine or a salt of paroxetine, preferably the hydrochloride salt and more preferably the crystalline hemihydrate or anhydrate hydrochloride salts.. The process of this invention confers the same advantages of yield and purity as our previous manufacturing process, but with a much more convenient procedure, especially since it may utilise toluene as the main reaction solvent. In addition to the advantages for manufacture inherent in avoiding the use of chlorinated solvents, using fewer types of solvent, and avoiding process steps for changing from one solvent to another and isolating crystalline solids, we have found that the product of the process of this invention has an improved purity. In one embodiment, the method of the invention comprises treating a solution or suspension in toluene or xylene of a 1- substituted 4-(4'-4-fluorophenyl)-3-hydroxymethyl-piperidine (compound (2), where Y is hydroxy and X is as defined above) with an active derivative of a sulphonic acid, for example benzenesulphonyl chloride, methanesulphonyl chloride, or toluensulphonyl chloride in the presence of a base. The compound of structure (2) where X is a methyl group may be prepared by conventional published procedures, such as described in US 4,007,196, Example 1, and US 4,902,801, Examples 5 and 8. These procedures may be adapted using conventional techniques to introduce alternative X groups, such as a phenyl, methyl, ethyl, tertiary butyl or benzyl group. Some starting materials (2) are not very soluble in the solvent, for example (2) where R is methyl requires in excess of 10 litres per kilogramme to dissolve completely, however we have discovered that complete dissolution is not essential and there is no disadvantage to using the starting material as a slurry. Accordingly, a suitable ratio of solvent to starting material is from 3 to 10 litres per kilogramme, preferably from 4 to 8, more preferably from 4.5 to 7.5. Preferably the base is an amine, such as triethylamine, trimethylamine, diethylmethylamine or dimethylethylamine. More preferably, the amine is dimethylethylamine. Suitably from 1 to 3 equivalents of base are used, preferably from 1.4 to 2.3 equivalents, more preferably from 1.5 to 2.0 equivalents. The sulphonic acid derivative is preferably added to the solution slowly at a temperature from -15°C to -ι-15 0 C, more preferably from -5°C to +5°C. Suitably from 0.8 to 2.5 equivalents are used, preferably from 1.1 to 1.9 equivalents, and more preferably from 1.2 to 1.6 equivalents, however the ratio of base to the sulphonic acid derivative should be controlled closely withing the ranges of 1.05 to 1.4 to 1, preferably about 1.2 to 1. The time of addition is suitably from 0.5 to 3 hours, preferably from 1 to 2 hours. If a temperature below 10°C is used for the addition, it is advantageous to allow the reaction mixture to warm up to from 10°C to 15°C after the addition is complete and to stir for an additional 0.5 to 2 hours. Once the reaction is complete, excess sulphonating agent may be destroyed by means of an aqueous quench. Although a quench with water may be used, we have found that a precipitate can form which makes phase separation difficult, and use of a dilute aqueous base, suitably dilute sodium hydroxide solution, is preferred. Suitably a quench volume from 3 to 6 litres per kilogramme of starting material is used, but this is not critical. High temperatures are undesirable for stability of the sulphonate intermediate (2), so a quench temperature of from 10°C to 15°C is preferred. Suitably the mixture is stirred vigorously for from 10 to 30 minutes, then the phases separated and the aqueous phase discarded. The reaction with sesamol is not particularly sensitive to water, so the organic phase after quenching may be used without further treatment, but we have found that some impurities are reduced if a drying step is added, either with anhydrous magnesium sulphate followed by filtration, or by azeotropic distillation. We have discovered that the coupling reaction with sesamol may be carried out in toluene or xylene, as used in the previous stage. However it is advantageous to use an additional solvent since this permits a more complete reaction in a shorter time and at lower temperature, hence with reduced side reactions. If an additional solvent is used, it is convenient to reduce the volume of the first solvent to improve vessel occupancy, and this may be achieved in the same process step as azeotropic drying. The additional solvent should be one that increases the overall polarity of the solvent mixture, for example, N,N - dimethylformamide, acetone, dimethylsulphoxide, or tetrahydrofuran, preferably one that is easily removed from toluene and xylene, most preferably it is N,N'-dimethylformamide. The additional solvent may be used in any proportion, and the benefits of shorter time and lower temperature are obtained in approximate proportion to the amount used up to a ratio of about 1: 1. However, a high ratio, particularly of N,N -dimethylformamide, can lead to loss of yield during work-up. In the case of toluene and N,N -dimethylformamide mixtures, a suitable volume of N,N -dimethylformamide as a proportion of the volume of the toluene phase is from 1: 10 to 1:1, preferably from 1:4 to 1:2. A suitable total solution volume at this stage is from 5 to 15 litres per kilogramme of starting material, preferably from 7 to 11, more preferably from 8 to 10. The reaction of compound (2) with sesamol is typically carried out in the presence of a base. Suitable bases are alkali metal hydroxides and alkoxides, for example sodium or potassium methoxide or hydroxide. We have found that sodium methoxide is quick to dissolve in the reaction medium, whereas sodium hydroxide pellets dissolve slowly. If sodium or potassium hydroxide is to be used, it is advantageous to use it in the form of a flake. The base may be added to the solution of compound (2) and sesamol, or the base and sesamol may be dissolved in the additional solvent, for example N,N - dimethylformamide, and added to the solution of compound (2). Suitably, the amount of sesamol is from 0.9 to 1.5 equivalents of the starting material, preferably from 1.0 to 1.2 equivalents, and the amount of base used is sufficient to form the sesamolate, suitably the base is equimolar to the sesamol. The base is advantageously added to the compound (2) and sesamol solution in portions, for example in three approximately equal portions, over a period of from 15 minutes to 2 hours, preferably from 30 minutes to 1 hour. Alternatively, the pre-formed sesamolate solution is added over the same time