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WO2000021917A1 - Pharmaceutical intermediate for the synthesis of fluoxetine and a process for the preparation thereof - Google Patents

Pharmaceutical intermediate for the synthesis of fluoxetine and a process for the preparation thereof Download PDF

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Publication number
WO2000021917A1
WO2000021917A1 PCT/HU1999/000068 HU9900068W WO0021917A1 WO 2000021917 A1 WO2000021917 A1 WO 2000021917A1 HU 9900068 W HU9900068 W HU 9900068W WO 0021917 A1 WO0021917 A1 WO 0021917A1
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Prior art keywords
dimethyl
propyl
phenyl
amine
process according
Prior art date
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Ceased
Application number
PCT/HU1999/000068
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French (fr)
Inventor
Józsefné REITER
Gyula Simig
Tibor Mezei
János IMRE
Györgyi VERECZKEYNÉ DONÁTH
Kálmán NAGY
Norbert Németh
Tibor SZABÓ
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Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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Priority to AU62242/99A priority Critical patent/AU6224299A/en
Publication of WO2000021917A1 publication Critical patent/WO2000021917A1/en
Anticipated expiration legal-status Critical
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    • 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
    • C07C217/04—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 acyclic and saturated
    • C07C217/06—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 acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—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 acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—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 acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—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 acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms

Definitions

  • the invention relates to a new pharmaceutical intermediate and a process for the preparation thereof.
  • the new compound of the Formula I is a valuable pharmaceutical intermediate which can be used by the preparation of fluoxetine (INN), a well-known antidepressant.
  • INN fluoxetine
  • antidepressant which is a selective cerebral serotonin reuptake inhibitor and also acts on the dopamine and norepinephrine systems (HU-173,323).
  • fluoxetine is prepared by setting free 3-dimethylamino-propiophenone of the Formula
  • N,N-dimethyl- ⁇ 3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ fluoxetine is obtained by demethylation (HU-173,723 and Hungarian patent application Ser. No. 2469/96).
  • the compound N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ is a key intermediate of the synthesis of fluoxetine.
  • a N,N-dimethyi intermediate of high purity is required because the contaminations remaining in said intermediate can be removed but with great difficulties and contaminate the end product.
  • N,N-dimethyl- - ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ there are several methods for purifying N,N-dimethyl- - ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ . According to HU-173,723 N,N-dimethyl- ⁇ 3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine ⁇ is obtained in the form of the base after complicated recovery and from said base an oxalate is formed in ethyl acetate. However, an intermediate having a quality required for the preparation of fluoxetine can be obtained only by recrystallization from ethyl acetate. This method is accompanied by several drawbacks.
  • the intermediate N,N-dimethyl- ⁇ 3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine ⁇ can be further purified via the hydrochloride salt thereof.
  • the hydrochloride is such a hygroscopic compound that it is unsuitable for use on industrial scale.
  • a further possibility is purification of N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ by means of distillation in vacuo.
  • N,N-dimethyl- ⁇ 3-phenyl-3- -[(4-thfluoromethyl)-phenoxy]-propyl-amine ⁇ is prepared as follows.
  • the N,N-dimethyl-(3-hydroxy-3-phenyl-propyl)-amine of the Formula IV is treated with sodium hydride in a 15-fold amount of dimethyl sulfoxide as solvent and the salt thus obtained is reacted with 1-fluoro-4-thfluoromethyl-benzene of the Formula
  • the desired compound is obtained by diluting the dimethyl sulfoxide solution with a 75-fold amount of water, extracting with ether, evaporating the ether and converting the base into the oxalate in ethyl acetate as medium.
  • This process has many drawbacks.
  • the use of sodium hydride and ether increases the risks of fire and explosion to a very great extent and the unusually high reaction volume required makes industrial scale application of the process very difficult and uneconomical.
  • the present invention is based on the recognition that the compound of the Formula I can be prepared in highly pure, crystalline, easily workable and processable form and N,N- -dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl- -amine ⁇ of high purity can be readily set free from said salt. From the highly pure N,N-dimethyl base intermediate product fluoxetine, which meets the severe requirements of Pharmacopoeia, can be obtained by a simple and favourable method.
