+

WO2001029032A1 - Nouveaux procedes - Google Patents

Nouveaux procedes Download PDF

Info

Publication number
WO2001029032A1
WO2001029032A1 PCT/GB2000/004066 GB0004066W WO0129032A1 WO 2001029032 A1 WO2001029032 A1 WO 2001029032A1 GB 0004066 W GB0004066 W GB 0004066W WO 0129032 A1 WO0129032 A1 WO 0129032A1
Authority
WO
WIPO (PCT)
Prior art keywords
trans
paroxetine
ester
piperidine
cis
Prior art date
Application number
PCT/GB2000/004066
Other languages
English (en)
Other versions
WO2001029032A8 (fr
Inventor
David Crowe
Neal Ward
Andrew Stephen Wells
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU10385/01A priority Critical patent/AU1038501A/en
Publication of WO2001029032A1 publication Critical patent/WO2001029032A1/fr
Publication of WO2001029032A8 publication Critical patent/WO2001029032A8/fr

Links

Classifications

    • 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

Definitions

  • This invention relates to processes for the manufacture of paroxetine and pharmaceutically acceptable salts thereof which are suitable for large scale commercial operation.
  • arecoline is used to prepare piperidines using a literature procedure (J.T. Plati, A.K Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume 22 pages 261-265).
  • Plati et al describe the reaction of arecoline with phenyl magnesium bromide in diethyl ether to prepare l-methyl-3-carbomethoxy-4-phenyl piperidine.
  • arecoline base is liberated from the hydrobromide salt and reacted with the Grignard reagent 4-fluorophenyl magnesium bromide using the procedure of Plati et al to give a piperidine ester of structure (2).
  • This piperidine ester is converted to a piperidine carbinol of structure (3), which is coupled with sesamol, then deprotected. to give paroxetine (4).
  • Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine.
  • the above described processes produce 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 (2) and (3) are thus compounds (A) and (B) which are in the (-) trans configuration:
  • R and R' are independently an alkyl, aryl, or arylalkyl group, most suitably lower alkyl, which comprises reacting a compound of structure (6) where R and R' are as defined for structure (5) R (6) with a Grignard reagent in a suitable non-ether reaction solvent, optionally in the presence of a proportion of an additional solvent.
  • the Grignard reagent may either be prepared in the chosen reaction solvent, or prepared in an ether solvent and the ether subsequently removed by distillation and replaced by the chosen solvent. When little or no additional solvent is employed, the Grignard reagent may be partially or completely insoluble, but the resulting reaction suspension is stirrable and compatible with large scale operation. When a significant proportion of suitable additional solvent is employed, a completely clear reaction solution may be obtained, rendering the process particularly suitable for industrial scale operation.
  • Compounds of formula (6) may be prepared from the natural products guvacine, arecaidine or arecoline, by conventional methods, or by synthesis from other materials.
  • a particularly convenient synthetic procedure involves the esterification, quaternisation and partial reduction of nicotinic acid [see for example Journal of Organic Chemistry (1955), volume 20, pages 1761-1765; Journal of Chemical Research (1983), volume 10, pages 2326 - 2342; Journal of Pharmaceutical Sciences (1992), volume 81, pages 1015 -1019; and references quoted therein].
  • 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 from an arecoline derivative and a 4-fluorophenylmagnesium halide which comprises the steps
  • this aspect of the invention comprises
  • 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).
  • the compound of formula (6) is most conveniently arecoline.
  • Suitable arecoline salts at step a) are the hydrobromide and hydrochloride.
  • a preferred arecoline salt is the hvdrobromide.
  • Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride.
  • a preferred halide is the bromide.
  • 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 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.
  • additional solvent is dependant on the individual chemical step.
  • a preferred additional solvent for the reaction of arecoline with a Grignard reagent is diethyl ether as this solvent selectively promotes the desired 1 ,4 addition reaction of the Grignard reagent to arecoline.
  • 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 arecoline by an alternative sequence of steps involving the formation and reduction of (-) trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine (A), and employed in the synthesis of paroxetine.
  • A trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine
  • trans ester of structure (5) can be prepared by enzymatic resolution of a racemic trans ester of structure (5), enabling paroxetine to be manufactured from arecoline by the steps outlined in Scheme 2.
  • a particular embodiment of this aspect of the invention comprises a) reacting an arecoline salt with a 4-fluorophenylmagnesium halide, optionally isolating the intermediate arecoline base, extracting and optionally isolating cis/trans l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine,
  • 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 arecoline salts at step a) are the hydrobromide and hydrochloride.
  • a preferred arecoline salt is the hydrobromide.
  • Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride. A preferred halide is the bromide.
  • 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 (C)
  • (C) 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 (C) 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.
  • additional solvent is dependant on the individual chemical step.
  • a preferred additional solvent for the reaction of arecoline with a Grignard reagent is diethyl ether as this solvent selectively promotes the desired 1 ,4 addition reaction of the Grignard reagent to arecoline.
  • 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 (5) by a novel procedure which comprises resolution of the racemic cis ester to give the (+) cis form, 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, via the formation of a salt with a chiral acid.
  • this aspect of the invention comprises