period. We have found that a small amount of water increases the rate of reaction, particularly where alkoxides are used as the base, for example from 0.1 to 1 molar equivalents, preferably from 0.2 to 0.4. A suitable temperature for the addition is from 40°C to 70°C, preferably from 40°C to 60°C. Higher temperatures are undesirable since the sulphonate ester may begin to degrade. When the addition is complete, the reaction temperature may be raised to ensure complete reaction, for example from 70 to 100°C, though high temperatures can cause discoloration and generation of impurities. In general, stirring at a temperature of 70- 75°C for from 1 to 4 hours is sufficient, preferably from 1 to 2 hours. At this stage, compound (1) may be isolated as a crystalline solid, for example by evaporation to remove the more volatile solvents and trituration with a suitable solvent. For example, trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l- methyl piperidine prepared in a mixture of toluene and N,N'-dimethylformamide may be isolated by evaporating the toluene and adding water to the residue. If the N,N'- dimethylformamide solution is allowed to cool before addition of water, the product is obtained as an oil, which may solidify, but may also entrain impurities. Water should be added to a warm N,N'-dimethylformamide solution which is then allowed to cool, whereupon a purer crystalline product is obtained, which can be isolated by filtration, washing with water and drying under vacuum. For example, the reaction mixture is warmed to about 50°C and a total of about 2 volumes of water is added over the course of 2-6, typically about 4, hours maintaining the temperature at or around this level. The mixture is allowed to cool to around 20°C, whereupon the product begins to crystallise out of solution. However, the most advantageous embodiment of this invention, particularly if the coupling is carried out in a toluene N,N'-dimethylformamide solvent mixture, is to proceed to the conversion of compound (1) into compound (3) in the same solvent as that used for the sulphonate ester formation. After the coupling reaction is complete, the mixture is cooled, suitably to from 40 to 60°C, and washed to remove excess reagents and by-products. A suitable washing regime is a water wash followed by an aqueous sodium hydroxide wash (suitably from 1 to 3 molar) and a final water wash. This also has the effect of removing N,N -dimethylformamide. Suitable volumes for the three washes are 5, 3, and 2 litres per kilogramme of starting material, though these are not critical and the procedure may be varied. At this point compound (1) may be isolated from the organic solution by evaporation, but advantageously the solution is dried, for example by by azeotropic distillation, and then treated directly with a haloformate of formula Hal-CO 2 R', where R' is an optionally substituted alkyl, arylalkyl or aryl group, preferably, the haloformate is phenyl chloroformate. Preferably the reaction is carried out at a temperature of 50-100°C, more preferably at from 55-70°C, most preferably from 58 to 68°C. Preferably, the solvent is toluene or xylene. Most preferably the solvent is toluene. The concentration of compound (1) is suitably from 1 kg in 3 litres to 1 kg in 10 litres, preferably about 1 kg in 5 litres. Preferably, the water content of the toluene solution should be less than 0.05% w/w. Alternatively, or additionally, this level may be conveniently achieved by heating the compound of formula (1) in the reaction solvent to reflux at around 65°C under reduced pressure or at atmospheric pressure to remove the solvents by distillation. Dean & Stark conditions have also been successfully used. Preferably the chloroformate is free of HC1 and water. Whilst following the prior art procedures the chloroformate can be added as a solution in toluene, preferably, it is added undiluted. Whilst EP-0 810 225 indicates that the presence of a base is essential for a successful conversion to the carbonate, this has not been found to be the case under the reaction conditions outlined above, certainly with organic bases which have led to lower yields and purities. Whilst not seeking to exclude the use of bases, their presence has been found to be largely unnecessary. Under the conditions described above, the reaction is very fast, typically being complete within about 1 - 2 hours. This is a considerable advantage over the prior art which mentions periods of 1 - 3 days in toluene. Yields are also very much improved, being in the order of 80-95%, compared with the 33% yield of EP-0 810 225. Whilst EP-0 810 225 merely filters and evaporates the reaction mixture to produce the crude carbamate (3), US 4 007 196 and EP 152 273 wash the solution with aqueous NaOH and then dilute HC1 before drying and evaporating to obtain the carbamate. It has been found that after cooling to around 20°C (room temperature), quenching with 10% aq. sulphuric acid provides surprising advantages. It removes unreacted starting material (compound of formula (2)) more efficiently than hydrochloric acid. It is also effective at hydrolysing unreacted phenyl chloroformate so affording a cheap and effective one step purification, ideally suited to commercial manufacture. This process step is more widely applicable to paroxetine analogues generally and forms another aspect of the present invention. In addition, the sulphate of the starting compound (formula (2)) is insoluble in both the organic and inorganic phases. As such, one would not anticipate that excess starting material could be removed by the quenching step described above. However, it has been found that the sulphate is, in fact, associated with the aqueous phase, as a distinct phase and so can be easily removed, for example, by phase separation. The non-aqueous phase is then washed, optionally more than once, with water at ambient temperature - a suitable volume for each water wash is from 1 : 10 of the solvent volume to 1 :2, preferably from 1:5 to 1:8, optionally dried, and filtered, preferably with use of a filter agent such as celite. 7> γ .?