  • the compound of the Formula IV is converted into an alkali salt by reacting with an alkali hydroxide in dimethyl sulfoxide solution.
  • alkali hydroxide sodium hydroxide or potassium hydroxide can be used. It is preferred to use potassium hydroxide.
  • the formation of the alkali salt can be carried out at a temperature between 80°C and the boiling point of the solvent. One may preferably work at 90-110°C.
  • the reaction time is 4-10 hours, advantageously 7-8 hours.
  • the molar ratio of alkali hydroxide and N,N-dimethyl-(3-hydroxy-3-phenyl-propyl)-amine of the Formula IV is 1-6:1 , preferably 2-4:1.
  • the dimethyl sulfoxide solvent can be used in an amount of 2-6 ml/g, preferably 3-4 ml/g, related to the starting material of the Formula IV.
  • the alkali salt of the compound of the Formula IV thus obtained is then reacted with a compound of the general Formula VII. It is preferred to use 1-chloro-4-trifluoromethyl- -benzene, i.e. the compound of the Formula VII in which X stands for chlorine. Thereafter to the reaction mixture an aromatic organic solvent and an aqueous solution of an inorganic salt are added.
  • aromatic solvent preferably benzene, toluene, o-, m- or ⁇ -xylene, or a commercially available xylene mixture, or chloro benzene, 1 ,2-dichloro benzene, o-chloro-xylene, m-chloro-xylene or rj-chloro-xylene can be used.
  • toluene is used as aromatic organic solvent.
  • the N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ enters into the aromatic organic phase.
  • the aqueous solution of the inorganic salt washes out the inorganic contaminations (excess of alkali hydroxide, alkali chloride formed in the reaction) and the excess of dimethyl sulfoxide.
  • said impurities can be easily removed by separating the aromatic organic solvent phase from the aqueous inorganic salt layer.
  • inorganic salt preferably alkali halides, ammonium halides, alkali sulfates or ammonium sulfate can be used. It is preferred to use sodium chloride, sodium sulfate, ammonium sulfate, potassium sulfate or ammonium chloride.
  • the following inorganic salt solutions can be used: a 5-30 % aqueous sodium chloride solution, a 5-20 % aqueous sodium sulfate solution, a 10-40 % by weight aqueous ammonium sulfate solution, a 5-10 % by weight aqueous potassium sulfate solution or a 20-50 % by weight aqueous ammonium chloride solution.
  • a 5-30 % aqueous sodium chloride solution a 5-20 % aqueous sodium sulfate solution, a 10-40 % by weight aqueous ammonium sulfate solution, a 5-10 % by weight aqueous potassium sulfate solution or a 20-50 % by weight aqueous ammonium chloride solution.
  • a 10 % aqueous sodium chloride solution aqueous sodium chloride solution
  • a 10-40 % by weight aqueous ammonium sulfate solution a 5-10 % by weight
  • N,N-dimethyl- ⁇ 3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ salt can be formed by two methods.
  • p_-toluene sulfonic acid monohydrate is added.
  • Said acid may be used in a molar ratio of 1-1.3:1 , preferably 1-1.05:1 (related to 1 mole of N,N- -dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl- -amine ⁇ ).
  • the p_-toluene sulfonic acid monohydrate is preferably added in one portion to the solution of the base formed with the aromatic organic solvent. After addition of ⁇ _- -toluene sulfonic acid the reaction mixture is warmed until dissolution takes place, whereupon the excess of the aromatic organic solvent is removed at this temperature under mild vacuo.
  • the compound of the Formula I of high purity precipitates in crystalline form, which can be promoted by adding ethyl acetate.
  • the precipitated crystalline compound of the Formula I can be simply isolated by means of filtration or centrifuging and can be directly used for the preparation of fluoxetine without any purification.
  • salt formation is performed as follows: the aromatic organic phase containing the N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxyj-propyl-amine ⁇ is evaporated, the residual base is dissolved in an organic solvent and p_-toluene sulfonic acid monohydrate is added to the solution.
  • organic solvent aliphatic alcohols (e.g. ethanol or isopropanol) or esters (e.g. ethyl acetate) can be used.
