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WO2001029031A1 - Process for the preparation of paroxetine - Google Patents

Process for the preparation of paroxetine Download PDF

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Publication number
WO2001029031A1
WO2001029031A1 PCT/GB2000/004060 GB0004060W WO0129031A1 WO 2001029031 A1 WO2001029031 A1 WO 2001029031A1 GB 0004060 W GB0004060 W GB 0004060W WO 0129031 A1 WO0129031 A1 WO 0129031A1
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WIPO (PCT)
Prior art keywords
paroxetine
trans
ester
piperidine
fluorophenyl
Prior art date
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Ceased
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PCT/GB2000/004060
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French (fr)
Inventor
Gary Thomas Borrett
David Crowe
Neal Ward
Andrew Stephen Wells
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
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Priority to AU10379/01A priority Critical patent/AU1037901A/en
Publication of WO2001029031A1 publication Critical patent/WO2001029031A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • 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

Definitions

  • This invention relates to a process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which -s suitable for large scale commercial operation.
  • a particularly useful starting material employed in EP 0219,934 is a quaternary py ⁇ dimum salt of formula (1), where R.3 and R.4 are alkyl groups.
  • paroxetine may be prepared from a compound of structure (1) where R3 and R4 are methyl groups by reduction to a cis - piperidine ester of structure (3), which is epimerised to a trans piperidine ester of structure (4), converted to a piperidine carbinol of structure (5), coupled with sesamol, then deprotected, to give paroxetine (6).
  • Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine.
  • the above described process produces compounds of structure (2) as a mixture of enantiomers, and conversion of compounds of structure (2) to useful pharmaceuticals will normally require a resolution stage.
  • Particularly useful forms of compounds (4) and (5) are thus compounds (A) and (B) which are in the (-) trans configuration:
  • the streamlined nature of the improved process enables one or more steps to be combined in a continuous operation in a single vessel.
  • a first aspect of this invention provides a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising
  • the process may start from a quaternary pyridinium salt of structure (1A) C0 2 CH 3
  • two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
  • Suitable pyridinium salts at step a) are the iodide, bromide and chloride.
  • a preferred pyridinium salt is the bromide.
  • the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
  • Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide.
  • a preferred strong base is sodium methoxide.
  • a preferred hydride reducing agent at step c) is lithium aluminium hydride.
  • Suitable chiral acids at step d) include dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid.
  • a preferred chiral acid is (-) ditoluoyl tartaric acid.
  • the resolved product is liberated at step d) using a basic reagent such as aqueous sodium carbonate, aqueous sodium hydroxide, and the corresponding potassium salts.
  • a basic reagent such as aqueous sodium carbonate, aqueous sodium hydroxide, and the corresponding potassium salts.
  • Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
  • Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate
  • a preferred carbamate is the phenyl carbamate.
  • the carbamate is hydrolysed by heating with potassium hydroxide.
  • Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.
  • Suitable reaction solvents include dichloromethane and toluene.
  • a preferred reaction solvent is toluene.
  • Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol.
  • a particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
  • a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
  • a preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.
  • a preferred additional solvent for the resolution step is acetone, as this promotes efficient crystallisation of the desired optical isomer of the salt of the trans carbinol with the chiral acid.
  • a preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
  • Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.
  • Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.
  • (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine may be prepared from a pyridinium salt of structure (1 A) by an alternative sequence of steps involving the formation and reduction of (-) trans 1- methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine (A), and employed in the synthesis of paroxetine.
  • A pyridinium salt of structure (1 A)
  • the process may start from a pyridinium salt of structure (1A), and comprise the steps of
  • a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
  • two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
  • Suitable pyridinium salts at step a) are the iodide, bromide and chloride.
  • a preferred pyridinium salt is the bromide.
  • the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
  • Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide.
  • a preferred strong base is sodium methoxide.
  • the chosen enzyme may selectively hydrolyse the unwanted (+) trans isomer to the corresponding acid, which may be removed by a conventional extraction, for example with an aqueous base, leaving the desired (-) trans isomer as the ester for further processing.
  • the chosen enzyme may selectively hydrolyse the desired (-) trans isomer of the ester to the corresponding (-) trans acid, compound (D) ns
  • (D) which is recovered by extraction with an aqueous base, and re-esterified to give the (-) trans ester.
  • the (+) trans ester is unaffected by the enzyme treatment and may be recovered from the organic phase of this extraction.
  • the (-) trans acid of formula (D) is reduced directly to the desired (-) trans carbinol, for example with a borohydride reducing agent, thus avoiding the re-esterification step.
  • Suitable enzymes for selective hydrolysis at step c) include Porcine liver esterase (PLE), Subtilisin Carlsberg , Subtilisin BPN, Pig liver acetone powder, Bovine liver acetone powder and Horse liver acetone powder.
  • Porcine liver esterase PLE
  • Subtilisin Carlsberg Subtilisin Carlsberg
  • Subtilisin BPN Pig liver acetone powder
  • Bovine liver acetone powder and Horse liver acetone powder.
  • Suitable solvents for the enzymatic resolution include aqueous N,N '-dimethyl formamide and aqueous dimethyl sulphoxide.
  • a preferred hydride reducing agent at step d) is lithium aluminium hydride.
  • Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
  • Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate
  • a preferred carbamate is the phenyl carbamate.
  • the carbamate is hydrolysed by heating with potassium hydroxide.
  • Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid.
  • Preferred acids are methane sulphonic acid and hydrochloric acid.
  • Suitable reaction solvents include dichloromethane and toluene.
  • a preferred reaction solvent is toluene.
  • Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as ether, tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol.
  • a particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
  • a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
  • a preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.
  • a preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
  • Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.
  • Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595
  • the desired (-) trans ester of structure (A) can be obtained from a racemic cis ester of structure (3) by a novel procedure which comprises resolution of the racemic cis ester to give the (+) cis form, compound (C), followed by reaction with a strong base.
  • this process inversion of configuration occurs, providing, for example, the (-) trans ester (A) in good yield in high optical purity, suitable for reduction to the (-) trans form of the carbinol, compound (B).
  • the resolution may be carried out for example, by the formation of a salt with a chiral acid.
  • the process may start from a pyridinium salt of structure (1A) and comprise the steps of
  • a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
  • two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
  • Suitable pyridinium salts at step a) are the iodide, bromide and chloride.
  • a preferred pyridinium salt is the bromide.
  • the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
  • Suitable chiral acids at step b) are dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid.
  • crystallisation of chiral acid salts of the cis-ester at Step 2 gives unpredictable results, so the chiral acid must be selected with care.
  • the salt generated from (-) dibenzoyl tartaric acid produces the desired (+) cis ester, whereas the corresponding (-) ditoluoyl tartaric acid gives the unwanted (-) cis isomer.
