WO2003072104A1 - Preparation of paroxetine involving novel intermediates - Google Patents
Preparation of paroxetine involving novel intermediates Download PDFInfo
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- WO2003072104A1 WO2003072104A1 PCT/US2002/013826 US0213826W WO03072104A1 WO 2003072104 A1 WO2003072104 A1 WO 2003072104A1 US 0213826 W US0213826 W US 0213826W WO 03072104 A1 WO03072104 A1 WO 03072104A1
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- paroxetine
- solvent
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- 0 **(CC1)CC(COc2ccc3OCOc3c2)C1c(cc1)ccc1F Chemical compound **(CC1)CC(COc2ccc3OCOc3c2)C1c(cc1)ccc1F 0.000 description 1
- MOJZPKOBKCXNKG-UHFFFAOYSA-N CN(CC1)CC(COc2ccc3OCOc3c2)C1c(cc1)ccc1F Chemical compound CN(CC1)CC(COc2ccc3OCOc3c2)C1c(cc1)ccc1F MOJZPKOBKCXNKG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- 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
- the present invention relates to processes for the synthesis of intermediates useful in preparing paroxetine (P X); processes for preparing paroxetine using such intermediates; and, to intermediates of the disclosed processes. More particularly, the present invention relates to a novel process for the preparation of paroxetine by dealkylation of N-alkylparoxetine, such as N-methylparoxetine (Me-PRX), and to novel intermediates of this process.
- N-alkylparoxetine such as N-methylparoxetine (Me-PRX
- Paroxetine has formula (I):
- Example 2 of U.S. Patent No. 4,007,196 discloses formation of paroxetine by demethylation of N-methylparoxetine (Me-PRX) having formula (II):
- Me-PRX is demethylated by reaction with phenylchloroformate in methylene chloride to form the corresponding phenyl carbamate intermediate.
- the phenyl carbamate intermediate is hydrolyzed to yield paroxetine by refluxing in benzene with potassium hydroxide and methyl cellosolve for four hours.
- disadvantages of this process are the low conversion of Me-PRX to the phenyl carbamate, resulting in low yields of paroxetine. This process also results in large quantities of phenol as an undesirable by-product.
- U.S. Patent No. 4,721,723 describes a process for preparing paroxetine wherein Me-PRX is reacted with ⁇ -chloroethyl-chloroformate (1-chloroethyl-chloroformate) to form the corresponding 1-chloroethyl carbamate of paroxetine, which is then hydrolyzed under acidic conditions to yield paroxetine.
- a significant disadvantage of this process is the long time required for the conversion of Me-PRX to paroxetine under the conditions disclosed in, for example, Examples 6 and 7 of the '723 patent.
- EP 0 810 225 Al discloses a process for producing paroxetine by reacting Me-PRX with a lower alkyl, lower cycloalkyl, aralkyl orC m F 2m+1 ester of haloformic acid to yield a carbamate intermediate.
- the corresponding carbamate intermediate is hydrolyzed in an appropriate solvent under alkaline conditions to yield paroxetine, which is extracted from the reaction mixture with an appropriate solvent such as toluene.
- the hydrolysis of the carbamate intermediate took from 2-3 days of reflux with alkali and produced low to moderate yields of paroxetine.
- WO 00/78753 discloses forming a finely divided complex of a base (preferably potassium hydroxide), and a carbamate intermediate obtained from the demethylation of Me-PRX and refluxing in a solvent (preferably toluene) to yield paroxetine.
- a base preferably potassium hydroxide
- a carbamate intermediate obtained from the demethylation of Me-PRX and refluxing in a solvent (preferably toluene) to yield paroxetine.
- the present invention is directed to a compound of formula (Nil):
- R ⁇ is a haloalkyl other than 1-monohaloalkyl or perfluoroalkyl.
- R t is 2-chloroethyl.
- R j is 2,2,2- trichloroethyl.
- the present invention is directed to a process for preparing a compound of formula (Nil) comprising reacting a compound of formula (N) with compound of formula (VI) in a suitable organic solvent,
- Z is a halogen
- Ri is as defined above
- R 2 is a lower alkyl.
