EP0929514A1 - Verfahren zur herstellung von fluoxetin - Google Patents

Verfahren zur herstellung von fluoxetin

Info

Publication number
EP0929514A1
EP0929514A1 EP97943082A EP97943082A EP0929514A1 EP 0929514 A1 EP0929514 A1 EP 0929514A1 EP 97943082 A EP97943082 A EP 97943082A EP 97943082 A EP97943082 A EP 97943082A EP 0929514 A1 EP0929514 A1 EP 0929514A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
reaction
phenyl
propyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97943082A
Other languages
English (en)
French (fr)
Inventor
Józsefné REITER
Zoltán Budai
Gyula Simig
Gábor Blasko
Tibor Mezei
János IMRE
Kálmán NAGY
Lászlú LADANYI
Péter TÖMPE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals 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 Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP0929514A1 publication Critical patent/EP0929514A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings

Definitions

  • fluoxetine is a valuable antidepressant which exhibits its effect by a selective serotonine reuptake inhibiting activity (Hungarian patent N 172.723)
  • US patent N Q 4 018,895 the use of fluoxetine for the treatment of depression is described
  • N° 173,723 fluoxetine is . prepared as follows The compound 3- dimethylamino-propiophenone is reduced in tetrahydrofurane with diborane, the N,N-d ⁇ methyl-(3-hydroxy-3-phenyl-propyl)- amine thus obtained is treated with hydrochloric acid and thionyl chloride, the N.N-d ⁇ methyl-(3-phenyl-3-chloro-propyl)- amine-hydrochlo ⁇ de is heated to boiling with 4-t ⁇ fluoromethyl- phenol in alkaline medium for 5 days The N.N-dimethyl- ⁇ 3- phenyl-3-[4-(tr ⁇ fluoromethyl)-phenoxy]-propyl ⁇ -amine of the Formula III
  • the dimethylamino derivative of the Formula III is reacted with cyanogene bromide, whereupon the N-methyl-N-cyano- ⁇ 3- phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl ⁇ -am ⁇ ne is heated to boiling with ethylene glycol in potassium hydroxide at 130°C for 2 hours.
  • the fluoxetine base of the Formula I is purified via the oxalate salt and is finally converted into fluoxetine hydrochlonde by reacting with gaseous hydrogen chloride in ether. This process is accompanied by several drawbacks. On the one hand poisonous materials detrimental to the environment (e.g.
  • Ns 204,769 fluoxetine of the Formula I is prepared starting from N-benzyl-N-methyl-(2- benzoyl-ethyl)-amine.
  • the starting material is hydrogenated in the presence of a plati ⁇ -palladium catalyst applied on a carbon support in ethyl acetate in an autoclave with hydrogen gas at 50°C at a pressure of 5.10 5 Pa.
  • the N-methyl-(3-hydroxy-3- phenyl-propyl)-amine thus obtained selectively is O-arylated with 4-chloro-trifluoromethyl-benzene, in N-methyl-pyrroiidone, in the presence of potassium tertiary butylate and potassium iodide.
  • Fluoxetine of the Formula I thus obtained is converted into the hydrochloride.
  • the disadvantage of this process is that the N-methyl-benzyl-amine used as starting material is a difficultly available expensive substance.
  • a further drawback resides in the fact that the process necessitates the use of a special catalyst and the purification of the product is complicated. In the cited patent the specification and availability of the catalyst is not disclosed.
  • N-methyl-(3- hydroxy-3-phenyl-propyl)-amine is reacted in dimethyl sulfoxide with a small excess of sodium amide, whereupon to the homogeneous reaction mixture at 60-80°C a small excess of 4-chloro-trifluoromethyl-benzene or a solution thereof formed with dimethyl sulfoxide is added.
  • the reaction having been completed the dimethylsulfoxide or a part of the solvent is distilled off in vacuo.
  • the reaction mixture is poured into water, the fluoxetine of the Formula I thus obtained is extracted, converted into hydrochlo ⁇ de and the salt is recrystallized
  • fluoxetine of the Formula I is prepared by reacting 4-t ⁇ fluoromethyl-phenol with a molar equivalent amount of N-ethoxycarbonyl-N-methyl- (3-phenyl-3-methanesulfonyloxy-propyl)-amine or N-acetyl-N- methyl-(3-phenyl-3-methanesulfonyloxy-propyl)-amine in the presence of alkali hydroxide in alcohol as medium at 60- 100°C.
  • the protective group is split off by treatment with 3-6 N mineral acid (e.g. hydrochloric acid, sulfuric acid, hydrogen bromide) in ethanol or aqueous medium or in aqueous ethanol.
  • the reaction is carried out at the boiling point of the reaction mixture.
  • the oily fluoxetine base of the Formula I thus obtained is purified on a silica column.
  • This process is accompanied by several drawbacks.
  • the 4-trifluoromethyl phenol used as starting material is a difficultly available, expensive substance detrimental to health.
  • a further disadvantage resides in the fact that two protective groups are to be introduced onto the propyi amine derivative.