  • Preferred chiral acids are (-) dibenzoyl tartaric acid and (+) ditoluoyl tartaric acid
  • Suitable strong bases at step c) include sodium methoxide, sodium ethoxide and potassium tert-butoxide.
  • a preferred strong base is sodium methoxide.
  • a preferred hydride reducing agent at step d) is lithium aluminium hydride.
  • Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
  • Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate
  • a preferred carbamate is the phenyl carbamate.
  • the carbamate is hydrolysed by heating with potassium hydroxide.
  • Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.
  • Suitable reaction solvents include dichloromethane and toluene.
  • a preferred reaction solvent is toluene.
  • Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol.
  • a particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
  • a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
  • a suitable additional solvent for the resolution with a chiral acid is methanol.
  • a preferred additional solvent for the reduction of the (-) trans piperidine ester to the (-) trans carbinol is tetrahydrofuran. as this solubilises the hydride reducing agent.
  • a preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
  • Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.
  • Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.
  • the present invention includes within its scope the compound paroxetine, particularly paroxetine mesylate or paroxetine hydrochloride, especially paroxetine hydrochloride anhydrate or paroxetine hydrochloride hemihydrate, when obtained via any aspect of this invention.
  • 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 mesylate or paroxetine hydrochloride, obtained using this invention
  • the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine mesylate or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of paroxetine or paroxetine hydrochloride obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and a method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine mesylate or paroxetine hydrochloride obtained using the process of this invention to a person suffering from one or more of the disorders.
  • the cis and trans piperidine compounds of this invention can be readily distiguished by conventional analytical techniques such as HPLC and NMR.
  • the optical activity of the piperidine compounds of this invention may be determined in a suitable solvent, such as methanol, using a conventional polarimeter.
  • the ratio of (+) and (-) isomers may be determined by chiral HPLC, or preferably by chiral capillary electrophoresis (CCE).
  • CCE capillary electrophoresis
  • 4-(4'-fluorophenyl)-3-methoxycarbonyl-l -methyl pyridinium bromide (15.91g, prepared according to Example 1 of EP 0219,934), is dissolved in a mixture of toluene and ethanol and hydrogenated at atmospheric pressure for 24 hours at 45 to 50°C in the presence of platinum oxide (0.5 g). The catalyst is removed by filtration, the filtrate diluted with further toluene and washed with 10% sodium carbonate solution (100 ml).
  • the toluene phase is separated, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine.
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis-1- methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine as a crystalline solid, which may be purified by recrystallisation.
  • Step 2 of Schemes 1 and 2 A nitrogen purged vessel is charged with a solution of cis l-methyl-3-carbomethoxy-4- (4'-fluorophenyl) piperidine ( 1 15 g) in toluene (1000 ml) and sodium methoxide (8.0 g) is added. The mixture is stirred and heated to the reflux temperature and the progress of the reaction is monitored by HPLC analysis. When the epimerisation is complete (about 3 hours) the vessel is cooled to 20°C, water (200 ml) is added, the mixture stirred thoroughly, then the lower aqueous phase is separated and discarded.
  • the toluene solution may be further distilled under reduced pressure until no more solvent can be removed, to give trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine as an oil
  • a solution of trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (47.3g) in toluene (400 ml) is added dropwise over about 20 minutes to a nitrogen purged vessel containing lithium aluminium hydride in tetrahydrofuran ( 1.0 molar, 200 ml) maintaining a temperature of less than 10°C throughout the addition.
  • the mixture is stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% aqueous sodium hydroxide solution (10 ml).
  • the precipitated solids are removed by filtration through celite and washed with toluene (2 x 100 ml).
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give trans-4- (4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine as a crystalline solid.
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give
  • Racemic trans- l-methyl-3-carbornethoxy-4-(4'-fluorophenyl)-piperidine (1.0 g) is dissolved in N,N'-dimethylformamide (3 ml), then added to water (30 ml) and the pH adjusted to 7.00 with 1.0 molar hydrochloric acid.
  • Commercial Porcine Liver Esterase suspension (0.3 ml) is added and the mixture stirred at 25 C, maintaining the pH at 7.00 by the addition of dilute aqueous ammonia. After 6 hours, dichloromethane (60 ml) is added and the mixture is filtered through celite.
  • aqueous phase is adjusted to pH 8.0 with aqueous ammonia and the dichloromethane layer is separated and evaporated under reduced pressure to give (+) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine as an oil.
  • Chiral capillary electrophoresis shows the trans ester to have a ratio of (-) trans to (+) trans of about 95:5
  • Cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine ( 1.0 g) prepared by the method of Example 2 of EP 0219934, was dissolved in acetone (5 ml) and mixed with a solution of (+)-di-p-toluoyl-D- tartaric acid monohydrate (1.6g) in acetone (5 ml). Crystals separated on stirring and the suspension was left to stand for several hours. The crystals were collected by filtration, washed with acetone (5 ml) and dried under vacuum.
  • (+)Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine-(-)-dibenzoyl-tartrate crystals were collected by filtration, washed with acetonitrile (5ml) and dried under vacuum.
  • (+)-cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (0.35g) is dissolved in dry toluene ( 10 ml) and treated with sodium methoxide (0.15g). The mixture is heated to reflux under nitrogen for 2 hours, then allowed to cool to ambient temperature. The solution is washed with water (10 ml) followed by saturated aqueous sodium chloride (10 ml) and the toluene is evaporated under reduced pressure to give (-)-trans-l-methyl- 3-carbomethoxy-4-(4'-fluorophenyl)piperidine as an oil.
  • a yield of about 0.30g is obtained, having the following properties:
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans- 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine as a crystalline solid.
  • Toluene (210 ml) is 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 (35.10 g) is added with stirring to ensure dissolution.
  • the vessel contents are cooled to 5°C and dimethylethylamine (25.5 ml) is added, and then a nitrogen purge is attached and the vessel contents further cooled to 0°C.
  • a mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) is added slowly from a headflask over 70 minutes, maintaining the temperature between -2°C and +2°C. On completion of the addition, the mixture is stirred for 20 minutes, allowing the temperature to rise to 10°C.
  • a mixture of saturated sodium chloride (105 ml) and sodium hydroxide (3.5 g) dissolved in water (105 ml) is charged to the vessel over 10 minutes and stirring continued for 15 minutes at 10°C.
  • the mixture is left to settle for 15 minutes and the aqueous phase is separated.
  • the aqueous phase is extracted with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (5.1 g) for 10 minutes.
  • the solution is then filtered and the magnesium sulphate washed with toluene (10 ml).
  • Approximately 100 ml of toluene is then removed by low pressure distillation, to leave about 200 ml of a dry solution of the intermediate sulphonate ester in toluene.
  • the aqueous phase is extracted 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 is then dried over anhydrous magnesium sulphate (10.4 g), filtered, and the magnesium sulphate washed with toluene (25 ml).