- Z is chlorine
- R ⁇ is 2-chloroethyl or 2,2,2-trichloroethyl
- R 2 is methyl.
- the reaction is conducted in the presence of a tertiary amine base.
- a particularly preferred tertiary amine base is a trialkylamine such as triethylamme or tributylamine.
- the present invention is directed to a process for preparing paroxetine comprising hydrolyzing a compound of formula (Nil), preferably under alkaline conditions.
- the hydrolysis is conducted in the presence of a glycol monoether.
- a particularly preferred glycol monoether is propylene glycol monomethyl ether (PGME).
- the present invention is directed to a compound of formula (VIII):
- the present invention is directed to a process for preparing a compound of formula (NIII) comprising hydrolyzing of a compound of formula (VII), preferably under alkaline conditions, in the presence of propylene glycol monomethyl ether (PGME).
- PGME propylene glycol monomethyl ether
- the present invention is directed to a process for preparing paroxetine comprising the steps of reacting ⁇ -alkyl paroxetine with a haloformic acid ester of formula (NI) in a suitable organic solvent to form a carbamate intermediate of formula (Nil), and hydrolyzing the carbamate intermediate of formula (VII), preferably under alkaline conditions, to obtain paroxetine.
- the carbamate intermediate is hydrolyzed in the presence of a glycol monoether.
- Paroxetine base may be recovered from the reaction mixture.
- An acid addition salt, preferably a pharmaceutically acceptable acid addition salt of paroxetine may then be formed from the paroxetine base.
- paroxetine HC1 in any of the various polymorphic forms of paroxetine HC1 as are known in the art.
- polymorphic forms of paroxetine HC1 are included crystalline paroxetine HC1 hemihydrate, anhydrous paroxetine HC1 and paroxetine HC1 solvates, for example the isopropanolate of paroxetine HC1.
- the present invention is directed to a process for preparing a novel carbamate intermediate of paroxetine having formula (VII) wherein R ⁇ is a haloalkyl group, other than 1-monohaloalkyl or perfluoroalkyl, by the dealkylation of N- alkylparoxetine of formula (V) wherein R 2 is a lower alkyl.
- haloalkyl refers to a - alkyl group in which one or more of the carbon atoms is substituted with one or more halogen atoms.
- Preferred haloalkyl groups are C r C 4 alkyl groups in which one or more of the carbon atoms is substituted with one or more halogen atoms.
- the alkyl group may be a straight or branched-chain alkyl group.
- the halogen atom is one or more of fluorine, chlorine, bromine and iodine.
- 2-haloalkyl groups such as 2-haloethyl and 2-halopropyl.
- 2-haloalkyl refers to a C 2 -C 6 alkyl group in which the carbon atom at the 2- position is substituted with one or more halogen atoms.
- preferred 2-haloalkyl groups are 2-chloroethyl and 2,2,2-trichloroethyl.
- 1-monohaloalkyl refers to a C 2 -C 6 alkyl radical having only a single halogen atom, which halogen atom is at the 1 -position of the alkyl radical.
- the term "1-monohaloalkyl,” for example, does not include 1,2-dichloroethyl, 1,1-dichloroethyl or chloromethyl.
- perfluoroalkyl refers to the group C m F 2m+1 , where m is an integer of from 1 to 6.
- lower alkyl refers to a straight or branched chain C r C 6 alkyl group.
- R 2 in the compound of formula (V) are ethyl and methyl.
- R 2 is methyl
- the compound of formula (V) is N-methyl paroxetine (Me-PRX) having formula (II).
- Compound (V) is dealkylated by reacting it with a haloformic acid ester of formula (VI), wherein Z is a halogen atom such as fluorine, chlorine, bromine or iodine, and R j is as defined above.
- haloformic acid esters of formula (VI) are the 2- haloalkyl esters.
- a particularly preferred 2-haloalkyl ester of haloformic acid is the 2- chloroethyl ester wherein Z is chlorine, i.e., 2-chloroethyl-chloroformate ("CECF").