  • the desired compound of the Formula I is formed as a contaminated oil which must be purified on a silica column.
  • the compound of the Formula I is prepared by reducing ethyl benzoyl acetate in methanol as medium with sodium borohydride, reacting the ethyl-3-hydroxy-3-phe ⁇ yl-propionate in alcoholic medium with methyl amine and 0-arylat ⁇ ng the N-methyl-(3-hydroxy-3- phenyl-prop ⁇ on ⁇ c)-am ⁇ de in tetrahydrofurane in the presence of t ⁇ phenyl phosphine and azodicarboxylic acid with 4- tnfluoromethyl-chloro-benzene
  • the reaction mixture is worked up reduced to fluoxetine base of the Formula I in tetrahydrofurane with lithium aluminium hydride whereon salt formation is carried out in a manner known per se
  • the process necessitates the use of toxical combustible materials injurious to environment and for this reason the process is not suitable for industrial scale production
  • a further drawback is that the product obtained is
  • Ns T/63144 fluoxetine of the Formula I and acid addition salts are prepared via new intermediates According to this process N N-d ⁇ methyl-(3-hydroxy-3-phenyl-propyl)-am ⁇ ne of the Formula IV
  • sodium salt is formed in N,N-dimethyl aceta ide with sodium hydride in a known manner, whereupon the sodium salt thus obtained is O-arylated with 4- chloro-trifluoromethyl-benzene.
  • the hydrochlo ⁇ de is formed in toluene as medium with gaseous hydrogen chloride.
  • the crude fluoxetine hydrochlo ⁇ de is purified by recrystal zation from hot water and the hot aqueous solution is optionally treated with charcoal. It is noteworthy that it is specifically mentioned in the laid-open patent application that the N- methyl-N-ethoxycarbonyl- ⁇ 3-phenyl-3-[4-(trifluoromethyl)- phenoxy]-propyl ⁇ -amine of the Formula II
  • N-benzyl-N-methyl-(3- hydroxy-3-phenyl-propyl)-amine is reacted with 4-chloro- trifluoromethyl-benzene in dimethyl acetamide.
  • the N-benzyl- N-methyl- ⁇ 3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl]- amine obtained is reacted with methyl chloro formate, whereupon the N-methyl-N-methoxycarbony!- ⁇ 3-phenyl-3-[4- (t ⁇ fluoromethyl)-phenoxy]-propyl ⁇ -amine thus obtained is hydrolized into fluoxetine of the Formula I in methanol with sodium hydroxide.
  • the fluoxetine base is converted into oxalate in a manner known per se
  • the drawback of the process is that two protective groups are to be used
  • the removal of the two protective groups and the hydrolysis carried out in alkaline-methanoiic medium results in a strongly contaminated base of the Formula I, which is purified through the oxalate salt; the latter step is carried out by converting the oxalate salt into the base and forming hydrochioride from the free base.
  • N,N- dimethyl-(3-hydroxy-3-phenyl-propyl)-amine is etherified with 4-chloro-trifluoromethyl-benzene, whereupon the dimethyl derivative thus obtained is demethylated with the less toxical phenyl-chloro formate in the place of the poisonous cyanogene bromide.
  • a strongly contaminated product is obtained which is to be purified by HPLC. The process is expensive and unsuitable for industrial scale production. Summary of the invention
  • the present invention is based on the recognition that in the course of the preparation of the compound of the Formula I the majority of the contaminations is* formed during the demethylation of the compound of the Formula III on the one hand and during the alkaline hydrolysis and decarboxylation of the compound of the Formula II on the other.
  • hydrolysis of the urethane derivative of the Formula II is carried out in the presence of water and optionally n-butanol, in the same reaction mixture, at the boiling point of the reaction mixture.
  • reaction of the compound of the Formula III and ethyl chloro formate is carried out in toluene or xylene at 80- 90°C
  • One may work preferably by 80-85°C
  • reaction medium industrial xylene consisting of a mixture of o-, m- and p_-xylene may also be used
  • the xylene isomers do not influence the reaction and for this reason pure xylene isomers may be successfully replaced by the industrial xylene consisting of an isomer mixture
  • the reaction is continued until the evolution of methyl chloride gas stops
  • the reaction mixture is extracted with an aqueous acid
  • aqueous acid For this purpose preferably diluted hydrochloric acid may be used It is preferred to use 0 75-0.85 moles - particularly 0 8 mole - of a diluted mineral acid, particularly diluted hydrochloric acid, related to 1 mole of the starting material of the Formula III
  • the contaminations are present in the aqueous acidic phase which can be simply separated from the upper organic layer
  • the organic layer is a clear contamination-free solution of the compound of the Formula II and can be directly used for the alkaline hydrolysis without isolating the compound of the Formula II