-(-)-4-(4-fluorophenyl)-3-(3 ',4'-methylenedioxyphenoxymethyl)- 1 -phenoxy carbonylpiperidine is a difficult compound to isolate in a pure form and no satisfactory isolation method has been provided in existing publications. Distillation under vacuum removes the toluene and leaves an oil or unmanageable solid lump, and such processes can only be used on the laboratory scale. However efficient removal of solvent from an oil is difficult to achieve on the manufacturing scale, and is time consuming and expensive. The resulting oil or lump is difficult to remove from the distillation vessel and is not suitable for storage as an intermediate. In an industrial context, this means that stockpiling is not conveniently possible, and this greatly reduces the flexibility of plant utilisation. It has now been determined that a crystalline form of the product can be prepared and this overcomes the disadvantages mentioned above. After most of the toluene has been removed (complete removal of toluene is no longer necessary), hot propan-2-ol is added to dissolve the residue, and the solution cooled to give a crystalline solid with improved purity and handling properties. A similar result can be achieved by progressively replacing toluene by fresh propan-2-ol during the course of the azeotropic distillation . This variation offers an advantage in that it allows manufacturing apparatus to be used which can only remove a smaller proportion of the total solvent. Crystallisation from propan-2-ol provides a mobile slurry suitable for transfer and filtration using convenient industrial apparatus. Ethanol or denatured industrial methylated spirits may also be used. Any novel intermediates obtained using the process of the invention form a further aspect of the invention. The process of this invention may be used to prepare active compounds described in US- A-3912743 and US-A-4007196, and preferably to prepare paroxetine. Paroxetine may be used as the free base, but is preferably obtained as or converted to a pharmaceutically acceptable derivative such as a salt, more especially the hydrochloride salt and most preferably 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 is the (-)-trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. Following the procedure of EP-0 152 273, optical resolution may be carried out prior to coupling with the phenol. Alternatively, resolution may be carried out at other stages, such as after deprotection of the piperidine nitrogen Paroxetine obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595, 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". The compositions prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention. The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day. Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents. Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or a pharmaceutically acceptable salt of paroxetine obtained using the process of this invention and a pharmaceutically acceptable carrier, the use of paroxetine or pharmaceutically acceptable salt of paroxetine obtained using the process of this invention to manufacture a medicament 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 pharmaceutically acceptable salt of paroxetine obtained using the process of this invention to a person suffering from one or more of the disorders. This invention is illustrated by the following Examples. Trans-(-)-4-(4-fluorophenyl)-3- hydroxymethyl- 1-methylpiperidine used as a starting material may be prepared as described in US 4,007,196 or US 4,902,801 mentioned above. Example 1 Toluene (210 ml) was charged to a clean, dry 500 ml jacketed vessel fitted with an overhead stirrer and a glycol circulator, and trans-(-)-4-(4-fluorophenyl)-3- hydroxymethyl- 1-methylpiperidine was added (35.10 g, 96.07% w/w purity) with stirring to ensure dissolution. The vessel contents were cooled to 5°C and dimethylethylamine (25.5 ml) was added, and then a nitrogen purge was attached and the vessel contents further cooled to 0°C. A mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) was added slowly from a headflask over 70 minutes, maintaining the temperature between -2°C and +2°C. On completion of the addition, the mixture was stirred for 20 minutes, allowing the temperature to rise to 10°C. A mixture of saturated brine (105 ml) and sodium hydroxide (3.5 g) dissolved in water (105 ml) was charged to the vessel over 10 minutes and stirred for 15 minutes at 10°C. The mixture was left to settle for 15 minutes and the aqueous phase (229 ml) was separated. The aqueous phase was washed with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (5.1 g) for 10 minutes. The solution was then filtered and the magnesium sulphate washed with toluene (10 ml). Approximately 100 ml of toluene was then removed by low pressure distillation, to leave about 200 ml of a dry solution of sulphonate ester in toluene. This solution was transferred to a clean, dry vessel, and N,N - dimethylformamide (100 ml) was added. This mixture was stirred, warmed to 50°C, and a solution of sesamol (22.8g) and sodium methoxide (9.33 g) in N,N -dimethylformamide (50 ml) was added over 20 minutes. Water (0.85 ml) was added and the mixture heated to 70°C, and stirred at that temperature for 1 hour. After cooling to 50°C, water (250 ml) was added, and the mixture stirred for 15 minutes, allowed to settle, and the aqueous phase removed. The aqueous phase was washed with toluene (50 ml) and the combined toluene phases washed with 2.5 molar aqueous sodium hydroxide solution (2 x 100 ml) and water (100 ml). The resulting toluene phase was then dried over anhydrous magnesium sulphate (10.4 g), filtered, and the magnesium sulphate washed with toluene (25 ml). The toluene was removed by distillation at reduced pressure to form a pale yellow solid, which was dried in a vacuum oven (40°C) overnight. Trans-(-)-4-(4 -fiuorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine: 47.29 g, 87.6% weight yield, purity 96.4%. Example 2 Toluene (210 ml) was charged to a clean, dry 500 ml jacketed vessel fitted with an overhead stirrer and a glycol circulator, and trans-(-)-4-(4-fluorophenyl)-3- hydroxymethyl- 1-methylpiperidine was added (35.08 g, 96.07% w/w purity) with stirring to ensure dissolution. The vessel contents were cooled to 5°C and dimethylethylamine (25.5 ml) was added, and then a nitrogen purge was attached and the vessel contents further cooled to 0°C. A mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) was added slowly from a headflask over 85 minutes, maintaining the temperature between -2°C and +2°C. On completion of the addition, the mixture was stirred for 30 minutes, allowing the temperature to rise to 10°C. A mixture of saturated brine (105 ml) and sodium hydroxide (3.5 g) dissolved in water (105 ml) was charged to the vessel and stirred for 15 minutes at 10°C. The mixture was left to settle for 15 minutes and the aqueous phase (288 ml) was separated. The aqueous phase was washed with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (6.2 g) for 10 minutes. The solution was then filtered and the magnesium sulphate washed with toluene (10 ml). Approximately 100 ml of toluene was then removed by low pressure distillation, to leave about 200 ml of a dry solution of sulphonate ester in toluene. This solution was transferred to a clean, dry vessel, and N,N'-dimethylformamide (100 ml) was added. This mixture was stirred, warmed to 50°C, and a solution of sesamol (22.7 g) and sodium hydroxide (6.97 g) in N,N'-dimethylformamide (50 ml) was added over 25 minutes. Water (0.85 ml) was added and the mixture heated to 70°C, and stirred at that temperature for 2 hours. After cooling to 50°C, water (250 ml) was added, and the mixture stirred for 15 minutes, allowed to settle, and the aqueous phase removed. The aqueous phase was washed with toluene (50 ml) and the combined toluene phases washed with 2.5 molar aqueous sodium hydroxide solution (2 x 100 ml) and water (100 ml). The resulting toluene phase was then dried over anhydrous magnesium sulphate (10.4 g), filtered, and the magnesium sulphate washed with toluene (25 ml). The toluene was removed by distillation at reduced pressure to form a pale yellow solid, which was dried in a vacuum oven overnight. Trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine: 47.3 g, 87.7% weight yield, purity 90.8%. 25 g of the above material was dissolved in hot propan-2-ol (185 ml), and cooled to 2°C over 4 hours. Water (300 ml) was added over 60 minutes, and the crystallising slurry stirred for a further 1 hour at 2°C. The product was isolated by filtration, washed with propan-2-ol (2 x 185 ml), and dried under vacuum. Yield: 22.9 g, 91.6%. Purity: 98.4%. Example 3 Toluene (210 ml) was charged to a clean, dry 500 ml jacketed vessel fitted with an overhead stirrer and a glycol circulator, and trans-(-)-4-(4-fluorophenyl)-3- hydroxymethyl- 1-methylpiperidine was added (35.08 g, 96.07% w/w purity) with stirring to ensure dissolution. The vessel contents were cooled to 5°C and dimethylethylamine (25.5 ml) was added, and then a nitrogen purge was attached and the vessel contents further cooled to 0°C. A mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) was added slowly from a headflask over 75 minutes, maintaining the temperature between -2°C and +2°C. On completion of the addition, the mixture was stirred for 30 minutes, allowing the temperature to rise to 10°C. Water (210 ml) was charged to the vessel over 5-10 minutes and stirred for 15 minutes at 10°C. The mixture was left to settle for 15 minutes and the aqueous phase was separated. The aqueous phase was washed with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (11 g) for 10 minutes. The solution was then filtered and the magnesium sulphate washed with toluene (10 ml). Approximately 100 ml of toluene was then removed by low pressure distillation, to leave about 200 ml of a dry solution of sulphonate ester in toluene. This solution was transferred to a clean, dry vessel, and N,N'- dimethylformamide (100 ml) was added. This mixture was stirred, warmed to 50°C, and a solution of sesamol (22.7g) and sodium methoxide (9.32 g) in N,N'-dimethylformamide (50 ml) was added over 25 minutes. Water (0.85 ml) was added and the mixture heated to 70°C, and stirred at that temperature for 70 minutes. After cooling to 65°C, water (250 ml) was added, and the mixture stirred for 15 minutes, allowed to settle, and the aqueous phase removed. The toluene phase was washed with 2.5 molar aqueous sodium hydroxide solution (2 x 100 ml) and water (100 ml). The resulting toluene phase was then dried over anhydrous magnesium sulphate ( 10 g), filtered, and the magnesium sulphate washed with toluene (25 ml). The toluene solution containing trans-(-)-4-(4 -fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)- 1 -methyl piperidine was diluted with toluene to a volume of 250 ml and charged to a clean, dry vessel. The vessel contents were heated to 62°C, and phenyl chloroformate (19 ml, 97% purity) was added over 35-40 minutes. On completion of the addition, the headflask was flushed with toluene (15 ml) and the wash added to the vessel. The resulting mixture was stirred at 62°C for 65 minutes and then cooled to 20°C over 70 minutes. A solution of concentrated sulpuric acid (6 ml) in water (57 ml) was added to the vessel over 5 minutes. The vessel contents were stirred for 10 minutes and then left to settle for 10 minutes at 20°C. The lower phase was separated off, water (78 ml) added, and the mixture stirred for 10 minutes. After settling for 10 minutes, the lower aqueous phase was removed and the toluene phase washed again with water (78 ml). The toluene phase was stirred with celite (1.3 g), filtered, and the filtrate evaporated at reduced pressure to an oil. Hot propan-2-ol (260 ml) was added, and distillation continued to form an oil again. A further 340 ml of hot propan-2-ol was added, and a white crystalline suspension formed, which was was transferred to a clean, dry vessel, and washed in with propan-2-ol (20 ml). The suspension was cooled to 0-5°C, and stirred for 3 hours at 0°C. The resulting product was isolated by vacuum filtration, washed with propan-2-ol (80 ml), and dried overnight in a vacuum oven (50°C). Yield of trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxy)-l- phenoxycarbonylpiperidine: 43.01 g. Example 4 An automated laboratory reactor (Lab Max) was programmed to a jacket temperature of 20°C and an agitation rate of 150 r.p.m. Toluene (300 ml) and trans-(-)-4-(4- fluorophenyl)-3-hydroxymethyl- 1-methylpiperidine (50.09 g) were charged to the vessel and the solution temperature was lowered to 5°C over 10 minutes, then dimethylethylamine (56.6 ml) was charged to the vessel and the solution temperature was lowered to 0°C over 5 minutes. A mixture of benzenesulphonyl chloride and toluene (50:50 by volume, 112.45 g) was added to the vessel over 60 minutes, maintaining the solution temperature at 0°C. On completion of the addition, the solution was warmed to 10°C over 30 minutes and stirred for 10 minutes. A solution of sodium hydroxide in water (2%, 225 g) was added to the reactor over 15 minutes and the mixture stirred for 10 minutes then left to settle. After 10 minutes, the aqueous phase was removed and the volume of the toluene phase was reduced to 239 ml by evaporation at reduced pressure. Fresh toluene was added to make the volume up to 300 ml, then N,N'-dimethylformamide (160 ml) was added, the temperature adjusted to 55°C over 20 minutes, and the agitator speed increased to 175 r.p.m. A mixture of sesamol (37.18 g and N,N - dimethylformamide (70 ml) was added to the vessel, and after 5 minutes the first portion of sodium methoxide (5.08 g). After stirring for 10 