- Another preferred haloformic acid ester is 2,2,2-trichloroethyl-chloroformate.
- the dealkylation of compound (V), i.e., N-alkylparoxetine, is conducted in a suitable organic solvent.
- suitable organic solvents include dichloromethane, chloroform, diethyl ether, t-buryl methyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane, petroleum ether, methyl acetate, ethyl acetate, N,N-dimethylformamide and N,N-dimethylacetamide.
- Aromatic solvents such as toluene are among those preferred for conducting the dealkylation of compound (V). Dry toluene is a particularly preferred solvent for conducting the dealkylation reaction. For example, toluene having a water content within the range of from about 0.10% (technical grade toluene) to about 0.001% (extra dry toluene) may be used as the solvent for conducting the dealkylation.
- the N-alkylparoxetine and haloformic acid ester are preferably added to toluene kept at a temperature of from about 0°C to about 10°C, more preferably about 5 °C.
- the reaction temperature is preferably in the range of from about 10° to about 150°C, more preferably from about 20° to about 120°C.
- the reaction mixture may be heated to a temperature near or, preferably, at reflux conditions and the reaction is preferably conducted for a time sufficient to effect substantially complete conversion of the N- alkylparoxetine to the corresponding carbamate.
- the haloformic acid ester may be added dropwise at the reflux temperature of the reaction mixture and continuing reflux for up to about 10 hours, or until substantially complete conversion of the N- alkylparoxetine to the corresponding carbamate has occurred.
- substantially complete conversion refers to conversion of about 90% or more, preferably about 95% or more and, more preferably, about 99% or more of the N-alkylparoxetine to the corresponding carbamate.
- the dealkylation of compound (V) is conducted in the presence of a base.
- suitable bases include, for example, an organic amine, of which tertiary amines are preferred, an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal hydride, an alkaline earth metal hydride or an alkali or alkaline earth metal carbonate or hydrogencarbonate salt.
- suitable bases include, for example, l,8-bis(N,N-dimethylamino)napthalene, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium carbonate and basic alumina.
- Preferred bases are tertiary amines such as trialkylamines of the general formula (R) 3 N, wherein each R is the same or different C r C 6 straight or branched-chain alkyl.
- Preferred triallcylamines are tributylamine (Bu 3 N) and triethylamine (Et 3 N).
- Tributylamine is a particularly preferred trialkylamine base.
- the organic layer is separated, and preferably washed and dried. Water may be used to wash the separated organic layer and a suitable drying agent such as Na 2 SO 4 may be used to dry the washed organic layer.
- a suitable drying agent such as Na 2 SO 4 may be used to dry the washed organic layer.
- the mixture is preferably cooled, such as by adding water to cool the reaction mixture to room temperature. The preferably cooled reaction mixture is concentrated to dryness by, for example, evaporation.
- the resultant product is a carbamate intermediate of paroxetine having formula (VII).
- the compound of formula (VII) is novel compound in accordance with the present invention.
- a particularly preferred novel carbamate intermediate in accordance with this aspect of the present invention is a compound of formula (IV), i.e., the compound of formula (VII) wherein R is 2-chloroethyl:
- This compound is referred to herein as the 2-chloroethyl carbamate of paroxetine or "CECB".
- CECB 2-chloroethyl carbamate of paroxetine
- Another preferred carbamate is the 2,2,2-trichloroethyl carbamate of paroxetine, which has the following structure (IX):
- Another aspect of the present invention is a process for preparing paroxetine by hydrolyzing a carbamate intermediate of formula (VII), preferably under alkaline conditions, to yield paroxetine.
- the carbamate intermediate of formula (VII) is hydrolyzed in an appropriate solvent to yield paroxetine.
- the reaction temperature is preferably from 10 to 150 °C, more preferably from 20 to 120 °C.
- the reaction mixture may be heated to a temperature near or, preferably, at reflux conditions and the reaction is preferably conducted for a time sufficient to effect substantially complete conversion of the carbamate intermediate of formula (VII) to paroxetine.
- the hydrolysis of the carbamate may be conducted under acidic or, preferably, under alkaline conditions.
