WO2001004113A2 - Process for the preparation of paroxetine and synthetic intermeditates thereof - Google Patents
Process for the preparation of paroxetine and synthetic intermeditates thereof Download PDFInfo
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- WO2001004113A2 WO2001004113A2 PCT/GB2000/002638 GB0002638W WO0104113A2 WO 2001004113 A2 WO2001004113 A2 WO 2001004113A2 GB 0002638 W GB0002638 W GB 0002638W WO 0104113 A2 WO0104113 A2 WO 0104113A2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Definitions
- the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
- the piperidine nitrogen is protected by a group R, usually an alkyl (typically methyl) or arylalkyl 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.
- 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.
- 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.
- 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.
- the present invention provides a process for the preparation of a compound of formula (1):
- 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.
- R is a phenyl, methyl, ethyl, tertiary butyl or benzyl group.
- 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.
- 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.
- 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.
- 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.
- the base is an amine, such as triethylamine, trimethylamine, diethylmethylamine or dimethylethylamine. More preferably, the amine is dimethylethylamine.
- amine such as triethylamine, trimethylamine, diethylmethylamine or dimethylethylamine.
- the amine is dimethylethylamine.
- 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 - ⁇ -15 0 C, more preferably from -5°C to +5°C.
- 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.
- excess sulphonating agent may be destroyed by means of an aqueous quench.
- a quench with water 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.
- 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.
- 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.
- a drying step is added, either with anhydrous magnesium sulphate followed by filtration, or by azeotropic distillation.
- the coupling reaction with sesamol may be carried out in toluene or xylene, as used in the previous stage.
- 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.
- a high ratio, particularly of N,N -dimethylformamide can lead to loss of yield during work-up.
- 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).
- 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.
- the pre-formed sesamolate solution is added over the same time period.
- 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.
- 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.
- stirring at a temperature of 70- 75°C for from 1 to 4 hours is sufficient, preferably from 1 to 2 hours.
- 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.
- 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.
- a purer crystalline product is obtained, which can be isolated by filtration, washing with water and drying under vacuum.
- 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.
- the most advantageous embodiment of this invention is to proceed to the conversion of compound (1) into compound (3) in the same solvent as that used for the sulphonate ester formation.
- 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.
- 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.
- 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.
- 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.
- the water content of the toluene solution should be less than 0.05% w/w.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- optical resolution may be carried out prior to coupling with the phenol.
- 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.
- paroxetine especially paroxetine hydrochloride, obtained using this invention
- 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.
- 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.
- the present invention also provides:
- compositions 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,
- 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;
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Example 4 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.
- 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 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.
- 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.
- 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
- Weight yields ranged from 81.5-89.3% Purities ranged from 48.9-98.7%
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU59959/00A AU5995900A (en) | 1999-07-09 | 2000-07-07 | Novel process |
JP2001509723A JP2003504365A (en) | 1999-07-09 | 2000-07-07 | New method |