  • 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).
  • the compound of formula (6) is most conveniently arecoline.
  • Suitable arecoline salts at step a) are the hydrobromide and hydrochloride.
  • a preferred arecoline salt is the hydrobromide.
  • Suitable 4-fluorophenylmagnesium halides at step a) are 4-fluorophenylmagnesium bromide and 4-fluorophenylmagnesium chloride.
  • a preferred halide is the bromide.
  • 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 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.
  • additional solvent is dependant on the individual chemical step.
  • a preferred additional solvent for the reaction of arecoline with a Grignard reagent is diethyl ether as this solvent selectively promotes the desired 1 ,4 addition reaction of the Grignard reagent to arecoline.
  • 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 as the base, and also particularly as 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.
  • 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”.
  • PMS pre-menstrual syndrome
  • the paroxetine products obtainable by the present invention is applied to the treatment of depression, OCD and panic.
  • compositions containing paroxetine products prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
  • the composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
  • Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
  • compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
  • Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
  • compositions include those described EP-B- 0223403, and US 4,007, 196 in which the anhydrate product of the present invention may be used as the active ingredient.
  • 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
  • a 60% dispersion of sodium hydride in mineral oil (2.0 g) is added carefully to a suspension of arecoline hydrobromide (1 1.8 g) in toluene and the mixture cooled to about -10°C.
  • a solution of 4-fluorophenylmagnesium bromide in diethyl ether (2.0M, 50 ml) is added slowly with stirring under argon, maintaining the temperature at about - 10°C, and the mixture is stirred at this temperature for 3 hours
  • reaction is quenched by adding 2M hydrochloric acid (250 ml).
  • the aqueous layer is washed with toluene (100 ml) then covered with fresh toluene (100 ml) and ad j usted to pH 9-10 by the cautious addition of anhydrous potassium carbonate.
  • the precipitated solids are removed by filtration, the phases are separated and the aqueous phase is extracted twice more with toluene (100 ml).
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as an oily solid.
  • dichloromethane 100 ml
  • the phases are separated, and the aqueous phase further extracted with dichloromethane (2 x 250 ml).
  • the organic solutions are combined, washed with saturated sodium chloride (50 ml) and partially evaporated at atmospheric or reduced pressure to give an anhydrous dichloromethane solution of cis/trans 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine.
  • the dichloromethane solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as an oily solid.
  • Piperidine ester made in this way has a cis/trans ratio, measured by HPLC or NMR analysis, of about 2.2: 1
  • the toluene solution may be further distilled at atmospheric or reduced pressure until no more solvent can be removed, to give cis/trans l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine as an oily solid.
  • Piperidine ester made in this way has a cis/trans ratio, measured by HPLC or NMR analysis, of about 2.9: 1
  • a nitrogen purged vessel is charged with a solution of cis/trans l-methyl-3- carbomethoxy-4-(4'- fluorophenyl) piperidine (115 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.
  • 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 (-) trans-4-(4'-fluorophenyl)-3-hydroxymethyl- l -methylpiperidine as a crystalline solid, which may be further purified by recrystallisation
  • Racemic trans- l-methyl-3-carbomethoxy-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.
  • a yield of about 0.5 g is obtained.
  • Chiral capillary electrophoresis shows the trans ester to have a ratio of (-) trans to (+) trans of about 95:5
  • Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-dibenzoyl-L- tartrate ( 15.0g) is dissolved in hot methanol (100 ml) the solution allowed to cool to room temperature, then stored at 5°C for 3 days.
  • the crystals of (+) cis -l-methyl-3- carbomethoxy-4-(4 -fluorophenyl) piperidine (-)-dibenzoyl-L-tartrate are collected by filtration, washed with acetone (10 ml) and dried under vacuum.
  • Chiral capillary electrophoresis shows the salt to have a ratio of (+) cis to (-) cis of about 96:4
  • (+) cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-dibenzoyl-L- tartrate (1.5g) is suspended in a mixture of ethyl acetate (30 ml) and water (15 ml), and 10%w/w aqueous sodium hydroxide (5 ml) is added. The layers are separated and the aqueous layer extracted again with ethyl acetate (50 ml).
  • a yield of about 0.6 g is obtained, having the following properties:
  • N.M.R ⁇ (CDC13) - 7.25 (m, 2H), 6.95 (m, 2H), 3.51 (s, 3H, methyl ester), 3.15 (m, IH), 2.96 (m, 2H), 2.80 (m, IH), 2.65 (m, IH), 2.35 (m, IH), 2.28 (s, 3H), 2.10 (m, IH), 1.80 (m, IH)
  • (+)-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 U 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)-l- 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- ⁇ henoxycarbonyl 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)- 1 -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 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
  • toluene 300 ml
  • concentrated hydrochloric acid 5.2 ml
  • 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.
  • 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.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne trois schémas (1, 2 and 3) de procédés destinés à la fabrication de paroxétine à partir d'arécoline.
PCT/GB2000/004066 1999-10-20 2000-10-20 Nouveaux procedes WO2001029032A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10385/01A AU1038501A (en) 1999-10-20 2000-10-20 Novel processes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9924882.5A GB9924882D0 (en) 1999-10-20 1999-10-20 Novel process
GB9924882.5 1999-10-20