- suitable bases for conducting the alkaline hydrolysis are included, for example, an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali or alkaline earth metal carbonate or hydrogencarbonate salt.
- suitable bases include, for example, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and calcium carbonate.
- Preferred bases include, for example, the alkali metal hydroxides such as sodium hydroxide and potassium hydroxide and the alkaline earth metal hydroxides.
- solvents for conducting the alkaline hydrolysis of the carbamate intermediate are included, for example, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane, petroleum ether, methanol, ethanol, isopropanol, t-butanol, glycol monoethers, water, and mixtures of any of the foregoing.
- solvents for conducting the alkaline hydrolysis of the carbamate intermediate are included, for example, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane, petroleum ether, methanol, ethanol, iso
- lower alkanols such as methanol, ethanol, isopropanol, t-butanol and mixtures of one or more of such lower alkanols with water
- glycol monoethers and mixtures thereof with water and/or another solvent such as described above.
- glycol monoethers refers to the mono-(C r C 6 , straight- or branched- chain)alkyl ethers of lower alkylene glycols such as, for example, ethylene glycol, propylene glycol, 1,3-butylene glycol and 2,3-butylene glycol.
- preferred glycol monoethers are, for example, ethylene glycol monomethyl ether ("methyl cellosolve”, 2- methoxyethanol), ethylene glycol monoethyl ether ("ethyl cellosolve”, 2-ethoxyethanol) and propylene glycol monomethyl ether ("PGME", l-methoxy-2-propanol).
- this lower alkyl carbamate intermediate is a rate-limiting step in yielding paroxetine.
- the alkaline hydrolysis is conducted in the presence of a glycol monoether, it is believed that the hydrolysis proceeds through a different carbamate intermediate. It is believed, in accordance with HPLC-MS data, that this carbamate intermediate is formed by reesterification of the carbamate of formula (VII) with the glycol monoether. The hydrolysis of this intermediate evidently proceeds more quickly than that of the alkyl carbamate intermediate formed using a lower alkanol such as ethanol.
- another aspect of the present invention is a process for the preparation of paroxetine comprising hydrolyzing a carbamate intermediate of formula (VII) under alkaline conditions in the presence of a glycol monoether.
- Applicants have found that conducting the alkaline hydrolysis of the carbamate intermediate of formula (VII) in the presence of PGME is particularly advantageous.
- the glycol monoether is PGME
- the present invention is directed to a novel intermediate of formula (VIII) formed during this alkaline hydrolysis:
- Table 1 provides comparative data obtained by conducting the hydrolysis of the carbamate intermediate of foraiula (IV) in (a) a solvent comprising a mixture of a lower alkanol and water and (b) a solvent comprising a mixture of a glycol monoether and water.
- the lower alkanols used in these examples were (i) isopropanol ("IP A"), (ii) methanol (“MeOH”), and (iii) ethanol (“EtOH”).
- the glycol monoethers used in these examples were (i) propylene glycol monomethyl ether ("PGME”) and (ii) glycol ethyl ether (“GEE”).
- the base used during the alkaline hydrolysis was either sodium or potassium hydroxide.
- paroxetine yield is greater than about 90% and is achieved in a relatively short time frame of from about 2 to about 3 hours.
- paroxetine formation is substantially complete in this time frame, as shown by the fact that extending the reaction time to 16 hours only resulted in a 0.1% increase (i.e., from 90.3% to 90.4%) in paroxetine yield relative to the yield obtained after reaction for 2 hours.
- the paroxetine yield obtained using a solvent comprising a mixture of a lower alkanol such as IP A, MeOH or EtOH and water remains substantially lower despite a significantly longer reaction time.
- the present invention is directed to a process for preparing paroxetine comprising (a) dealkylating N-alkylparoxetine of formula (V) by reacting it with a haloformic acid ester of formula (VI) in a suitable solvent to form a paroxetine carbamate intermediate of formula (VII) and (b) hydrolyzing the paroxetine carbamate intermediate of formula (VII) under alkaline conditions in a suitable solvent to yield paroxetine.