minutes a second portion of sodium methoxide (5.08 g) was added, and after another 15 minutes stirring the final portion of sodium methoxide (4.55 g) was added. On completion of the addition, the reaction temperature was raised to 70°C over 15 minutes and the mixture stirred for 90 minutes. The reaction temperature was then lowered to 50°C over 15 minutes, water (225 ml) added over 20 minutes, and the mixture stirred at 50°C for 10 minutes. Stirring was then stopped, the mixture allowed to settle for 5 minutes, and the aqueous phase was removed. A solution of sodium hydroxide in water was added (10%, 150 ml); the mixture was stirred at 50°C for 10 minutes, left to settle for 5 minutes, and the aqueous phase removed. After a final water wash (100 ml), with 10 minutes stirring at 50°C, 5 minutes settling time, and removal of the aqueous phase, the toluene phase was dried over anhydrous magnesium sulphate (15 g). The toluene solution was filtered and the solid material washed through with toluene (15 ml), then the solvent was removed by evaporation at reduced pressure. The resulting solid product was dried in a vacuum oven (40°C) overnight. Yield of trans-(-)-4-(4 -fluorophenyl)-3-(3 ",4"-methylenedioxyphenoxymethyl)- 1 -methyl piperidine: 67.91 g, 88.2% by weight. Purity 94.4%. Example 5 The procedure of Example 4 was repeated with variations in the following parameters: Amount of benzenesulphonyl chloride charge: 1.35 equivalents, 1.75 equivalents, and 1.55 equivalents. Stirring time post benzenesulphonyl chloride addition: 40 minutes, 120 minutes, 80 minutes. Weight yields between 86.2% and 88.2% and purities between 91.2% and 95.4% were obtained. Example 6 An automated laboratory reactor (Lab Max) was programmed to a jacket temperature of 20°C and an agitation rate of 150 r.p.m. Toluene (230 ml) and trans-(-)-4-(4- fluorophenyl)-3-hydroxymethyl- 1-methylpiperidine (50.04 g) were charged to the vessel and the solution temperature was lowered to 5°C over 10 minutes, then dimethylethylamine (48.5 ml) was charged to the vessel and the solution temperature was lowered to 0°C over 5 minutes. A mixture of benzenesulphonyl chloride and toluene (50:50 by volume, 98.4g) was added to the vessel over 60 minutes, maintaining the solution temperature at 0°C. On completion of the addition, the solution was warmed to 10°C over 30 minutes. A solution of sodium hydroxide in water (2%, 300 g) was added to the reactor over,T5 minutes and the mixture stirred for 10 minutes then left to settle. After 10 minutes, the aqueous phase was removed and the the toluene phase dried by evaporation at reduced pressure. Fresh toluene was added to make the volume up to 300 ml, then N,N -dimethylformamide (160 ml) was added, the temperature adjusted to 40°C over 20 minutes, and the agitator speed increased to 175 r.p.m. A mixture of sesamol (37.11 g), N,N -dimethylformamide (70 ml), and sodium methoxide (14.52 g) was added to the vessel over a period of 45 minutes. On completion of the addition, the reaction temperature was raised to 70°C over 15 minutes and the mixture stirred for 120 minutes. The reaction temperature was then lowered to 50°C over 15 minutes, water (300 ml) added over 20 minutes, and the mixture stirred at 50°C for 10 minutes. Stirring was then stopped, the mixture allowed to settle for 5 minutes, and the aqueous phase was removed. A solution of sodium hydroxide in water was added (10%, 100 ml); the mixture was stirred at 50°C for 10 minutes, left to settle for 5 minutes, and the aqueous phase removed. The toluene phase was dried over anhydrous magnesium sulphate (15 g), filtered and the solid material washed through with toluene (15 ml), then the solvent was removed by evaporation at reduced pressure. The resulting solid product was dried in a vacuum oven (40°C) overnight. Yield of trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine: 85.3% by weight. Purity 93.99%. Example 7 An automated laboratory reactor (Lab Max) was programmed to a jacket temperature of 20°C and an agitation rate of 150 r.p.m. Toluene (230 ml) and trans-(-)-4-(4- fluorophenyl)-3 -hydroxymethyl- 1-methylpiperidine (50.04 g) were charged to the vessel and the solution temperature was lowered to 5°C over 10 minutes, then dimethylethylamine (48.5 ml) was charged to the vessel and the solution temperature was lowered to 0°C over 5 minutes. A mixture of benzenesulphonyl chloride and toluene (50:50 by volume, 98.4 g) was added to the vessel over 120 minutes, maintaining the solution temperature at 0°C. On completion of the addition, the solution was warmed to 10°C over 30 minutes and stirred for another 30 minutes. A solution of sodium hydroxide in water (2%, 150 g) was added to the reactor over 15 minutes and the mixture stirred for 10 minutes then left to settle. After 10 minutes, the aqueous phase was removed and the the toluene phase dried over anhydrous magnesium sulphate, filtered and the cake washed with toluene (15 ml). Fresh toluene was added to make the volume up to 300 ml, then N,N'-dimethylformamide (160 ml) was added, the temperature adjusted to 40°C over 20 minutes, and the agitator speed increased to 175 r.p.m. A mixture of sesamol (37.11 g), N,N -dimethylformamide (70 ml), and sodium methoxide (14.52 g) was added to the vessel over a period of 45 minutes. On completion of the addition, the reaction temperature was raised to 70°C over 15 minutes and the mixture stirred for 60 minutes. The reaction temperature was then lowered to 50°C over 15 minutes, water (150 ml) added over 20 minutes, and the mixture stirred at 50°C for 10 minutes. Stirring was then stopped, the mixture allowed to settle for 5 minutes, and the aqueous phase was removed. A solution of sodium hydroxide in water was added (10%, 200 ml); the mixture was stirred at 50°C for 10 minutes, left to settle for 5 minutes, and the aqueous phase removed. After a final water wash (150 ml), with 10 minutes stirring at 50°C, 5 minutes settling time, and removal of the aqueous phase, the toluene phase was dried over anhydrous magnesium sulphate (15 g). The toluene solution was filtered and the solid material washed through with toluene (15 ml), then the solvent was removed by evaporation at reduced pressure. The resulting solid product was dried in a vacuum oven (40°C) overnight. Yield of trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methyienedioxyphenoxymethyl)-l-methyl piperidine: 84.4%) by weight. Purity 98.67%. Example 8 An automated laboratory reactor (Lab Max) was programmed to a jacket temperature of 20°C and an agitation rate of 150 r.p.m. Toluene (370 ml) and trans-(-)-4-(4- fluorophenyl)-3-hydroxymethyl- 