  • toluene sulfonic acid in the salt formation reaction j toluene sulfonic acid can be used in a molar ratio of 1-1.3:1 , preferably 1-1.05:1 (related to 1 mole of the N,N-dimethyl- ⁇ 3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ base). Salt formation may be carried out under heating, preferably at the boiling point of the reaction mixture. On cooling the reaction mixture the compound of the Formula I precipitates in such a highly pure form that it can be directly used for the preparation of fluoxetine without purification.
  • Salt formation may be carried out at 0-100°C, preferably at 20-50°C.
  • the compound of the Formula I can be directly used for the preparation of fluoxetine without further purification;
  • reaction mixture can be worked-up in a very simple manner
  • the process is suitable for industrial scale use (small volume; no special apparatus is required; the use of combustible and explosive sodium hydride and ether is eliminated; environment-friendly technology; the by-products formed in the process can be easily destroyed without contaminating the environment).
  • Example 1 Further details of the present invention are to be found in the Examples without limiting our invention to said Examples.
  • Example 1 Further details of the present invention are to be found in the Examples without limiting our invention to said Examples.
  • the reaction mixture is cooled, 300 ml of toluene are added and the mixture is composed by adding 250 ml of a 10 % (ml/g) sodium chloride solution under cooling with icecold water. The mixture is stirred for 30 minutes, whereupon a further 300 ml of toluene are added. The phases are separated, the toluene layer is washed with 200 ml of a saturated 25 % sodium chloride solution, filtered and the active ingredient content is analysed.
  • the product can be directly used for the preparation of N,N-dimethyl- ⁇ 3-phenyl-3-[(4- -trifluoromethyi)-phenoxy]-propyl-amine ⁇ -p-toluenesulfonate.
  • the purity of the product is above 99.5 %.
  • the product is directly suitable for the preparation of fluoxetine.
  • This product is filtered and washed with ethyl acetate. Mp.: 149-151 °C. Total yield 93.0 %.
  • Example 4 One proceeds as described in Example 1 except that the toluene solution of N,N-dimethyl- ⁇ 3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine ⁇ obtained at the end of the reaction is evaporated in vacuo. Thus the desired title compound is obtained in pure form (purity 98 % by GC). Yield 57.4 g (89 %). The product is directly suitable for the preparation of N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ -p-toluenesulfonate.
  • Example 4 Example 4
  • Example 2 One proceeds as described in Example 1 except that in the place of potassium hydroxide 24.0 g (0.6 mole) of powdered sodium hydroxide is used and dimethyl sulfoxide is used in an amount of 130 ml rather than 120 ml. The reaction is carried out at 100°C for 12 hours. Thus 640 ml of a toluene solution are obtained which contains 56.3 g of N,N-dimethyl- - ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ according to GC. Yield 87 %.
  • Example 5 The solution may be directly converted into N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ -p-toluenesulfonate by the method described in Example 2.
  • Example 5 N,N-dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine ⁇ -p-toluenesulfonate by the method described in Example 2.
  • Example 6 One proceeds as described in Example 1 except that on working up the reaction mixture toluene is replaced by a commercially available xylene mixture. Thus 620 ml of a xylene solution are obtained, which contains 55.8 g N,N- -dimethyl- ⁇ 3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine ⁇ by GC. Yield 86 %. The solution is directly suitable for the preparation of N,N-dimethyl- ⁇ 3-phenyl-3-[(4-thfluoromethyl)- -phenoxy]-propyl-amine ⁇ -p-toluenesulfonate.
  • Example 6 Example 6

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p-toluenesulfonate of Formula (I) and an improved process for the preparation thereof. The new compound of Formula (I) is a valuable pharmaceutical intermediate useful in the preparation of the antidepressant having the generic name fluoxetine.

Description

PHARMACEUTICAL INTERMEDIATE FOR THE SYNTHESIS OF FLUOXETINE AND A PROCESS FOR THE PREPARATION THEREOF
Technical field of the invention
The invention relates to a new pharmaceutical intermediate and a process for the preparation thereof.
More particularly it is concerned with N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p-toluene- sulfonate of the Formula
Figure imgf000003_0001
and a process for the preparation thereof.