- N-methylparoxetine is dealkylated by reaction with 2-chloroethylchloroformate in the presence of a trialkylamine base and the corresponding carbamate intermediate is hydrolyzed under alkaline conditions in the presence of a glycol monoether.
- the resultant product of the hydrolysis is paroxetine base.
- Paroxetine base in crude form, may then be recovered from the reaction mixture by, e.g., extraction into an appropriate organic solvent, such as toluene, benzene or xylene, or a mixture of any one or combination of such solvents with water.
- the organic phase(s) obtained from the extraction are preferably washed with, for example, water and brine.
- the extraction solvent may optionally be removed by, e.g., evaporation and a solution of paroxetine base in a different solvent may be formed.
- Paroxetine base in solution may then be converted to a pharmaceutically acceptable acid addition salt.
- a preferred pharmaceutically acceptable acid addition salt is paroxetine HC1, which may be made in any of the various polymorphic forms thereof known in the art.
- paroxetine HC1 is included crystalline paroxetine hydrochloride hemihydrate as disclosed in U.S. Patent No. 4,721,723, which is incorporated herein in its entirety; and, any of the paroxetine hydrochloride anhydrate and solvate forms, particularly the isopropanolate, disclosed in U.S. Patent No. 6,080,759, which is incorporated herein in its entirety.
- Paroxetine base in solution may be converted into paroxetine HC1 by, for example, contacting a solution of paroxetine base, such as the toluenic solution obtained from the alkaline hydrolysis and extraction steps, as described above, with aqueous or gaseous HC1 followed by crystallization in an appropriate solvent to obtain the desired polymorphic form.
- a solution of paroxetine base such as the toluenic solution obtained from the alkaline hydrolysis and extraction steps, as described above
- aqueous or gaseous HC1 followed by crystallization in an appropriate solvent to obtain the desired polymorphic form.
- a solvent solution of paroxetine base is preferably contacted with dry hydrogen chloride gas or a solvent substantially free of water wherein the solvent has hydrogen chloride gas dissolved therein.
- U.S. Patent No. 6,080,759 discloses methods for the preparation of anhydrous forms of paroxetine HCl.
- the solvents used to form the anhydrates are substantially free of water, meaning that there is insufficient water present at the time of crystallization to effect conversion to a hydrated form of paroxetine HCl such as the hemihydrate.
- a solvent substantially free of water may be obtained by drying the solvent with a conventional drying agent such as a molecular sieve.
- Anhydrous solvents may also be purchased commercially.
- crude paroxetine hydrochloride hemihydrate may be formed, for example, from a toluenic solution of paroxetine base by contacting the solution of paroxetine base with aqueous HCl followed by crystallization in an appropriate solvent as generally disclosed in U.S. Patent No. 4,721,723.
- Crystalline paroxetine hydrochloride hemihydrate may then be prepared by recrystallization of the crude paroxetine hydrochloride hemihydrate in a suitable solvent.
- suitable solvents include lower alkanols such as methanol and ethanol; ketones such as acetone; esters such as ethyl acetate; and, mixtures of any of the foregoing such as methanol/acetone.
- Anhydrous forms of paroxetine hydrochloride may be formed by the methods as generally disclosed in U.S. Patent No. 6,080,759. The anhydrous form is free of bound solvents.
- Anhydrous paroxetine hydrochloride may be prepared by contacting, in a dry N 2 environment, a solution of paroxetine base in an organic solvent, such as isopropanol, with dry hydrogen chloride gas.
- the solution of paroxetine base in an organic solvent may be contacted with a solvent substantially free of water wherein the solvent has dry hydrogen chloride gas dissolved therein.
- the reaction mixture is heated to ensure complete dissolution of the paroxetine hydrochloride. Seed crystals of anhydrous paroxetine may be added to improve the crystallization process.
- anhydrous forms of paroxetine free of bound solvent may also be prepared from the paroxetine hemihydrate by dissolving the hemihydrate in an appropriate solvent substantially free of water which forms an azeotrope with water.