  • the combined toluene solutions are partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)- 1 -methylpiperidine.
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, and the residue dried in a vacuum oven at 40°C to give (-) trans 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)- 1 -methylpiperidine as a pale yellow solid.
  • the toluene phase is washed with water (10 ml) and the combined aqueous phases further are extracted with toluene (10 ml).
  • the combined toluene phases are washed with water (10 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3,'4'-methylenedioxy phenoxymethyl)-l-phenoxycarbonyl piperidine.
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans 4-(4'-fluorophenyl)-3-(3,'4'-methylenedioxy phenoxymethyl)-l- phenoxycarbonyl piperidine as a crystalline solid, which may be further purified by recrystallisation, for example from propan-2-ol.
  • Powdered potassium hydroxide (3.0 g) is added to a solution of (-) trans 4-(4'- fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l-phenoxycarbonyl piperidine (3.6g) in toluene (100 ml) and the well stirred mixture is refluxed for 2 hours. The mixture is cooled to ambient temperature, treated with water (100 ml), stirred well and the phases separated. The toluene phase is washed with water (50 ml), and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of paroxetine free base.
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give paroxetine free base as an oil.
  • a toluene solution (1.0 L) containing unpurified paroxetine base (approximately 225 g) is charged to a nitrogen purged reactor and stirred at 20°C.
  • the vessel is seeded with paroxetine methanesulfonate, then a solution of methane sulfonic acid (70 g) in propan- 2-ol (0.4L) is added slowly over a period of 50 minutes.
  • Paroxetine methansulfonate is precipitated as a white crystalline solid during the addition, and the temperature at the end of the addition rises to about 30°C.
  • the suspension is stirred for a further 1 hour, during which time the temperature is reduced to 22°C.
  • the product is collected by filtration, washed on the filter with propan-2-ol (2 x 0.4 L) and dried in a vacuum oven at 40°C for 24 hours.
  • paroxetine free base (13.5 g) in toluene (300 ml) is stirred at room temperature and concentrated hydrochloric acid (5.2 ml) is added. The mixture is stirred for 2 hours, then the product is collected, washed with a 1 : 1 mixture of toluene and water (25 ml) and dried at 50°C to give paroxetine hydrochloride hemihydrate.
  • the product may be recrystallised from aqueous propan-2-ol.
  • paroxetine hydrochloride acetone solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.
  • paroxetine hydrochloride propan-2-ol solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.

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Abstract

Three process schemes (1), (2) and (3) for a complete route to paroxetine from a pyridine ester are disclosed.

Description

PROCESS FOR THE PREPARATION OF PAROXETINE
This invention relates to a process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which -s suitable for large scale commercial operation.
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'- methylenedιoxyphenoxymethyl)-pιpeπdιne. This compound is used in therapy as the hydrochloπde salt to treat inter aha depression, obsessive compulsive disorder (OCD) and panic.
Vaπous processes have been described for the preparation of paroxetine, for example in US 4,007,196, EP 0219,934, EP 0300,617 and Acta Chemica Scandmavica (1996) volume 50 page 164. A particularly useful starting material employed in EP 0219,934 is a quaternary pyπdimum salt of formula (1), where R.3 and R.4 are alkyl groups.
Figure imgf000002_0001
In the process described in EP 0219,934 a quaternary pyπdinium salt of formula (1) is reduced to a pipendine ester of structure (2)
Figure imgf000003_0001
Thus by following the process of EP 0219934, paroxetine may be prepared from a compound of structure (1) where R3 and R4 are methyl groups by reduction to a cis - piperidine ester of structure (3), which is epimerised to a trans piperidine ester of structure (4), converted to a piperidine carbinol of structure (5), coupled with sesamol, then deprotected, to give paroxetine (6).
Figure imgf000003_0002
(6) Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. The above described process produces compounds of structure (2) as a mixture of enantiomers, and conversion of compounds of structure (2) to useful pharmaceuticals will normally require a resolution stage. Particularly useful forms of compounds (4) and (5) are thus compounds (A) and (B) which are in the (-) trans configuration:
Figure imgf000004_0001
(A) (B)
The prior art processes for the preparation of paroxetine (6) from a pyridinium salt of structure (1) suffer from a number of disadvantages which render them unsuitable for large scale manufacture. The reduction of the pyridinium salt (see Example 2 of EP 0219934) is conducted in ethanol, and the ethanol is subsequently removed by evaporation and replaced with a mixture of aqueous sodium carbonate and dichlorome thane. The organic phase is then dried and evaporated and the residue is crystallised from ethyl acetate. This procedure involves the use of 3 different organic solvents and 2 evaporation steps and is unsuitable for large scale manufacture.
Hereinafter we describe improved processes for the preparation of paroxetine starting from a pyridinium salt of formula (1) which are suitable for large scale manufacture. These processes proceed through an intermediate of formula (2) above, which is advantageously made by the above described improved process rather than the previously known process of EP 0219,934.
A procedure for the conversion of a pyridinium salt of structure (1) to paroxetine is outlined in EP 0219934. The first part of this procedure is represented in Scheme ( 1), the (-) trans carbinol of structure (B) being converted to paroxetine by the further steps of coupling to sesamol, and deprotecting.
Scheme 1
Figure imgf000005_0001
-) trans carbinol racemic trans carbinol
A procedure for carrying out Step 1 of Scheme 1 is described in Example 2 of EP 0219,934
Procedures for carrying out Step 2 of Scheme 1 are described in Example 1 of US-A- 4007196 and Example 2 of EP 0219,934
A procedure for carrying out Step 3 of Scheme 1 is outlined on page 3 of EP 0219,934
Procedures for carrying out Step 4 of Scheme 1 are described in Examples 5 and 8 of EP 0223,334 We have developed an improved overall process for the preparation of paroxetine from a pyridinium salt of structure (1) following Scheme 1 which is more efficient, more convenient to operate, and is less hazardous than the prior art processes, and is particularly suitable for large scale manufacture.
Important features of this new, improved process are that it is streamlined, employing a common solvent over a number of chemical steps, and that it enables a solution of an intermediate produced from one step to be carried forward and employed directly in the next step without the need for further manipulation or switching of solvents.
Furthermore, the streamlined nature of the improved process enables one or more steps to be combined in a continuous operation in a single vessel.