The new compound of the Formula I is a valuable pharmaceutical intermediate which can be used by the preparation of fluoxetine (INN), a well-known antidepressant. Background of the invention
It is known that N-methyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine} hydrochloride (fluoxetine) of the Formula
Figure imgf000003_0002
is an antidepressant which is a selective cerebral serotonin reuptake inhibitor and also acts on the dopamine and norepinephrine systems (HU-173,323).
According to HU-173,723 fluoxetine is prepared by setting free 3-dimethylamino-propiophenone of the Formula
Figure imgf000004_0001
from its hydrochloride salt and reducing said compound in tetrahydrofurane as medium with diborane. The N,N-dimethyl- -(3-hydroxy-3-phenyl-propyl)-amine of the Formula
Figure imgf000004_0002
thus obtained is treated with hydrogen chloride and thionyl chloride and the isolated N,N-dimethyl-(3-chloro-3-phenyl- -propyl)-amine is heated to boiling with 4-thfluoromethyl-phenol of the Formula
OH
V
CF3 under alkaline conditions for 5 days. From N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} fluoxetine is obtained by demethylation (HU-173,723 and Hungarian patent application Ser. No. 2469/96). The compound N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine} is a key intermediate of the synthesis of fluoxetine. In order to obtain fluoxetine which meets the requirements of Pharmacopoeia a N,N-dimethyi intermediate of high purity is required because the contaminations remaining in said intermediate can be removed but with great difficulties and contaminate the end product.
There are several methods for purifying N,N-dimethyl- -{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}. According to HU-173,723 N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} is obtained in the form of the base after complicated recovery and from said base an oxalate is formed in ethyl acetate. However, an intermediate having a quality required for the preparation of fluoxetine can be obtained only by recrystallization from ethyl acetate. This method is accompanied by several drawbacks. The process consists of many steps, the reaction time is very long, isolation and recrystallization of the product are complicated. Moreover we have found that recrystallization from ethyl acetate can only be carried out in a very large volume and requires the use of about 90-100-fold amount of ethyl acetate. HU-173,723 is silent in disclosing the yield of the preparation of the base and the oxalate. A further disadvantage resides in the fact that oxalic acid used for salt formation is a highly toxical compound.
The intermediate N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} can be further purified via the hydrochloride salt thereof. However, the hydrochloride is such a hygroscopic compound that it is unsuitable for use on industrial scale. A further possibility is purification of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine} by means of distillation in vacuo. This route is not feasible either because the N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} base decomposes during distillation in vacuo and the decomposition products formed contaminate the fluoxetine prepared from said intermediate.
According to GB-2, 060,618 N,N-dimethyl-{3-phenyl-3- -[(4-thfluoromethyl)-phenoxy]-propyl-amine} is prepared as follows. The N,N-dimethyl-(3-hydroxy-3-phenyl-propyl)-amine of the Formula IV is treated with sodium hydride in a 15-fold amount of dimethyl sulfoxide as solvent and the salt thus obtained is reacted with 1-fluoro-4-thfluoromethyl-benzene of the Formula
Figure imgf000006_0001
at 80°C. The desired compound is obtained by diluting the dimethyl sulfoxide solution with a 75-fold amount of water, extracting with ether, evaporating the ether and converting the base into the oxalate in ethyl acetate as medium. This process has many drawbacks. The use of sodium hydride and ether increases the risks of fire and explosion to a very great extent and the unusually high reaction volume required makes industrial scale application of the process very difficult and uneconomical. Summary of the invention
It is the object of the present invention to eliminate the above drawbacks of the known procedures and to provide a simple, economical and easily feasible process for the preparation of N,N-dimethyl-{3-phenyl-3-[(4-thfluoromethyl)- -phenoxy]-propyl-amine} of high purity.
The above object is solved according to the present invention by preparing and using N,N-dimethyl-{3-phenyl-3- -[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p-toluenesulfonate of the Formula I.