- solvent is removed by distillation and fresh solvent is added until all of the water is removed.
- the anhydrous forms free of bound solvent may also be made by crystallizing paroxetine hydrochloride in an organic solvent or a mixture of solvents which form a solvate with the paroxetine hydrochloride and displacing the solvated solvent or solvents from the paroxetine hydrochloride solvate using a displacing agent.
- a displacing agent Preferably, gaseous or liquid water may be used as the displacing agent. It is important that the paroxetine hydrochloride solvate is contacted with enough water and for sufficient time to displace the solvent but insufficient to cause conversion to the hydrochloride hemihydrate.
- Paroxetine HCl can also be prepared in various solvate forms as disclosed in U.S. Pat. No. 6,080,759.
- paroxetine hydrochloride isopropanolate as disclosed in Examples 1-3 of U.S. Patent No. 6,080,759.
- Paroxetine HCl isopropanolate may be formed by displacing water from paroxetine HCl hemihydrate in, e.g., a mixture of toluene and isopropanol followed by crystallization.
- Paroxetine HCl isopropanolate may also be formed by contacting a solution of paroxetine base in isopropanol with dry hydrogen chloride gas followed by crystallization.
- the isopropanolate may also be formed by contacting a solution of paroxetine base in dry isopropanol with a solution of dry hydrogen chloride gas in dry isopropanol followed by crystallization.
- Solvates other than the isopropanolate can be made by similar methods as disclosed in U.S. Patent No. 6,080,759.
- solvates from solvents such as alcohols other than isopropanol such as 1-propanol and ethanol; from organic acids such as acetic acid; from organic bases such as pyridine; from nitriles such as acetonitrile; from ketones such as acetone and butanone; from ethers such as tetrahydrofuran; from chlorinated hydrocarbons such as chloroform and from hydrocarbons such as toluene.
- solvents such as alcohols other than isopropanol such as 1-propanol and ethanol
- organic acids such as acetic acid
- organic bases such as pyridine
- nitriles such as acetonitrile
- ketones such as acetone and butanone
- ethers such as tetrahydrofuran
- chlorinated hydrocarbons such as chloroform and from hydrocarbons such as toluene.
- Examples 1-3 disclose the formation of the 2-chloroethyl carbamate of paroxetine ("CECB", l-(2-chloroethoxycarbonyl)-4-(p-fluorophenyl)-3-[5-(l,3- dioxanindanyl)oxymethyl]piperidine) by reaction of N-methyl paroxetine with 2- chloroethyl-chloroformate ("CECF").
- Example 4 discloses the alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine to yield paroxetine.
- Example 5 discloses the alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine in propylene glycol monomethyl ether ("PGME”) and water.
- Example 6 discloses the alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine in ethanol and water.
- Example 7 discloses the alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine in propylene glycol monomethyl ether to form paroxetine base.
- Example 8 discloses the formation of 2,2,2- trichloroethyl-carbamate of paroxetine ( 1 -(2,2,2-trichloroefhoxycarbonyl)-4-(p- fluorophenyl)-3-[5-(l,3-dioxanindanyl)oxymethyl]piperidine) by reaction of N- methylparoxetine with 2,2,2-trichloroethyl-chloroformate.
- Example 9 discloses a multistage process for producing paroxetine hydrochloride hemihydrate comprising preparation of the 2-chloroethyl carbamate of paroxetine; hydrolysis thereof to yield paroxetine base; formation of crude paroxetine hydrochloride hemihydrate from the paroxetine base; and, recrystallization of the crude paroxetine hydrochloride hemihydrate to yield crystalline paroxetine hydrochloride hemihydrate.
- Example 10 discloses the preparation of paroxetine hydrochloride anhydrous from a solution of paroxetine base in toluene.
- Me-PRX (3 g) and extra dry toluene (40 ml, less than 0.001% water) are charged into dried equipment under a dry N 2 stream.
- the reaction mixture is cooled to 4°C with an ice bath.
- CECF (2.7 mL, 3 eq., purchased from SNPE) is added drop wise for several minutes.