Accordingly a first aspect of this invention provides a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising
a) reducing a pyridinium salt of formula (1)
Figure imgf000006_0001
to obtain a cis piperidine ester of formula (2)
Figure imgf000007_0001
b) converting the cis piperidine ester of formula (2) to the corresponding trans ester by epimerising with a strong base,
c) reducing the trans piperidine ester of formula (2) with a hydride reducing agent to obtain the corresponding trans carbinol,
d) resolving the racemic trans carbinol by use of a chiral acid, liberating and extracting the free base of the (-) trans carbinol,
e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,
g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
More specifically, the process may start from a quaternary pyridinium salt of structure (1A) C02CH3
N Hal(-) I CH3 (1A)
and comprises the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as a crystalline solid,
b) converting cis- l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine to the corresponding trans ester by epimerising with a strong base, with optional isolation of the trans ester,
c) reducing trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the trans carbinol, that is trans-4-(4 - fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,
d) resolving the trans carbinol by use of a chiral acid, liberating, extracting and optionally isolating the free base of the (-) trans carbinol,
e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol. and optionally isolating the resulting N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base, g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
Preferably two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
Suitable pyridinium salts at step a) are the iodide, bromide and chloride. A preferred pyridinium salt is the bromide. Suitably the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.
A preferred hydride reducing agent at step c) is lithium aluminium hydride.
Suitable chiral acids at step d) include dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid. A preferred chiral acid is (-) ditoluoyl tartaric acid.
Suitably the resolved product is liberated at step d) using a basic reagent such as aqueous sodium carbonate, aqueous sodium hydroxide, and the corresponding potassium salts.
Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate A preferred carbamate is the phenyl carbamate. Suitably the carbamate is hydrolysed by heating with potassium hydroxide. Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.
Suitable reaction solvents include dichloromethane and toluene. A preferred reaction solvent is toluene.
Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol. A particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
The nature of the additional solvent is dependant on the individual chemical step. Thus a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
A preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.
A preferred additional solvent for the resolution step is acetone, as this promotes efficient crystallisation of the desired optical isomer of the salt of the trans carbinol with the chiral acid.
A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation. Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.
We have also found that (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine (B) may be prepared from a pyridinium salt of structure (1 A) by an alternative sequence of steps involving the formation and reduction of (-) trans 1- methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine (A), and employed in the synthesis of paroxetine. Such a process is outlined in Scheme 2
Scheme 2
Figure imgf000011_0002
racemic trans ester
Figure imgf000011_0001
(-) trans carbinol (-) trans ester
A procedure for carrying out Step 1 of Scheme 2 is described in Example 2 of EP 0219,934. Procedures for carrying out Step 2 of Scheme 2 are described in Example 1 of US-A- 4007196 and Example 2 of EP 0219.934
An outline method for the chemical resolution of trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (Step 3 of Scheme 2) using unspecified optical forms of mandelic acid or dibenzoyl tartaric acid has been described in the literature in the form of a flowchart [Acta Chemica Scandinavica ( 1996) volume 50 page 164], but no details of the conditions are given. The same flowchart outlines the reduction of the (-) trans ester (A) to the (-) trans carbinol (B), step 4 of Scheme 2.
We have made numerous attempts carry out this resolution procedure but have been unable to obtain any crystallise salts using either mandelic acid or dibenzoyl tartaric acid in a wide range of organic solvents. In addition, no chemical or physical properties for the individual (+) and (-) optical isomers of trans l-methyl-3- carbomethoxy-4-(4 '-fluorophenyl) piperidine or analogous trans compounds of structure (2) have been reported, either as salts or in the free base form.
We therefore conclude that no workable process for obtaining (-) trans l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine (A) or analogous resolved trans compounds of structure (2) is available in the prior art.
We have surprisingly found that the desired (-) form of a trans ester of structure (2) can be prepared by enzymatic resolution of a racemic trans ester of structure (2), enabling paroxetine to be manufactured from a pyridinium salt of structure (1A) by the steps outlined in Scheme 2. In addition to the advantages described for the process based on Scheme 1 , this novel process is much cheaper to operate because the usage of lithium aluminium hydride is very significantly reduced compared with Scheme 1 , as the reduction step in Scheme 2 is carried out after the resolution, not before as in Scheme 1. Accordingly in a second aspect of this invention we provide a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising a) reducing a pyridinium salt of formula (1)
Figure imgf000013_0001
to obtain a cis piperidine ester of formula (2)
Figure imgf000013_0002
b) converting the cis piperidine ester of formula (2) to the corresponding trans ester by epimerising with a strong base,
c) resolving the racemic trans piperidine ester enzymatically to give the (-) trans piperidine ester,
d) reducing the (-) trans piperidine ester with a hydride reducing agent to obtain the corresponding (-) trans carbinol, e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,
g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
More specifically, the process may start from a pyridinium salt of structure (1A), and comprise the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine as a crystalline solid,
b) epimerising the cis- l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine to the corresponding trans ester with a strong base, with optional isolation of the trans ester, and
c) enzymatic resolution of the trans ester to give the (-) trans ester, liberating, extracting and optionally isolating the (-) trans ester,
d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4 -fluorophenyl)-3-hydroxymethyl-l-methylpiperidine,
e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine, f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,
g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
Preferably two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
Suitable pyridinium salts at step a) are the iodide, bromide and chloride. A preferred pyridinium salt is the bromide. Suitably the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
Suitable strong bases at step b) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.
At step c), the chosen enzyme may selectively hydrolyse the unwanted (+) trans isomer to the corresponding acid, which may be removed by a conventional extraction, for example with an aqueous base, leaving the desired (-) trans isomer as the ester for further processing.
Alternatively, the chosen enzyme may selectively hydrolyse the desired (-) trans isomer of the ester to the corresponding (-) trans acid, compound (D) ns
Figure imgf000016_0001
(D) which is recovered by extraction with an aqueous base, and re-esterified to give the (-) trans ester. The (+) trans ester is unaffected by the enzyme treatment and may be recovered from the organic phase of this extraction.
In a particularly useful alternative aspect, the (-) trans acid of formula (D) is reduced directly to the desired (-) trans carbinol, for example with a borohydride reducing agent, thus avoiding the re-esterification step.
Suitable enzymes for selective hydrolysis at step c) include Porcine liver esterase (PLE), Subtilisin Carlsberg , Subtilisin BPN, Pig liver acetone powder, Bovine liver acetone powder and Horse liver acetone powder.
Suitable solvents for the enzymatic resolution include aqueous N,N '-dimethyl formamide and aqueous dimethyl sulphoxide.
A preferred hydride reducing agent at step d) is lithium aluminium hydride.
Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate A preferred carbamate is the phenyl carbamate. Suitably the carbamate is hydrolysed by heating with potassium hydroxide.
Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.
Suitable reaction solvents include dichloromethane and toluene. A preferred reaction solvent is toluene.
Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as ether, tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol. A particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
The nature of the additional solvent is dependant on the individual chemical step. Thus a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
A preferred additional solvent for the reduction of the trans piperidine ester to the trans carbinol is tetrahydrofuran, as this solubilises the hydride reducing agent.