According to the present invention there is provided a process for the preparation of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine}-p-toluenesulfonate of the Formula
Figure imgf000007_0001
which comprises reacting N,N-dimethyl-(3-hydroxy-3-phenyl- -propyl)-amine of the Formula
Figure imgf000008_0001
with an alkali hydroxide in dimethyl sulfoxide as medium, condensing the alkali salt obtained with a 1-halogeno-4-
-(thfluoromethyl)-benzene of the Formula X
VII
CF3
(wherein X stands for chlorine or fluorine), adding an aromatic organic solvent and an aqueous solution of an inorganic salt to the reaction mixture, and thereafter forming the salt of the Formula I from the solution of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} in the aromatic organic solvent, if desired after removal of the aromatic organic solvent, by reacting with ^-toluene sulfonic acid or the monohydrate thereof. Detailed description of the invention
The present invention is based on the recognition that the compound of the Formula I can be prepared in highly pure, crystalline, easily workable and processable form and N,N- -dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl- -amine} of high purity can be readily set free from said salt. From the highly pure N,N-dimethyl base intermediate product fluoxetine, which meets the severe requirements of Pharmacopoeia, can be obtained by a simple and favourable method.
According to the process of the present invention the compound of the Formula IV is converted into an alkali salt by reacting with an alkali hydroxide in dimethyl sulfoxide solution. As alkali hydroxide sodium hydroxide or potassium hydroxide can be used. It is preferred to use potassium hydroxide. The formation of the alkali salt can be carried out at a temperature between 80°C and the boiling point of the solvent. One may preferably work at 90-110°C. The reaction time is 4-10 hours, advantageously 7-8 hours. The molar ratio of alkali hydroxide and N,N-dimethyl-(3-hydroxy-3-phenyl-propyl)-amine of the Formula IV is 1-6:1 , preferably 2-4:1. The dimethyl sulfoxide solvent can be used in an amount of 2-6 ml/g, preferably 3-4 ml/g, related to the starting material of the Formula IV.
The alkali salt of the compound of the Formula IV thus obtained is then reacted with a compound of the general Formula VII. It is preferred to use 1-chloro-4-trifluoromethyl- -benzene, i.e. the compound of the Formula VII in which X stands for chlorine. Thereafter to the reaction mixture an aromatic organic solvent and an aqueous solution of an inorganic salt are added. As aromatic solvent preferably benzene, toluene, o-, m- or β-xylene, or a commercially available xylene mixture, or chloro benzene, 1 ,2-dichloro benzene, o-chloro-xylene, m-chloro-xylene or rj-chloro-xylene can be used. According to a preferred embodiment of the process of the present invention toluene is used as aromatic organic solvent. The N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine} enters into the aromatic organic phase. The aqueous solution of the inorganic salt washes out the inorganic contaminations (excess of alkali hydroxide, alkali chloride formed in the reaction) and the excess of dimethyl sulfoxide. Thus said impurities can be easily removed by separating the aromatic organic solvent phase from the aqueous inorganic salt layer. As inorganic salt preferably alkali halides, ammonium halides, alkali sulfates or ammonium sulfate can be used. It is preferred to use sodium chloride, sodium sulfate, ammonium sulfate, potassium sulfate or ammonium chloride. According to an advantageous embodiment of the present invention the following inorganic salt solutions can be used: a 5-30 % aqueous sodium chloride solution, a 5-20 % aqueous sodium sulfate solution, a 10-40 % by weight aqueous ammonium sulfate solution, a 5-10 % by weight aqueous potassium sulfate solution or a 20-50 % by weight aqueous ammonium chloride solution. One may particularly preferably use a 10 % aqueous sodium chloride solution.
From the aromatic organic solution of N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} salt can be formed by two methods. According to a preferable method to the aromatic organic solution p_-toluene sulfonic acid monohydrate is added. Said acid may be used in a molar ratio of 1-1.3:1 , preferably 1-1.05:1 (related to 1 mole of N,N- -dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl- -amine}). The p_-toluene sulfonic acid monohydrate is preferably added in one portion to the solution of the base formed with the aromatic organic solvent. After addition of Ό_- -toluene sulfonic acid the reaction mixture is warmed until dissolution takes place, whereupon the excess of the aromatic organic solvent is removed at this temperature under mild vacuo. The compound of the Formula I of high purity precipitates in crystalline form, which can be promoted by adding ethyl acetate. The precipitated crystalline compound of the Formula I can be simply isolated by means of filtration or centrifuging and can be directly used for the preparation of fluoxetine without any purification.