- the mixture is heated to reflux for 7 hours providing the substantially complete conversion of Me-PRX (HPLC) to the carbamate.
- Water 50 mL is added to cool the reaction mixture to room temperature.
- Example 2 The same procedure as described in Example 1 is repeated, except that the equipment is not previously dried, technical grade toluene (less than 0.10% water) is used instead of extra dry toluene, and the reactants are not charged under a dry N 2 stream.
- the reaction mixture before addition of CECF, also contains 2.05 g (1.2 eq.) of Bu 3 N. After 1.5 hours of reflux, substantially complete conversion of Me-PRX to the corresponding carbamate takes place.
- the carbamate i.e., the 2-chloroethyl carbamate of paroxetine (CECB) is separated from the reaction mixture using the same procedures as described in Example 1.
- CECB 2-chloroethyl carbamate of paroxetine
- Example 2 The same procedure as described in Example 1 is repeated, except that the equipment is not previously dried, technical grade toluene is used instead of extra dry toluene, and the reactants are not charged under a dry N 2 stream. Conversion of Me-PRX to the corresponding carbamate after 3 hours is 47% (reaction stopped).
- Me-PRX 150g is dissolved in toluene (450ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloiOethyl-chloroformate (120ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300ml) and water (300ml) is added. The organic phase is separated and washed with water (500ml), followed by brine (500ml). The organic phase is then separated, dried over MgSO 4 , filtered. Toluene is then removed under reduced pressure to give 280.2g of the 2,2,2-trichloroethyl carbamate of paroxetine.
- the carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base.
- Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein.
- Example 9 Preparation of Paroxetine Hydrochloride Hemihydrate from N-methvI Paroxetine Preparation of CECB
- N-methylparoxetine ( 1 OOg) and toluene (300ml) are charged into a one liter flask.
- the mixture is heated to reflux.
- CECF (125g) is added dropwise during about 3 hours at reflux. Stirring at reflux of the reaction mixture is continued for about 10 hours.
- the mixture is cooled to room temperature.
- Water (75ml) and NH 4 OH (75ml) are added to the reaction mixture.
- the mixture is heated to 40°C and stirred for 30 minutes.
- the organic phase is separated, washed twice with water (2 100ml) and with brine (100ml).
- Toluene is replaced with isopropyl alcohol during distillation and the carbamate (CECB) is filtered and dried to give 117g CECB.
- CECB carbamate
- a solution of paroxetine base in toluene (355g, 9.9% w/w) is charged into a batch stirred reactor.
- the solvent is distilled under reduced pressure at a temperature not higher than 90°C. The distillation is continued until distillate is no longer observed.
- Nitrogen gas is purged into the reactor to obtain ambient pressure. A nitrogen environment is maintained throughout the conversion to paroxetine hydrochloride anhydrous.
- Isopropanol extra dry (80 mL, water content less than 0.01%) is charged into the reactor. Isopropanol is then distilled under reduced pressure until distillate is no longer observed. Nitrogen gas is then purged into the reactor to obtain ambient pressure. The process of feeding isopropanol extra dry and distilling under reduced pressure is repeated two additional times. After the end of the third distillation, isopropanol extra dry (598.4 grams) and isopropanol solution (91.94 grams) containing 3.31 grams of hydrogen chloride gas are charged into the reactor under an inert nitrogen environment. The reaction mixture is heated to 70°C to obtain complete dissolution of the paroxetine hydrochloride.
- the solution is cooled to 51°C.
- the solution is seeded with crystals of paroxetine hydrochloride anhydrous to facilitate the crystallization process.
- the solution is stirred at 51°C and subsequently cooled to 25°C over 12 hours.
- the temperature of the reaction mixture reaches 25°C, the mixture is stirred for an additional hour.
- the resultant slurry is filtered under nitrogen and dried to give 25.4 g paroxetine hydrochloride anhydrous.
- this Example crystallizes out of isopropanol, the product is paroxetine hydrochloride anhydrous rather than the isopropanolate.
- the main reason for obtaining anhydrous form rather than the isopropanolate is the use of extra dry isopropanol along with a dry atmosphere throughout the process.