1-methylpiperidine (50.08 g) were charged to the vessel and the solution temperature was lowered to 5°C over 10 minutes, then dimethylethylamine (36.5 ml) was charged to the vessel and the solution temperature was lowered to 0°C over 5 minutes. A mixture of benzenesulphonyl chloride and toluene (50:50 by volume, 78.7 g) was added to the vessel over 120 minutes, maintaining the solution temperature at 0°C. On completion of the addition, the solution was warmed to 10°C over 30 minutes. A solution of sodium hydroxide in water (2%, 150 g) was added to the reactor over 15 minutes and the mixture stirred for 10 minutes then left to settle. After 10 minutes, the aqueous phase was removed and the volume of the toluene phase dried by evaporation at reduced pressure. Fresh toluene was added to make the volume up to 300 ml, then N,N -dimethylformamide (160 ml) was added, the temperature adjusted to 40°C over 20 minutes, and the agitator speed increased to 175 r.p.m. A mixture of sesamol (37.1 1 g and N,N -dimethylformamide (70 ml) was added to the vessel, and after 5 minutes the first portion of sodium methoxide (5.0 g). After stirring for 10 minutes a second portion of sodium methoxide (5.0 g) was added, and after another 15 minutes stirring the final portion of sodium methoxide (4.52 g) was added. On completion of the addition, the reaction temperature was raised to 70°C over 15 minutes and the mixture stirred for 120 minutes. The reaction temperature was then lowered to 50°C over 15 minutes, water (150 ml) added over 20 minutes, and the mixture stirred at 50°C for 10 minutes. Stirring was then stopped, the mixture allowed to settle for 5 minutes, and the aqueous phase was removed. A solution of sodium hydroxide in water was added (10%, 100 ml); the mixture was stirred at 50°C for 10 minutes, left to settle for 5 minutes, and the aqueous phase removed. After a final water wash (150 ml), with 10 minutes stirring at 50°C, 5 minutes settling time, and removal of the aqueous phase, the toluene phase was dried over anhydrous magnesium sulphate (15 g). The toluene solution was filtered and the solid material washed through with toluene (15 ml), then the solvent was removed by evaporation at reduced pressure. The resulting solid product was dried in a vacuum oven (40°C) overnight. Yield of trans-(-)-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l-methyl piperidine: 85.4% by weight. Purity 97.0%. Example 9 The procedure of Example 4 was repeated with variations in the following parameters: Volume of dimethylethylamine: 36.5 ml/48.5 ml/42.5 ml Volume of benzenesulphonyl chloride/toluene charge: 78.7 g/98.4 g/88. g Benzenesulphonyl chloride/toluene addition time: 60 min/120 min/90 min Stirring time after benzenesulphonyl chloride addition at 10°C: 0 min/15 min/30 min Volume of 2% NaOH quench: 150 ml/300 r 7225 ml Volume of toluene after evaporation: 300 ml/400 ml/350 ml DMF volume: 160ml/60ml 110ml Temperature of sesamol addition: 40°C/70°C/55°C Weight of sesamol: 30.93 g/37.11 g/34.02 g Weight of sodium methoxide: 4.0 g,4.0 g,4.1 g/5.0 g,5.0 g,4.52 g/4.5 g,4.5 g,4.31 g Stirring time at 70°C: 60 min/120 min/90 min Water charge: 150 ml/300 ml/225 ml Caustic wash: 100 ml/ 150 ml/75 ml Weight yields ranged from 81.5-89.3% Purities ranged from 48.9-98.7%

Claims: CLAIMS 1. A process for the preparation of a compound of formula (1): where X is an optionally substituted C _6) alkyl, aryalkyl, allyl, or alkynyl group, which comprises preparing a compound of formula (2), in which Y is an optionally substituted alkyl, aryl or arylalkyl sulphonate group, and without isolating compound (2), reacting it with sesamol or a derivative of sesamol. 2. A process as claimed in claim 1 in which compound (1) is isolated and reacted with a haloformate to prepare a compound of formula (3) in which R is an optionally substituted C(i_6)alkyl, aryl, allyl, or arylalkyl group. 3. A process as claimed in claim 1 in which compound (1) is not isolated, but the solution istused directly for reaction with a haloformate to prepare a compound of formula (3) in which R is an optionally substituted Cn .g- j alkyl, aryl, allyl, or arylalkyl group. 4. A process as claimed in claim 2 or 3 in which R is a phenyl, methyl, ethyl, tertiary butyl or benzyl group. 5. A process as claimed in any one of claims 1 to 4 in which X is a methyl, ethyl, tertiary butyl, or benzyl group. 6. A process as claimed in any one of claims 1 to 5 in which Y is a benzenesulphonyloxy, toluenesulphonyloxy, or methylsulphonyloxy group. 7. A process as claimed in claim 1, 2 or 3 in which X is a methyl group, Y is a benzenesulphonyloxy group, and R is a phenyl group. 8. A process as claimed in any one of claims 1 to 7 which comprises treating a solution or suspension in toluene or xylene of a 1 -substituted 4-(4 '-4-fluorophenyl)-3-hydroxymethyl- piperidine (compound (2), where Y is hydroxy) with an active derivative of a sulphonic acid, for example benzenesulphonyl chloride, methanesulphonyl chloride, or toluensulphonyl chloride in the presence of a base. 9. A process as claimed in claim 8 in which the ratio of solvent to starting material is between 3 and 10 litres per kilogramme, preferably between 4 and 8, more preferably between 4.5 and 7.5. 10. A process as claimed in claim 8 or 9 in which the base is an amine, preferably triethylamine, trimethylamine, diethylmethylamine or dimethylethylamine, more preferably, the amine is dimethylethylamine. 11. A process as claimed in any one of claims 8 to 10 in which between 1 and 3 equivalents of base are used, preferably between 1.4 and 2.3 equivalents, more preferably between 1.5 and 2.0 equivalents. 12. A process as claimed in any one of claims 8 to 11 in which the sulphonic acid derivative is added to the solution at a temperature between -15°C and +15°C, more preferably between -5°C and +5°C. 13. A process as claimed in any one of claims 8 to 12 in which between 0.8 and 2.5 equivalents of the sulphonic acid derivative are used, preferably between 1.1 and 1.9 equivalents, and more preferably between 1.2 and 1.6 equivalents. 14. A process as claimed in any one of claims 8 to 13 in which the molar ratio of base to sulphonic acid derivative is between 1.05 to 1.4 to 1, preferably about 1.2 to 1. 15. A process as claimed in any one of claims 8 to 14 in which the time of addition of the sulphonic acid derivative is between 0.5 and 3 hours, preferably between 1 and 2 hours. 16. A process as claimed in any one of claims 8 to 16 in which, after the addition of the sulphonic acid derivative, the reaction mixture is allowed to warm up to between 10°C and 20°C and stirred for a further 0.5 to 2 hours. 