A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation. Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595
We have also surprisingly found that the desired (-) trans ester of structure (A) can be obtained from a racemic cis ester of structure (3) by a novel procedure which comprises resolution of the racemic cis ester to give the (+) cis form, compound (C), followed by reaction with a strong base. In this process inversion of configuration occurs, providing, for example, the (-) trans ester (A) in good yield in high optical purity, suitable for reduction to the (-) trans form of the carbinol, compound (B).
s
Figure imgf000018_0001
The resolution may be carried out for example, by the formation of a salt with a chiral acid.
This novel resolution procedure enables paroxetine to be manufactured from a pyridinium salt of formula (1 A) by the steps outlined in Scheme 3 In addition to the advantages described for the process based on Scheme 1 , this novel process is much cheaper to operate because the usage of lithium aluminium hydride is very significantly reduced compared with Scheme 1, as the reduction step in Scheme 3 is carried out after the resolution, not before as in Scheme 1 Scheme 3
Figure imgf000019_0001
racemic cis ester
Figure imgf000019_0002
(+) cis ester
Figure imgf000019_0003
(-) trans carbinol (-) trans ester
A procedure for carrying out Step 1 of Scheme 3 is described Example 2 of EP 0219,934.
An outline method for the reduction of the (-) trans ester (A) to the (-) trans carbinol (B), step 4 of Scheme 3, has been described in the literature in the form of a flowchart [Acta Chemica Scandinavica (1996) volume 50 page 164], but no details of the conditions are given.
Steps 2 and 3 of Scheme 3 have not previously been described.
Accordingly in a third aspect of this invention we provide a process for the large scale manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising a) reducing a pyridinium salt of formula (1)
Figure imgf000020_0001
R3
(1) to obtain a cis piperidine ester of formula (2
Figure imgf000020_0002
b) converting the racemic cis piperidine ester of formula (2) to the (+) cis ester,
c) epimerising the (+) cis piperidine ester with a strong base to form the corresponding (-) trans piperidine ester,
d) reducing (-) trans piperidine ester with a hydride reducing agent and to obtain the corresponding (-) trans carbinol,
e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base, g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
More specifically, the process may start from a pyridinium salt of structure (1A) and comprise the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine as a crystalline solid,
b) converting cis- l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine to the (+) cis ester, liberating and optionally isolating the (+) cis ester as a crystalline solid,
c) epimerising the (+) cis ester with a strong base to form the corresponding (-) trans ester, with optional isolation of the (-) trans ester,
d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4-
(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine,
e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,
g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product. Preferably two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents, and optionally combining one or more of the steps a) to g).
Suitable pyridinium salts at step a) are the iodide, bromide and chloride. A preferred pyridinium salt is the bromide. Suitably the reduction of the pyridium salt is carried out by hydrogenation in the presence of a catalyst, such as platinum oxide.
Suitable chiral acids at step b) are dibenzoyl tartaric acid, ditoluoyl tartaric acid and nitrotartranilic acid. However, we have found that crystallisation of chiral acid salts of the cis-ester at Step 2 gives unpredictable results, so the chiral acid must be selected with care. For example, when crystallised from methanol, the salt generated from (-) dibenzoyl tartaric acid produces the desired (+) cis ester, whereas the corresponding (-) ditoluoyl tartaric acid gives the unwanted (-) cis isomer. Preferred chiral acids are (-) dibenzoyl tartaric acid and (+) ditoluoyl tartaric acid
Suitable strong bases at step c) include sodium methoxide, sodium ethoxide and potassium tert-butoxide. A preferred strong base is sodium methoxide.
A preferred hydride reducing agent at step d) is lithium aluminium hydride.
Suitable sulphonate esters at step e) include those formed from the carbinol by reaction with methane sulphonyl chloride, benzene sulphonyl chloride or 4-toluene sulphonyl chloride.
Suitable carbamates at step f) include those formed by heating the N-protected paroxetine with ethyl chloroformate or phenyl chloroformate A preferred carbamate is the phenyl carbamate. Suitably the carbamate is hydrolysed by heating with potassium hydroxide. Suitable pharmaceutically acceptable acids at step g) include acetic acid, maleic acid, methane sulphonic acid and hydrochloric acid. Preferred acids are methane sulphonic acid and hydrochloric acid.
Suitable reaction solvents include dichloromethane and toluene. A preferred reaction solvent is toluene.
Suitable additional solvents include those which increase solubility, selectivity or reactivity, such as tetrahydrofuran, acetone, dimethyl formamide, methanol, ethanol or propan-2-ol. A particularly useful feature of an additional solvent is that it may be effectively removed during processing, for example by reason of volatility or aqueous solubility, allowing the reaction stream in the preferred reaction solvent to be carried forward to the next manufacturing step.
The nature of the additional solvent is dependant on the individual chemical step. Thus a preferred additional solvent for the reduction of the pyridinium salt to the cis piperidine ester is ethanol, as this solubilises the pyridinium salt.
A suitable additional solvent for the resolution with a chiral acid is methanol.
A preferred additional solvent for the reduction of the (-) trans piperidine ester to the (-) trans carbinol is tetrahydrofuran. as this solubilises the hydride reducing agent.
A preferred additional solvent for the reaction of the (-) trans carbinol with sesamol is dimethyl formamide as this promotes the coupling reaction.
Preferred additional solvents for the preparation of paroxetine mesylate or paroxetine hydrochloride hemihydrate are ethanol or propan-2-ol, as these solvent promote an efficient crystallisation.
Preferred additional solvents for the preparation of paroxetine hydrochloride anhydrate Form A are propan-2-ol or acetone, as these solvents promote the formation of paroxetine hydrochloride solvates, which may be de-solvated to give paroxetine hydrochloride anhydrate Form A using procedures described in WO96/24595.
The present invention includes within its scope the compound paroxetine, particularly paroxetine mesylate or paroxetine hydrochloride, especially paroxetine hydrochloride anhydrate or paroxetine hydrochloride hemihydrate, when obtained via any aspect of this invention.
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 mesylate or 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".
Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine mesylate or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of paroxetine or paroxetine hydrochloride obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and a method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine mesylate or paroxetine hydrochloride 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. Analytical Procedures
The cis and trans piperidine compounds of this invention can be readily distiguished by conventional analytical techniques such as HPLC and NMR.
The optical activity of the piperidine compounds of this invention may be determined in a suitable solvent, such as methanol, using a conventional polarimeter. The ratio of (+) and (-) isomers may be determined by chiral HPLC, or preferably by chiral capillary electrophoresis (CCE). A review entitled "Separation of optically active pharmaceuticals using capillary electrophoresis" by T.J. Ward, and K. D. Ward has been published in Chem. Anal. (N. Y.) (1997), volume 142 pages 317-344.
Example 1 Preparation of cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine (Step 1 of Schemes 1, 2 and 3)
4-(4'-fluorophenyl)-3-methoxycarbonyl-l -methyl pyridinium bromide (15.91g, prepared according to Example 1 of EP 0219,934), is dissolved in a mixture of toluene and ethanol and hydrogenated at atmospheric pressure for 24 hours at 45 to 50°C in the presence of platinum oxide (0.5 g). The catalyst is removed by filtration, the filtrate diluted with further toluene and washed with 10% sodium carbonate solution (100 ml). The toluene phase is separated, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis-1- methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine as a crystalline solid, which may be purified by recrystallisation.