  • the present invention is based on the further recognition that the compound of the Formula II can be hydrolized with an alkali hydroxide in toluene or xylene as medium in the presence of a small amount of water within a very short reaction time to yield the compound of the Formula I
  • the recognition is so much the more surprising as it is known from prior art that the t ⁇ fluoromethyl group is
  • the hydrolysis of the compound of the Formula II in methanol or ethanol as medium is very time-consuming and requires about 30 hours
  • the reaction time may be shortened to about 12-15 hours by carrying out the reaction in ethylene glycol but in this case the quality of the product does not meet the strict requirements of Pharmacopoeia even after repeated purification
  • the long reaction time and the severe reaction conditions cause the formation of secondary and tertiary decomposition products having very similar chemical-physical properties to the desired compound of the Formula I and for this reason such contaminations can be removed only very difficultly
  • reaction when carrying out the alkaline hydrolysis of the compound of the Formula II in toluene or xylene as medium in the presence of a small amount of water, the reaction becomes complete within 2-10 hours and at the same time by-products and decomposition products are formed either not at all or only in a minimal amount
  • the reaction is carried out in the presence of 20-40 ml - preferably 30 ml - of water, related to 1 mole of the urethane derivative of the Formula II.
  • the working-up of the reaction mixture can be facilitated by carrying out hydrolysis in the presence of n- butanol added in the same amount as water In this case the reaction mixture is more easy to be filtered and during extraction with water no difficultly decomposable emulsion is formed
  • One may proceed preferably by treating the organic phase - obtained on the reaction of the compound of the Formula III with ethyl chloro formate in toluene or xylene as medium, extraction of the reaction mixture with a diluted aqueous acid and separation of the aqueous acidic phase - with alkali hydroxide in the presence of water and n-butanol
  • alkali hydroxide sodium hydroxide, potassium hydroxide or a mixture thereof may be used
  • the reaction is carried out at the boiling point of the reaction mixture
  • the reaction time is 2-4 hours
  • the inorganic compounds may be easily removed from the reaction mixture by filtration or cent ⁇ fuging
  • the organic phase containing the compound of the Formula I is washed with water, dried and the base of the Formula I is isolated by evaporating the solution
  • One may also proceed by directly precipitating a pharmaceutically acceptable acid addition salt from the toluene or xylene solution by adding a solution of the desired mineral acid formed with an organic solvent
  • the hydrochlo ⁇ de of the compound of the Formula I is directly precipitated from the toluene or xylene solution with ethyl acetate containing hydrochloric acid
  • This method provides directly, without a further purification, Pharmacopoeia-grade compound of the Formula I
  • the pharmaceutically acceptable acid addition of the compounds of the Formula I may be formed with inorganic or organic acids (e.g. hydrogen halides, carbonate, hydrogen carbonate, sulfate, acetate, fumerate, maleate
  • the reaction mixture is diluted with 25 ml of xylene, whereupon it is extracted with a mixture of 5 ml of concentrated hydrochlo ⁇ d acid and 20 ml of water
  • the lower acidic-aqueous phase is separated, the organic layer is washed with 10 ml of an N sodium hydroxide solution
  • the xylene phase is separated and diluted with fresh xylene to 140 ml
  • the solution contains 22 4 g of N-methyl-N-ethoxycarbonyl- ⁇ 3-phenyl-3-[4-(t ⁇ fiuoro methyl)-phenoxy]-propyl ⁇ -am ⁇ ne (urethane)
  • reaction mixture is cooled to 25 C C, filtered in vacuo through a sintered glass filter and the precipitated product is washed with xylene.
  • the organic phase is washed three times with 40 ml of water each to pH 4 and dried over anhydrous magnesium sulfate.
  • the xylene solution is acidified with a calculated amount of hydrogen chloride in ethyl acetate (hydrogen chloride content about 10-20 %), the precipitated crystals are filtered and dried to constant weight.
  • 17.06 g of N-methyl- ⁇ 3-phenyl-3-[4- (trifluoromethyl)-phenoxy]-propyl ⁇ -amine hydrochloride are obtained in the form of white crystals. Yield: 83.95 %.
EP97943082A 1996-09-10 1997-09-10 Verfahren zur herstellung von fluoxetin Withdrawn EP0929514A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU9602469P 1996-09-10
HU9602469A HU226690B1 (en) 1996-09-10 1996-09-10 Process for producing fluoxetin
PCT/HU1997/000050 WO1998011054A1 (en) 1996-09-10 1997-09-10 Process for the preparation of fluoxetine

