WO2001029031A1 - Procede de preparation de paroxetine - Google Patents

Procede de preparation de 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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Prior art keywords
paroxetine
trans
ester
piperidine
fluorophenyl
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PCT/GB2000/004060
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English (en)
Inventor
Gary Thomas Borrett
David Crowe
Neal Ward
Andrew Stephen Wells
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Smithkline Beecham P.L.C.
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Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU10379/01A priority Critical patent/AU1037901A/en
Publication of WO2001029031A1 publication Critical patent/WO2001029031A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne trois schémas de procédé (1), (2) et (3) qui fournissent une voie complète menant à la paroxétine, à partir d'un ester de pyridine.
PCT/GB2000/004060 1999-10-20 2000-10-20 Procede de preparation de paroxetine WO2001029031A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10379/01A AU1037901A (en) 1999-10-20 2000-10-20 Process for the preparation of paroxetine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9924855.1A GB9924855D0 (en) 1999-10-20 1999-10-20 Novel processes
GB9924855.1 1999-10-20

Publications (1)

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WO2001029031A1 true WO2001029031A1 (fr) 2001-04-26

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PCT/GB2000/004060 WO2001029031A1 (fr) 1999-10-20 2000-10-20 Procede de preparation de paroxetine

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AU (1) AU1037901A (fr)
GB (1) GB9924855D0 (fr)
WO (1) WO2001029031A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1242378A1 (fr) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Nouveaux procedes
US7872022B2 (en) 2006-04-03 2011-01-18 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
CN101205211B (zh) * 2006-12-19 2011-12-14 北京德众万全药物技术开发有限公司 一种盐酸帕罗西汀重要中间体的制备方法
US8344161B2 (en) 2008-12-16 2013-01-01 Hoffmann-La Roche Inc. Process for the preparation of pyrollidine-3-carboxylic acids
CN108486170A (zh) * 2018-03-12 2018-09-04 江苏扬农化工股份有限公司 一种右旋反式二氯菊酸的制备方法
CN108486171A (zh) * 2018-03-12 2018-09-04 江苏扬农化工股份有限公司 一种右旋反式第一菊酸的制备方法
CN115724831A (zh) * 2022-11-18 2023-03-03 上海陶术生物科技有限公司 (3s,4r)-哌啶类化合物的制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0219934A1 (fr) * 1985-08-10 1987-04-29 Beecham Group Plc Procédé de préparation d'esters d'aryl-pipéridines
EP0223334A1 (fr) * 1985-08-10 1987-05-27 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0219934A1 (fr) * 1985-08-10 1987-04-29 Beecham Group Plc Procédé de préparation d'esters d'aryl-pipéridines
EP0223334A1 (fr) * 1985-08-10 1987-05-27 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1242378A1 (fr) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Nouveaux procedes
EP1242378A4 (fr) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Nouveaux procedes
US7872022B2 (en) 2006-04-03 2011-01-18 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
US8580821B2 (en) 2006-04-03 2013-11-12 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
CN101205211B (zh) * 2006-12-19 2011-12-14 北京德众万全药物技术开发有限公司 一种盐酸帕罗西汀重要中间体的制备方法
US8344161B2 (en) 2008-12-16 2013-01-01 Hoffmann-La Roche Inc. Process for the preparation of pyrollidine-3-carboxylic acids
CN108486170A (zh) * 2018-03-12 2018-09-04 江苏扬农化工股份有限公司 一种右旋反式二氯菊酸的制备方法
CN108486171A (zh) * 2018-03-12 2018-09-04 江苏扬农化工股份有限公司 一种右旋反式第一菊酸的制备方法
CN115724831A (zh) * 2022-11-18 2023-03-03 上海陶术生物科技有限公司 (3s,4r)-哌啶类化合物的制备方法和应用

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Publication number Publication date
GB9924855D0 (en) 1999-12-22
AU1037901A (en) 2001-04-30

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