A yield of about 10 g is obtained. Example 2
Preparation of trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine
(Step 2 of Schemes 1 and 2) A nitrogen purged vessel is charged with a solution of cis l-methyl-3-carbomethoxy-4- (4'-fluorophenyl) piperidine ( 1 15 g) in toluene (1000 ml) and sodium methoxide (8.0 g) is added. The mixture is stirred and heated to the reflux temperature and the progress of the reaction is monitored by HPLC analysis. When the epimerisation is complete (about 3 hours) the vessel is cooled to 20°C, water (200 ml) is added, the mixture stirred thoroughly, then the lower aqueous phase is separated and discarded. This step is repeated, then 100 ml of toluene is removed by distillation of the organic phase at atmospheric or reduced pressure to give an anhydrous toluene solution of trans 1- methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine.
If a solvent-free product is desired, the toluene solution may be further distilled under reduced pressure until no more solvent can be removed, to give trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine as an oil
A yield of about 110 g is obtained
Example 3
Preparation of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine
(Step 3 of Scheme 1)
A solution of trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (47.3g) in toluene (400 ml) is added dropwise over about 20 minutes to a nitrogen purged vessel containing lithium aluminium hydride in tetrahydrofuran ( 1.0 molar, 200 ml) maintaining a temperature of less than 10°C throughout the addition. The mixture is stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% aqueous sodium hydroxide solution (10 ml). The precipitated solids are removed by filtration through celite and washed with toluene (2 x 100 ml). The toluene solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give trans-4- (4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine as a crystalline solid.
A yield of about 39 g is obtained.
Example 4
Preparation of (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine (Step 4 of Scheme 1)
i) A warm solution of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine (10.0 g) in toluene (75 ml) is added to a solution of L(-)-di-p-toluoyl tartaric acid (22.5g) in acetone (75 ml), and the stirred mixture allowed to cool slowly to ambient temperature then held at 0°C for 1 hour. The crystals of (-) trans 4-(4'- fluorophenyl)-3-hydroxymethyl-l-methylpiperidine L(-)-di-p-toluoyl tartrate are collected by filtration, washed with acetone and dried.
A yield of about 12.5 g is obtained.
ii) (-) trans 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine L(-)-di-p- toluoyl tartrate (12.0 g) is stirred in toluene (240 ml) and water (120 g) and 10% aqueous sodium hydroxide (25 ml) is added to dissolve the salt. The phases are separated, the toluene solution optionally washed with saturated sodium chloride solution (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4 -fluorophenyl)-3-hydroxymethyl-l- methylpiperidine.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give
(-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine as a crystalline solid, which may be further purified by recrystallisation
A yield of about 4 g is obtained.
Example 5
Enzymatic resolution of trans-l-methyI-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine (Step 3 of Scheme 2)
i) Racemic trans- l-methyl-3-carbornethoxy-4-(4'-fluorophenyl)-piperidine (1.0 g) is dissolved in N,N'-dimethylformamide (3 ml), then added to water (30 ml) and the pH adjusted to 7.00 with 1.0 molar hydrochloric acid. Commercial Porcine Liver Esterase suspension (0.3 ml) is added and the mixture stirred at 25 C, maintaining the pH at 7.00 by the addition of dilute aqueous ammonia. After 6 hours, dichloromethane (60 ml) is added and the mixture is filtered through celite. The aqueous phase is adjusted to pH 8.0 with aqueous ammonia and the dichloromethane layer is separated and evaporated under reduced pressure to give (+) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine as an oil.
A yield of about 0.5 g is obtained.
Optical rotation [α]D ca. +36 ° (c =1, methanol)
ii) The aqueous phase is evaporated under reduced pressure to give (-) trans- 1- methyl-4-(4'-fluorophenyl)piperidine-carboxylic acid as a white solid. (Chiral capillary electrophoresis shows the trans acid to have a ratio of (-) trans to (+) trans of about 96:4) This is stirred in a mixture of methanol (15 ml) and tetrahydrofuran ( 15 ml) then trimethylsilyldiazomethane ( 1.6 ml of a 2 molar solution in hexane) is added. The reaction is stirred for 2 hours at room temperature then quenched with a few drops of acetic acid. The solvents are removed by evaporation under reduced pressure and the resulting oil is dissolved in a mixture of dichloromethane (30 ml) and water (30 ml). The pH is adjusted to 8.5 with dilute aqueous ammonia, the dichloromethane layer is separated, washed with water (30 ml), dried over sodium sulphate, and the solvent evaporated to leave the (-) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)- piperidine as an oil.
A yield of about 0.35g is obtained
Chiral capillary electrophoresis shows the trans ester to have a ratio of (-) trans to (+) trans of about 95:5
Example 6
Resolution of cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyI)-piperidine (Step 2 of Scheme 3)
i) Cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine ( 1.0 g) prepared by the method of Example 2 of EP 0219934, was dissolved in acetone (5 ml) and mixed with a solution of (+)-di-p-toluoyl-D- tartaric acid monohydrate (1.6g) in acetone (5 ml). Crystals separated on stirring and the suspension was left to stand for several hours. The crystals were collected by filtration, washed with acetone (5 ml) and dried under vacuum.
Yield 2.1 1 g.
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 1 : 1 ii) Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (+)-di-p-toluoyl-D- tartrate ( 1.0 g) was dissolved in hot methanol (5 ml) then allowed to cool. The flask was stored at 5°C for 18 hours during which time crystals separated. The crystals were collected, washed with methanol (5 ml) and dried under vacuum
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 90: 10.
(iii) A solution of (-)-dibenzoyl-L-tartaric acid monohydrate (0.75 g) in acetonitrile (10 ml) was mixed with a solution of racemic cis-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (0.5 g) in acetonitrile (15 ml) and stirred well. The crystals which separated within a few minutes were redissolved by heating to reflux, and the clear solution was allowed to cool to ambient temperature and stirred for 45 minutes. (+)Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine-(-)-dibenzoyl-tartrate crystals were collected by filtration, washed with acetonitrile (5ml) and dried under vacuum.
Yield 0.35 g.
Ratio (+) : (-) by chiral CE 94 : 6.
Example 7
Conversion of (+)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine. to (-) trans -l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine (Step 3 of Scheme 3)
(+)-cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (0.35g) is dissolved in dry toluene ( 10 ml) and treated with sodium methoxide (0.15g). The mixture is heated to reflux under nitrogen for 2 hours, then allowed to cool to ambient temperature. The solution is washed with water (10 ml) followed by saturated aqueous sodium chloride (10 ml) and the toluene is evaporated under reduced pressure to give (-)-trans-l-methyl- 3-carbomethoxy-4-(4'-fluorophenyl)piperidine as an oil.