17. A process as claimed in any one of claims 8 to 16 in which excess sulphonating agent is destroyed by means of an aqueous quench. 18. A process as claimed in claim 17 in which the aqueous quench is a dilute aqueous base, preferably dilute sodium hydroxide solution between 1 and 10% concentration, more preferably between 1 and 3%. 19. A process as claimed in claim 17 or 18 in which the quench volume is between 3 and 6 litres per kilogramme of starting material. 20. A process as claimed in any one of claims 17 to 19 in which the quench temperature is between 10°C and 15°C. 21. A process as claimed in any one of claims 1 to 20 in which the solution of sulphonate ester (2) is dried by means of a drying agent such as anhydrous sodium or magnesium sulphate, or by azeotropic distillation. 22. A process as claimed in any one of claims 1 to 21 in which the coupling reaction of sulphonate ester (2) with sesamol is carried out in toluene or xylene, as used for the formation of the sulphonate ester (2), but with a co-solvent. 23. A process as claimed in claim 22 in which the co-solvent is one that increases the overall polarity of the solvent mixture, for example and is easily separated from toluene or xylene. 24. A process as claimed in claim 22 in which the solvent is N,N -dimethylformamide, acetone, dimethylsulphoxide, or tetrahydrofuran. 25. A process as claimed in claim 22 in which the co-solvent is N,N -dimethylformamide. 26. A process as claimed in any one of claims 22 to 25 in which the co-solvent to primary solvent ratio is between 1: 10 and 1: 1, preferably between 1 :4 and 1 :2. 27. A process as claimed in any one of claims 22 to 26 in which the total solution volume for the coupling reaction with sesamol is between 5 and 15 litres per kilogramme of starting material, preferably between 7 and 11, more preferably between 8 and 10. 28. A process as claimed in any one of claims 1 to 27 in which the reaction of compound (2) with sesamol is carried out in the presence of a base. 29. A process as claimed in claim 28 in which the base is an alkali metal hydroxide or alkoxide. 30. A process as claimed in claim 28 or 29 in which the base is sodium methoxide. 31. A process as claimed in claim 28 or 29 in which the base is sodium hydroxide. 32. A process as claimed in claim 29 or 31 in which the alkali metal hydroxide is used in the form of flake. 33. A process as claimed in any of claims 1 to 32 in which the base is added to the solution of compound (2) and sesamol as a solid. 34. A process as claimed in claim 33 in which the solid base is added in portions, for example in 3 portions. 35. A process as claimed in any one of claims 28 to 32 in which the base and sesamol are dissolved in the co-solvent and added to the solution of compound (2). 36. A process as claimed in any one of the previous claims in which the amount of sesamol used in the coupling reaction is between 0.9 and 1.5 equivalents of the starting material, preferably between 1.0 and 1.2 equivalents 37. A process as claimed in any one of claims 28 to 37 in which the amount of base used is sufficient to convert all the sesamol to the sesamolate, suitably an approximately equimolar quantity. 38. A process as claimed in any one of the previous claims in which the base is added to the solution of compound (2) over a period of between 15 minutes and 2 hours, preferably between 30 minutes and 1 hour. 39. A process as claimed in any one of the previous claims in which a small amount of water is added to the coupling reaction mixture after the addition of the base. 40. A process as claimed in claim 39 in which the amount of water added is between 0.1 and 1 molar equivalents, preferably between 0.2 and 0.4. 41. A process as claimed in any one of the previous claims in which the sesamol is added to the compound (2) solution at a temperature between 40°C and 70°C, preferably between 40°C and 60°C. 42. A process as claimed in any one of the previous claims in which, after the addition is complete, the reaction temperature is raised to between 70°C and 100°C, preferably between 70°C -75°C. 43. A process as claimed in claim 42 in which the reaction mixture is stirred at the elevated temperature for between 1 and 4 hours, preferably between 1 and 2 hours. 44. A process as claimed in any one of the previous claims in which compound (1) is ' isolated as a crystalline solid by evaporation to remove the more volatile solvents and trituration with a suitable solvent, for example water. 45. A process as claimed in any one of the previous claims in which trans-(-)-4-(4'- fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)-l -methyl piperidine is isolated from a mixture of toluene and N,N -dimethylformamide by evaporating the toluene and adding water to the residue. 46. A process as claimed in claim 45 in which the water is added to the reaction mixture at a temperature of between 35°C and 65°C, preferably about 50°C. 47. A process as claimed in claim 45 or 46 in which the water is added slowly, preferably over the course of 2 to 6 hours, more preferably between 3 and 5 hours, in a quantity sufficient to ensure substantially complete crystallisation after cooling to below 20°C, typically between 2 and 4 volumes. 48. A process as claimed in any one of claims 1 to 43 in which compound (1) is converted into compound (3) in substantially the same solvent as that used for the sulphonate ester formation. 49. A process as claimed in claim 48 in which, after the coupling reaction is complete, the reaction mixture is cooled, suitably to between 40 and 60°C, and washed to remove excess reagents and by-products. 50. A process as claimed in claim 49 in which the coupling reaction mixture is quenched and washed with water and with an aqueous base solution. 51. A process as claimed in claim 50 in which the base is sodium hydroxide. 52. A process as claimed in claim 51 in which the aqueous sodium hydroxide solution has a concentration of between 1 and 3 molar. 53. A process as claimed in any one of claims 48 to 52 in which the solution of compound (1) is dried to remove water and then treated directly with a haloformate of formula Hal-CO 2 R', where R' is an optionally substituted alkyl, arylalkyl or aryl group. 54. A process as claimed in claim 53 in which the solvent is toluene and the water content of the toluene solution is less than 0.05% w/w. 55. A process as claimed in claim 54 in which the water content of the toluene solution is achieved by the solution to reflux under reduced pressure or at atmospheric pressure using a Dean and Stark apparatus or similar or by distilling part of the solvent. 