- Example 3 shows that the presence of Bu 3 N reduces the reaction time necessary to obtain substantially complete conversion of Me-PRX to the corresponding carbamate.
- Et 3 N shows that the same procedure with Et 3 N (Example 3) also reduces the reaction time relative to that required for substantially complete conversion of Me-PRX to the carbamate in Example 1.
- reflux for four hours in the presence of Et 3 N produces a 74% conversion to the carbamate while in the Comparative Example, conducted in the absence of Et 3 N, only a 47% conversion is achieved.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002259114A AU2002259114A1 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
PCT/US2002/013826 WO2003072104A1 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
IL16359302A IL163593A0 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
JP2003570850A JP2005524656A (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine using a novel intermediate |
CA002476723A CA2476723A1 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
EP02729099A EP1482939A4 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US35891602P | 2002-02-22 | 2002-02-22 | |
US60/358,916 | 2002-02-22 | ||
PCT/US2002/013826 WO2003072104A1 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
Publications (1)
Publication Number | Publication Date |
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WO2003072104A1 true WO2003072104A1 (en) | 2003-09-04 |
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ID=79169877
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2002/013826 WO2003072104A1 (en) | 2002-02-22 | 2002-05-01 | Preparation of paroxetine involving novel intermediates |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1482939A4 (en) |
JP (1) | JP2005524656A (en) |
AU (1) | AU2002259114A1 (en) |
CA (1) | CA2476723A1 (en) |
IL (1) | IL163593A0 (en) |
WO (1) | WO2003072104A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010260826A (en) * | 2009-05-08 | 2010-11-18 | Sumitomo Chemical Co Ltd | Method of manufacturing paroxetine hydrochloride semihydrate |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4721723A (en) * | 1985-10-25 | 1988-01-26 | Beecham Group P.L.C. | Anti-depressant crystalline paroxetine hydrochloride hemihydrate |
EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR001982A1 (en) * | 1995-02-06 | 1998-01-07 | Smithkline Beecham Plc | PAROXETINE CHLORHYDRATE ANHYDRATED, AND PROCEDURE FOR ITS PREPARATION |
GB9726907D0 (en) * | 1997-12-19 | 1998-02-18 | Smithkline Beecham Plc | Novel compounds |
GB9914583D0 (en) * | 1999-06-22 | 1999-08-25 | Smithkline Beecham Plc | Novel process |
JP2001139572A (en) * | 1999-11-17 | 2001-05-22 | Sumika Fine Chemicals Co Ltd | Method for producing anhydrous paroxetinic hydrochloride 2-propanol solvate |
-
2002
- 2002-05-01 JP JP2003570850A patent/JP2005524656A/en not_active Withdrawn
- 2002-05-01 CA CA002476723A patent/CA2476723A1/en not_active Abandoned
- 2002-05-01 AU AU2002259114A patent/AU2002259114A1/en not_active Abandoned
- 2002-05-01 IL IL16359302A patent/IL163593A0/en unknown
- 2002-05-01 WO PCT/US2002/013826 patent/WO2003072104A1/en active Application Filing
- 2002-05-01 EP EP02729099A patent/EP1482939A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4721723A (en) * | 1985-10-25 | 1988-01-26 | Beecham Group P.L.C. | Anti-depressant crystalline paroxetine hydrochloride hemihydrate |
EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
Non-Patent Citations (2)
Title |
---|
LEE ET AL.: "Asymmetric syntheses of trans-3,4- disubstituted 2-piperidinones and piperidines", TETRAHEDRON: ASYMMETRY, vol. 12, 2001, pages 419 - 426, XP002957648 * |
See also references of EP1482939A4 * |
Also Published As
Publication number | Publication date |
---|---|
JP2005524656A (en) | 2005-08-18 |
AU2002259114A1 (en) | 2003-09-09 |
CA2476723A1 (en) | 2003-09-04 |
EP1482939A1 (en) | 2004-12-08 |
EP1482939A4 (en) | 2005-10-12 |
IL163593A0 (en) | 2005-12-18 |
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