Publications (2)

Publication Number Publication Date
WO2001029032A1 true WO2001029032A1 (fr) 2001-04-26
WO2001029032A8 WO2001029032A8 (fr) 2001-05-25

Family

ID=10863097

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/004066 WO2001029032A1 (fr) 1999-10-20 2000-10-20 Nouveaux procedes

Country Status (3)

Country Link
AU (1) AU1038501A (fr)
GB (1) GB9924882D0 (fr)
WO (1) WO2001029032A1 (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
WO2004043921A1 (fr) * 2002-11-11 2004-05-27 Natco Pharma Limited Nouveau procede de preparation de 4-aryl-3-hydroxymethyl-1-methylpiperidines
WO2005063707A1 (fr) * 2003-12-26 2005-07-14 Natco Pharma Limited Procede enantiospecifique permettant de preparer un intermediaire de paroxetine
US7138523B2 (en) 2002-05-16 2006-11-21 Apotex Pharmachem Inc. Preparation of 4-(4-fluorophenyl)-N-alkylnipecotinate esters, 4-(4-fluorophenyl)-N-arylnipecotinate esters and 4-(4-fluorophenyl)-N-aralkylnipecotinate esters
WO2007015262A2 (fr) * 2005-04-25 2007-02-08 Sun Pharmaceutical Industries Limited Procede pour preparer de la (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine
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
CN117964546A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种尼拉帕利中间体的制备方法

Citations (8)

* 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
EP0614986A1 (fr) * 1993-03-03 1994-09-14 Synthelabo Dédoublement enzymatique de pipéridine-2-carboxylates d'alkyle et utilisation des composés obtenus comme intermédiaires de synthèse
WO1998002556A2 (fr) * 1996-07-15 1998-01-22 Smithkline Beecham Plc Criblage et utilisation d'esterase pour dedoublement stereospecifique
WO1998045263A1 (fr) * 1997-04-07 1998-10-15 Georgetown University Analogues de cocaine
US5948914A (en) * 1996-06-13 1999-09-07 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
WO2000020390A1 (fr) * 1998-10-07 2000-04-13 Georgetown University Heterocycles monomeres et dimeres et leurs utilisations therapeutiques