A yield of about 0.30g is obtained, having the following properties:
N.M.R. δ (CDC13) - 7.15 (m, 2H), 6.95 (q, 2H), 3.44 (s, 3H, methyl ester), 3.10 (m, 1H), 2.88 (m. 2H), 2.75 (m, 1H), 2.18 (m, 2H), 1.80 (m, 2H).
Optical rotation [α]D ca. - 44 ° (c =1, methanol)
Example 8
Preparation of (-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine
(Step 4 of Schemes 2 and 3)
A solution of (-) trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (47.3g) in toluene (400 ml) is added dropwise over about 20 minutes to a nitrogen purged vessel containing lithium aluminium hydride in tetrahydrofuran (1.0 molar, 200 ml) maintaining a temperature of less than 10°C throughout the addition. The mixture is stirred at ambient temperature for about 2 hours, then quenched by the cautious addition of water (35 ml) followed by 10% aqueous sodium hydroxide solution (10 ml). The precipitated solids are removed by filtration through celite and washed with toluene (2 x 100 ml). The toluene solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans- 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methylpiperidine as a crystalline solid.
A yield of about 39 g is obtained. Example 9
Preparation of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-rnethylenedioxy- phenoxymethyl)-l-methylpiperidine.
Toluene (210 ml) is 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 (35.10 g) is added with stirring to ensure dissolution. The vessel contents are cooled to 5°C and dimethylethylamine (25.5 ml) is added, and then a nitrogen purge is attached and the vessel contents further cooled to 0°C. A mixture of benzenesulphonyl chloride and toluene (25 ml + 25 ml) is added slowly from a headflask over 70 minutes, maintaining the temperature between -2°C and +2°C. On completion of the addition, the mixture is stirred for 20 minutes, allowing the temperature to rise to 10°C.
A mixture of saturated sodium chloride (105 ml) and sodium hydroxide (3.5 g) dissolved in water (105 ml) is charged to the vessel over 10 minutes and stirring continued for 15 minutes at 10°C. The mixture is left to settle for 15 minutes and the aqueous phase is separated. The aqueous phase is extracted with toluene (15 ml) and the combined toluene phases dried over anhydrous magnesium sulphate (5.1 g) for 10 minutes. The solution is then filtered and the magnesium sulphate washed with toluene (10 ml). Approximately 100 ml of toluene is then removed by low pressure distillation, to leave about 200 ml of a dry solution of the intermediate sulphonate ester in toluene.
This solution is transferred to a clean, dry vessel, and N,N'-dimethylformamide (100 ml) is added. This mixture is~stirred, warmed to 50°C, and a solution of sesamol (22.8g) and sodium methoxide (9.33 g) in N,N'-dimethylformamide (50 ml) is added over 20 minutes. Water (0.85 ml) is added and the mixture heated to 70°C, and stirred at that temperature for 1 hour. After cooling to 50°C, water (250 ml) is added, and the mixture stirred for 15 minutes, allowed to settle, and the aqueous phase removed. The aqueous phase is extracted 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 is then dried over anhydrous magnesium sulphate (10.4 g), filtered, and the magnesium sulphate washed with toluene (25 ml). The combined toluene solutions are partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)- 1 -methylpiperidine.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, and the residue dried in a vacuum oven at 40°C to give (-) trans 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)- 1 -methylpiperidine as a pale yellow solid.
A yield of about 47 g is obtained
Example 10
Preparation of (-) trans-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-l-phenoxycarbonylpiperidine.
(-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l-methyl piperidine is (3.43g) dissolved in toluene (100 ml) and about half the toluene is removed by distillation to remove any traces of water. The solution is then held at 60°C and a solution of phenyl chloroformate (1.40 ml) in toluene ( 10 ml) is added dropwise with stirring under nitrogen, over 25 to 30 minutes. The mixture is then stirred at 60°C for 1 hour and cooled to ambient temperature. 5% sulphuric acid (10 ml) is added, the mixture was stirred well and the phases separated. The toluene phase is washed with water (10 ml) and the combined aqueous phases further are extracted with toluene (10 ml). The combined toluene phases are washed with water (10 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3,'4'-methylenedioxy phenoxymethyl)-l-phenoxycarbonyl piperidine. If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give (-) trans 4-(4'-fluorophenyl)-3-(3,'4'-methylenedioxy phenoxymethyl)-l- phenoxycarbonyl piperidine as a crystalline solid, which may be further purified by recrystallisation, for example from propan-2-ol.
A yield of about 4 g is obtained
Example 11 Preparation of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy - phenoxymethyl) piperidine (paroxetine free base).
Powdered potassium hydroxide (3.0 g) is added to a solution of (-) trans 4-(4'- fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l-phenoxycarbonyl piperidine (3.6g) in toluene (100 ml) and the well stirred mixture is refluxed for 2 hours. The mixture is cooled to ambient temperature, treated with water (100 ml), stirred well and the phases separated. The toluene phase is washed with water (50 ml), and partially evaporated at atmospheric or reduced pressure to give an anhydrous toluene solution of paroxetine free base.
If a solvent-free product is desired, the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give paroxetine free base as an oil.
A yield of about 2.5 g is obtained
Example 12
Preparation of paroxetine methane sulphonate
A toluene solution (1.0 L) containing unpurified paroxetine base (approximately 225 g) is charged to a nitrogen purged reactor and stirred at 20°C. The vessel is seeded with paroxetine methanesulfonate, then a solution of methane sulfonic acid (70 g) in propan- 2-ol (0.4L) is added slowly over a period of 50 minutes. Paroxetine methansulfonate is precipitated as a white crystalline solid during the addition, and the temperature at the end of the addition rises to about 30°C. The suspension is stirred for a further 1 hour, during which time the temperature is reduced to 22°C. The product is collected by filtration, washed on the filter with propan-2-ol (2 x 0.4 L) and dried in a vacuum oven at 40°C for 24 hours.
A yield of about 230 g is obtained
Example 13
Preparation of paroxetine hydrochloride hemihydrate.
A solution of paroxetine free base (13.5 g) in toluene (300 ml) is stirred at room temperature and concentrated hydrochloric acid (5.2 ml) is added. The mixture is stirred for 2 hours, then the product is collected, washed with a 1 : 1 mixture of toluene and water (25 ml) and dried at 50°C to give paroxetine hydrochloride hemihydrate.
The product may be recrystallised from aqueous propan-2-ol.