EP00946071A EP1246821A2 (en) | 1999-07-09 | 2000-07-07 | Process for the preparation of paroxetine and synthetic intermeditates thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GBGB9916187.9A GB9916187D0 (en) | 1999-07-09 | 1999-07-09 | Novel process |
GB9916187.9 | 1999-07-09 |
Publications (2)
Publication Number | Publication Date |
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WO2001004113A2 true WO2001004113A2 (en) | 2001-01-18 |
WO2001004113A3 WO2001004113A3 (en) | 2001-07-12 |
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ID=10857006
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Application Number | Title | Priority Date | Filing Date |
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PCT/GB2000/002638 WO2001004113A2 (en) | 1999-07-09 | 2000-07-07 | Process for the preparation of paroxetine and synthetic intermeditates thereof |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1246821A2 (en) |
JP (1) | JP2003504365A (en) |
AU (1) | AU5995900A (en) |
GB (1) | GB9916187D0 (en) |
WO (1) | WO2001004113A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002006275A1 (en) * | 2000-07-17 | 2002-01-24 | Smithkline Beecham P.L.C. | Novel processes for the preparation of 4-phenylpiperidine derivatives |
US8822498B2 (en) | 2007-09-13 | 2014-09-02 | Concert Pharmaceuticals, Inc. | Synthesis of deuterated catechols and benzo[D][1,3]dioxoles and derivatives thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US3912743A (en) * | 1973-01-30 | 1975-10-14 | Ferrosan As | 4-Phenylpiperidine compounds |
EP0190496A2 (en) * | 1984-12-13 | 1986-08-13 | Beecham Group Plc | Piperidine derivatives having a gastro-intestinal activity |
EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
WO1998001424A1 (en) * | 1996-07-08 | 1998-01-15 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzylpiperidine and tetrahydropyridine derivatives |
WO1999007680A1 (en) * | 1997-08-07 | 1999-02-18 | Brantford Chemicals Inc. | Stereoselective preparation of 3-substituted 4-aryl piperidine compounds |
-
1999
- 1999-07-09 GB GBGB9916187.9A patent/GB9916187D0/en not_active Ceased
-
2000
- 2000-07-07 EP EP00946071A patent/EP1246821A2/en not_active Withdrawn
- 2000-07-07 JP JP2001509723A patent/JP2003504365A/en active Pending
- 2000-07-07 WO PCT/GB2000/002638 patent/WO2001004113A2/en not_active Application Discontinuation
- 2000-07-07 AU AU59959/00A patent/AU5995900A/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3912743A (en) * | 1973-01-30 | 1975-10-14 | Ferrosan As | 4-Phenylpiperidine compounds |
US4007196A (en) * | 1973-01-30 | 1977-02-08 | A/S Ferrosan | 4-Phenylpiperidine compounds |
EP0190496A2 (en) * | 1984-12-13 | 1986-08-13 | Beecham Group Plc | Piperidine derivatives having a gastro-intestinal activity |
EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
WO1998001424A1 (en) * | 1996-07-08 | 1998-01-15 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzylpiperidine and tetrahydropyridine derivatives |
WO1999007680A1 (en) * | 1997-08-07 | 1999-02-18 | Brantford Chemicals Inc. | Stereoselective preparation of 3-substituted 4-aryl piperidine compounds |
Non-Patent Citations (3)
Title |
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AMAT M ET AL: "Synthesis of Enantiopure 3,4-Disubstituted Piperidines. An Asymmetric Synthesis of (+)-Paroxetine" TETRAHEDRON: ASYMMETRY,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 7, no. 6, 1 June 1996 (1996-06-01), pages 1591-1594, XP004047642 ISSN: 0957-4166 * |
ENGELSTOFT M ET AL: "SYNTHESIS AND 5HT MODULATING ACTIVITY OF STEREOISOMERS OF 3-PHENOXYMETHYL-4-PHENYLPIPERIDINES" ACTA CHEMICA SCANDINAVICA,DK,MUNKSGAARD, COPENHAGEN, vol. 50, no. 2, 1996, pages 164-169, XP002074608 ISSN: 0904-213X * |
WILLOCKS K ET AL: "THE SYNTHESIS OF U14C-3S,4R-4-(4-FLUOROPHENYL)-3- (3,4-METHYLENEDIOXYPHENOXYMETHYL)PIPERIDIN E HYDROCHLORIDE (BRL 29060A), AND MECHANISTIC STUDIES USING CARBON-13 LABELLING" JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS,GB,SUSSEX, vol. 33, no. 8, 1993, pages 783-794, XP000645839 ISSN: 0362-4803 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002006275A1 (en) * | 2000-07-17 | 2002-01-24 | Smithkline Beecham P.L.C. | Novel processes for the preparation of 4-phenylpiperidine derivatives |
US8822498B2 (en) | 2007-09-13 | 2014-09-02 | Concert Pharmaceuticals, Inc. | Synthesis of deuterated catechols and benzo[D][1,3]dioxoles and derivatives thereof |
US9315483B2 (en) | 2007-09-13 | 2016-04-19 | Concert Pharmaceuticals, Inc. | Synthesis of deuterated catechols and benzo[D][1,3]dioxoles and derivatives thereof |
Also Published As
Publication number | Publication date |
---|---|
AU5995900A (en) | 2001-01-30 |
GB9916187D0 (en) | 1999-09-08 |
EP1246821A2 (en) | 2002-10-09 |
JP2003504365A (en) | 2003-02-04 |
WO2001004113A3 (en) | 2001-07-12 |
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