Patent Citations (8)

* 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
EP0614986A1 (fr) * 1993-03-03 1994-09-14 Synthelabo Dédoublement enzymatique de pipéridine-2-carboxylates d'alkyle et utilisation des composés obtenus comme intermédiaires de synthèse
US5948914A (en) * 1996-06-13 1999-09-07 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
WO1998002556A2 (fr) * 1996-07-15 1998-01-22 Smithkline Beecham Plc Criblage et utilisation d'esterase pour dedoublement stereospecifique
WO1998045263A1 (fr) * 1997-04-07 1998-10-15 Georgetown University Analogues de cocaine
WO2000020390A1 (fr) * 1998-10-07 2000-04-13 Georgetown University Heterocycles monomeres et dimeres et leurs utilisations therapeutiques

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
US7138523B2 (en) 2002-05-16 2006-11-21 Apotex Pharmachem Inc. Preparation of 4-(4-fluorophenyl)-N-alkylnipecotinate esters, 4-(4-fluorophenyl)-N-arylnipecotinate esters and 4-(4-fluorophenyl)-N-aralkylnipecotinate esters
WO2004043921A1 (fr) * 2002-11-11 2004-05-27 Natco Pharma Limited Nouveau procede de preparation de 4-aryl-3-hydroxymethyl-1-methylpiperidines
WO2005063707A1 (fr) * 2003-12-26 2005-07-14 Natco Pharma Limited Procede enantiospecifique permettant de preparer un intermediaire de paroxetine
WO2007015262A2 (fr) * 2005-04-25 2007-02-08 Sun Pharmaceutical Industries Limited Procede pour preparer de la (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine
WO2007015262A3 (fr) * 2005-04-25 2009-05-07 Sun Pharmaceutical Ind Ltd Procede pour preparer de la (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine
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
CN117964546A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种尼拉帕利中间体的制备方法

Also Published As

Publication number Publication date
AU1038501A (en) 2001-04-30
WO2001029032A8 (fr) 2001-05-25
GB9924882D0 (en) 1999-12-22

Similar Documents

Publication Publication Date Title
EP0223403B1 (fr) Dérivé de pipéridine, sa préparation et son utilisation comme médicament
EP0374801B1 (fr) Acides azahétérocycliques N-substitués
JP2010143925A (ja) （Ｒ）−α−（２，３−ジメトキシフェニル）−１−［２−（４−フルオロフェニル）エチル］−４−ピペリジンメタノールの製造方法
US6716985B2 (en) Process for making paroxetine
US20040087795A1 (en) Novel processes for the preparation of 4-phenylpiperidine derivatives
WO2001029032A1 (fr) Nouveaux procedes
WO2001029031A1 (fr) Procede de preparation de paroxetine
JP3819532B2 (ja) ピペリジン誘導体およびその製造方法
EP1560825A1 (fr) Nouveaux derives de 2,3-dihydro-4(1h)-pyridinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
AU660919B2 (en) N-substituted azaheterocyclic carboxylic acids and a pharmaceutical composition
WO2001014335A1 (fr) Procede de preparation d'un intermediaire de paroxetine
WO2001002357A2 (fr) Nouveau procede de preparation
WO2002032870A1 (fr) Procede de preparation de composes de -4-aryle piperidine substitue en position 3
EP1242378A1 (fr) Nouveaux procedes
WO2001029002A1 (fr) Preparation d'esters de 4-(fluorophenyl)piperidine
CZ421999A3 (cs) Nový způsob
WO2001017966A1 (fr) Procede de preparation de 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine
KR20010013102A (ko) 신규한 방법
AU1563002A (en) Novel process

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

AK Designated states

Kind code of ref document: C1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: C1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

CFP Corrected version of a pamphlet front page

Free format text: UNDER (54) PUBLISHED TITLE REPLACED BY CORRECT TITLE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载