Example 14
Preparation of paroxetine hydrochloride anhydrate Form A
i) Trans(-)-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-N- phenoxycarbonyl piperidine (25 g) and potassium hydroxide flake (22.5 g) are suspended in toluene (375 ml) and the reaction mixture heated to reflux under nitrogen with vigorous stirring for 3 hours. The suspension is cooled to room temperature, washed with water (250 ml), and the layers separated. The organic layer is warmed to 50°C, then concentrated hydrochloric acid (6 ml) is added and the reaction mixture heated to reflux. Approximately half the toluene is removed by distillation to give an anhydrous toluene solution of paroxetine hydrochloride. The cooled toluene solution is diluted with acetone (300 ml), and the crystalline paroxetine hydrochloride acetone solvate is collected, washed with acetone and dried in vacuum.
The paroxetine hydrochloride acetone solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.
ii) (-)-Trans-4-(4-fluorophenyl)-3-(3 ',4'-methylenedioxyphenoxymethyl)- 1 - phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) in toluene (1500 ml) at reflux for 3 hours, cooled, washed with hot water, acidified with hydrochloric acid, and distilled to approximately one quarter volume under vacuum. Hot propan-2-ol (2000 ml) is added and the mixture cooled slowly with vigorous stirring until the temperature reaches 20°C. After stirring for a further 2 hours, the product is filtered, washed with propan-2-ol, and dried under vacuum, to give paroxetine hydrochloride propan-2-ol solvate.
The paroxetine hydrochloride propan-2-ol solvate is desolvated to paroxetine hydrochloride anhydrate Form A as described in WO96/24595.

Claims

1. A process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising
a) reducing a pyridinium salt of formula (1)
Figure imgf000037_0001
to obtain a cis piperidine ester of formula (2)
Figure imgf000037_0002
b) converting the cis piperidine ester of formula (2) to the corresponding trans ester by epimerising with a strong base,
c) reducing the trans piperidine ester of formula (2) with a hydride reducing agent to obtain the corresponding trans carbinol,
d) resolving the racemic trans carbinol by use of a chiral acid, liberating and extracting the free base of the (-) trans carbinol, e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,
g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
2. A process according to claim 1 which comprises the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine as a crystalline solid,
b) converting cis- l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine to the corresponding trans ester by epimerising with a strong base, with optional isolation of the trans ester,
c) reducing trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the trans carbinol, that is trans-4-(4'- fluorophenyl)-3-hydroxymethyl- 1 -methylpiperidine,
d) resolving the trans carbinol. by use of a chiral acid, liberating, extracting and optionally isolating the free base of the (-) trans carbinol,
e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine, deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,
g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
3. A process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising a) reducing a pyridinium salt of formula ( 1 )
Figure imgf000039_0001
to obtain a cis piperidine ester of formula (2)
Figure imgf000039_0002
b) converting the cis piperidine ester of formula (2) to the corresponding trans ester by epimerising with a strong base, c) resolving the racemic trans piperidine ester enzymatically to give the (-) trans piperidine ester,
d) reducing the (-) trans piperidine ester with a hydride reducing agent to obtain the corresponding (-) trans carbinol,
e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,
g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
4. A process according to claim 3 which comprises the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine as a crystalline solid,
b) epimerising the cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine to the corresponding trans ester with a strong base, with optional isolation of the trans ester, and
c) enzymatic resolution of the trans ester to give the (-) trans ester, liberating, extracting and optionally isolating the (-) trans ester,
d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine, e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine,
deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,
g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
5. A process for the manufacture of paroxetine and pharmaceutically acceptable salts thereof comprising
a) reducing a pyridinium salt of formula (1)
Figure imgf000041_0001
to obtain a cis piperidine ester of formula (2
C02R4
N I R3
(2) b) converting the racemic cis piperidine ester of formula (2) to the (+) cis ester,
c) epimerising the (+) cis piperidine ester with a strong base to form the corresponding (-) trans piperidine ester,
d) reducing (-) trans piperidine ester with a hydride reducing agent and to obtain the corresponding (-) trans carbinol,
e) forming a sulphonate ester of the (-) trans carbinol then coupling with sesamol, to obtain an N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation of a carbamate, followed by hydrolysis to generate paroxetine base,
g) isolating the paroxetine base or forming a paroxetine salt by contacting the paroxetine base with a source of a preferably pharmaceutically acceptable acid, and isolating the salt.
6. A process according to claim 5 which comprises the steps of
a) reducing a l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) pyridinium salt and optionally isolating cis l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine as a crystalline solid,
b) converting cis- l-methyl-3-carbomethoxy-4-(4 '-fluorophenyl) piperidine to the (+) cis ester, liberating and optionally isolating the (+) cis ester as a crystalline solid,
c) epimerising the (+) cis ester with a strong base to form the corresponding (-) trans ester, with optional isolation of the (-) trans ester, d) reducing (-) trans l-methyl-3-carbomethoxy-4-(4 -fluorophenyl) piperidine with a hydride reducing agent and optionally isolating the (-) trans carbinol, that is (-) trans-4- (4'-fluoropheny l)-3-hydroxymethy 1- 1 -methylpiperidine,
e) forming and optionally isolating a sulphonate ester of the (-) trans carbinol then coupling with sesamol, and optionally isolating the resulting N-protected paroxetine,
f) deprotecting the N-protected paroxetine via formation and optional isolation of a carbamate, followed by a hydrolysis reaction, generating and optionally isolating paroxetine base,
g) forming a paroxetine salt by contacting the paroxetine base with a source of a pharmaceutically acceptable acid, optionally converting to a second paroxetine salt, and isolating drying and optionally recrystallising the final product.
7. A process according to any preceding claim in which two or more of the steps are carried out in a common reaction solvent, optionally with one or more additional solvents.
8. A process according to any preceding claim which comprises combining one or more of the steps a) to g).
9. A paroxetine product selected from the free base or a pharmaceutically acceptable paroxetine salt, especially the mesylate and hydrochloride obtained by a process as claimed in any one of claims 1 to 8.
10. A method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or a salt thereof such as paroxetine mesylate or paroxetine hydrochloride obtained using the process claimed in any one of claims 1 to 8 to a person suffering from one or more of the Disorders.
PCT/GB2000/004060 1999-10-20 2000-10-20 Process for the preparation of paroxetine Ceased WO2001029031A1 (en)

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US8580821B2 (en) 2006-04-03 2013-11-12 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
CN101205211B (en) * 2006-12-19 2011-12-14 北京德众万全药物技术开发有限公司 Method for preparing hydrochloric paroxetine key intermediates
US8344161B2 (en) 2008-12-16 2013-01-01 Hoffmann-La Roche Inc. Process for the preparation of pyrollidine-3-carboxylic acids
CN108486171A (en) * 2018-03-12 2018-09-04 江苏扬农化工股份有限公司 A kind of preparation method of the first chrysanthemumic acid of d-trans
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CN115724831A (en) * 2022-11-18 2023-03-03 上海陶术生物科技有限公司 Preparation method and application of (3S, 4R) -piperidine compound

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