56. A process as claimed in any one of claims 53 to 55 in which the haloformate is phenyl chloroformate. 57. A process as claimed in any one of claims 48 to 56 in which the reaction is carried out at a temperature of 50-100°C, more preferably at between 55-70°C, most preferably between 58 and 68°C. 58. A process as claimed in any one of claims 48 to 57 in which the concentration of compound (1) is between 1 kg in 3 litres and 1 kg in 10 litres, preferably about 1 kg in 5 litres. 59. A process as claimed in any one of claims 48 to 58 in which the chloroformate is substantially free of hydrogen chloride and water. 60. A process as claimed in any one of claims 48 to 59 in which the chloroformate is added undiluted. 61. A process as claimed in any one of claims 48 to 60 in which the reaction with the chloroformate is carried out in the absence of a base. 62. A process as claimed in any one of claims 48 to 61 in which the carbamate reaction mixture is cooled and quenched with a dilute aqueous sulphuric acid solution. 63. A process as claimed in claim 62 in which the reaction mixture is cooled to between 15°C and 25°C, preferably to about 20°C. 64. A process as claimed in claim 62 or 63 in which the concentration of the sulphuric acid is between 5 and 20%, preferably between 8 and 12 %. 65. A process as claimed in any one of claims 48 to 64 in which the non-aqueous phase is washed with water. 66. A process as claimed in claim 65 in which the non-aqueous phase is washed more than once. 67. A process as claimed in claim 65 or 66 in which the volume for each water wash is between 1: 10 and 1:2 of the solvent volume, preferably between 1:5 and 1:8. 68. A process as claimed in any one of claims 48 to 67 in which the non-aqueous phase is stirred with a filter agent, for example celite, and filtered, or filtered through a bed of a filter agent. 69. A process as claimed in any one of claims 48 to 68 in which a crystalline form of the carbamate (3) is isolated from the reaction mixture. 70. A process as claimed in claim 69 in which the carbamate (3) is crystallised from a mixture of hot toluene and propan-2-ol. 71. A process as claimed in claim 69 or 70 in which the toluene is partially removed by evaporation, hot propan-2-ol is added to dissolve any solid material, and the solution is cooled to give a crystalline solid. 72. A process as claimed in claim 69 or 70 in which the toluene is progressively displaced by addition of propan-2-ol during the course of a distillation . 73. A process as claimed in any one of claims 69 to 72 in which the propan-2-ol is replaced by ethanol or denatured industrial methylated spirits. 74. A process for preparation of (-)-?rcws-4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1-73. 75. (-)-rran5-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine whenever obtained by a process including the process of any one of claims 1 to 73. 76. (-)-rra« -4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine as claimed in claim 75 in the form of a pharmaceutically acceptable salt such as the hydrochloride salt. 77. (-)- ra/25-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine hydrochloride as an anhydrate when obtained a process including the process of any one ofclaims 1 to 73. 78. (-)-rrαrZJ'-4-(4 -fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine hydrochloride as a hemihydrate when obtained a process including the process of any one of claims 1 to 73. 79. A pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or pharmaceutically acceptable salt of paroxetine obtained using the process of this invention as claimed in any one of claims 75 to 78 and a pharmaceutically acceptable carrier. 80. The use of paroxetine or pharmaceutically acceptable salt of paroxetine obtained using the process of this invention as claimed in any one of claims 75 to 78 to manufacture a medicament for the treatment or prophylaxis of the Disorders. 81. A method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or pharmaceutically acceptable salt of paroxetine obtained using the process of this invention as claimed in any one of claims 75 to 78 to a person suffering from one or more of the disorders. 82. A process substantially as hereinbefore described in any one of Examples 1 to 9. 83. A process for the preparation of a compound of formula (3): where R is an optionally substituted C(i_6)alkyl, aryl, allyl, or arylalkyl, which comprises preparing a compound of formula ( 1), in which X is an optionally substituted C( i _g) alkyl, aryalkyl, allyl, or alkynyl group, and without isolating compound (1), reacting it with a haloformate to prepare a compound of formula (3), cooling the carbamate reaction mixture and quenching it with a dilute aqueous sulphuric acid solution. 84. A process as claimed in claim 83 in which the reaction mixture is cooled to between 15°C and 25°C, preferably to about 20°C. 85. A process as claimed in claim 83 or 84 in which the concentration of the sulphuric acid is between 5 and 20%, preferably between 8 and 12 %. 86. A process as claimed in any one of claims 83 to 84 in which compound (1) is prepared by reacting a compound of formula (2), in which Y is an optionally substituted alkyl, aryl or arylalkyl sulphonate group, with sesamol or a derivative of sesamol. 87. Crystalline rrαnj-(-)-4-(4-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)- 1- phenoxy carbonylpiperidine. 88. A process for preparing crystalline y-(-)-4-(4-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-l-phenoxy carbonylpiperidine which comprises providing a solution of rraAZ5-(-)-4-(4-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-l-phenoxy carbonylpiperidine in toluene or xylene, removing most of the toluene or xylene, adding hot propan-2-ol to dissolve the residue, and cooling the solution to give a crystalline solid. 89. A process for preparing crystalline tr «i , -(-)-4-(4-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-l-phenoxy carbonylpiperidine which comprises providing a solution of tr nj-(-)-4-(4-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-l-phenoxy carbonylpiperidine in toluene or xylene, subjecting the solutuion to azeotropic distillation, progressively replacing toluene or xylene by fresh propan-2-ol during the course of the azeotropic distillation, and cooling the propan-2-ol solution to give a crystalline solid .

Inventors: GORDON ALISON RUTH, GORDON, ALISON, RUTH
Applicants: GORDON ALISON RUTH, SMITHKLINE BEECHAM PLC, GORDON, ALISON, RUTH
Application year: 2000
Main classification: C07D405
IPC codes: A61K31, A61P3, A61P17, A61P25, C07D405