Publications (1)

Publication Number Publication Date
EP0929514A1 true EP0929514A1 (de) 1999-07-21

Family

ID=89994255

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97943082A Withdrawn EP0929514A1 (de) 1996-09-10 1997-09-10 Verfahren zur herstellung von fluoxetin

Country Status (7)

Country Link
EP (1) EP0929514A1 (de)
AU (1) AU4468997A (de)
CZ (1) CZ75299A3 (de)
HU (1) HU226690B1 (de)
PL (1) PL332141A1 (de)
SK (1) SK29099A3 (de)
WO (1) WO1998011054A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6025517A (en) * 1998-08-03 2000-02-15 Sepracor Inc. Fluoxetine process from benzoylacetonitrile
US6316672B1 (en) 2001-01-31 2001-11-13 Grayson Walker Stowell Form a of fluoxetine hydrochloride
US6310251B1 (en) 2001-01-31 2001-10-30 Grayson Walker Stowell Form a of fluoxetine hydrochloride
US6310250B1 (en) 2001-01-31 2001-10-30 Grayson Walker Stowell Form A of fluoxetine hydrochloride
US6258853B1 (en) 2001-01-31 2001-07-10 Grayson Walker Stowell Form a of fluoxetine hydrochloride
US6313350B1 (en) 2001-01-31 2001-11-06 Grayson Walker Stowell Form a of fluoxetine hydrochloride
US6846957B2 (en) 2002-11-22 2005-01-25 Board Of Regents, The University Of Texas System Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018895A (en) * 1974-01-10 1977-04-19 Eli Lilly And Company Aryloxyphenylpropylamines in treating depression
IL99316A (en) * 1991-08-27 1995-03-15 Teva Pharma Production of fluoxetine and new intermediates
US5618968A (en) * 1993-02-05 1997-04-08 Pliva Farmaceutska Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine and the procedure for their preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9811054A1 *

Also Published As

Publication number Publication date
HU226690B1 (en) 2009-06-29
PL332141A1 (en) 1999-08-30
SK29099A3 (en) 1999-08-06
AU4468997A (en) 1998-04-02
CZ75299A3 (cs) 1999-09-15
HUP9602469A2 (hu) 1998-09-28
HUP9602469A3 (en) 1999-06-28
WO1998011054A1 (en) 1998-03-19
HU9602469D0 (en) 1996-10-28

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