According to another form of realization of the invention salt formation is performed as follows: the aromatic organic phase containing the N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxyj-propyl-amine} is evaporated, the residual base is dissolved in an organic solvent and p_-toluene sulfonic acid monohydrate is added to the solution. As organic solvent aliphatic alcohols (e.g. ethanol or isopropanol) or esters (e.g. ethyl acetate) can be used. In the salt formation reaction j toluene sulfonic acid can be used in a molar ratio of 1-1.3:1 , preferably 1-1.05:1 (related to 1 mole of the N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} base). Salt formation may be carried out under heating, preferably at the boiling point of the reaction mixture. On cooling the reaction mixture the compound of the Formula I precipitates in such a highly pure form that it can be directly used for the preparation of fluoxetine without purification.
Salt formation may be carried out at 0-100°C, preferably at 20-50°C.
The process of the present invention has the following advantages:
- the compound of the Formula I is obtained in a highly pure, crystalline form and can be readily isolated;
- the compound of the Formula I can be directly used for the preparation of fluoxetine without further purification;
- the formation of the p_-toluene sulfonate of the Formula I can be directly carried out in the aromatic organic solvent used;
- the yield is excellent, above 90 %;
- the reaction mixture can be worked-up in a very simple manner;
- the process is suitable for industrial scale use (small volume; no special apparatus is required; the use of combustible and explosive sodium hydride and ether is eliminated; environment-friendly technology; the by-products formed in the process can be easily destroyed without contaminating the environment).
Further details of the present invention are to be found in the Examples without limiting our invention to said Examples. Example 1
N,N-dimethyl-{3-phenyl-3-r(4-trifluoromethyl)-phenoxy1-propyl- -aminei
To a solution of 36.6 g (0.2 mole) of 98 % N,N-dimethyl- -(3-hydroxy-3-phenyl-propyl)-amine and 120 ml of dimethyl sulfoxide 39.6 g (0.6 mole) of 86 % potassium hydroxide are added. The reaction mixture is heated to 100°C under stirring and stirred at this temperature for an hour. To the reaction mixture 51.6 g (0.28 mole) of 4-chloro-(trifluoromethyl)- -benzene are added dropwise within about 2-3 hours and reaction is carried out at 100°C for a further period of 8 hours under stirring. The reaction mixture is cooled, 300 ml of toluene are added and the mixture is composed by adding 250 ml of a 10 % (ml/g) sodium chloride solution under cooling with icecold water. The mixture is stirred for 30 minutes, whereupon a further 300 ml of toluene are added. The phases are separated, the toluene layer is washed with 200 ml of a saturated 25 % sodium chloride solution, filtered and the active ingredient content is analysed. The product can be directly used for the preparation of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyi)-phenoxy]-propyl-amine}-p-toluenesulfonate.
Thus 650 ml of a toluene solution are obtained, which contains 56.9 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxyj-propyl-amine}, yield 88 %. The product can be directly used for the preparation of N,N-dimethyl-{3-phenyl-3- -[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p-toluenesulfonate. Example 2
N,N-dimethyl-{3-phenyl-3-[(4-thfluoromethyl)-phenoxyl-propyl- -amine}-p-toluenesulfonate
To 650 ml of the toluene solution of N,N-dimethyl-{3- -phenyl-3-[(4-trifiuoromethyl)-phenoxy]-propyl-amine} prepared according to Example 1 [which contains 56.9 g (0.176 mole) of the base according to GC] at 25°C 33.8 g (0.176 mole) of 99 % p_-toluenesulfonic acid monohydrate are added. From the mixture at a pressure of 20 kPa toluene is distilled off under stirring until the crystallization of the solution takes place. To the crystal suspension at 40-42°C 100 ml of ethyl acetate are added and the mixture is cooled to 15-20°C under stirring. The precipitated crystals are filtered and washed with ethyl acetate. Thus 73.4 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine}-p-toluenesulfonate are obtained, yield 84.1 %, mp.: 150-152°C.
According to HPLC the purity of the product is above 99.5 %. The product is directly suitable for the preparation of fluoxetine. On evaporating the mother lye further 7.8 g (8.9 %) of the product are obtained, purity above 99.5 %. This product is filtered and washed with ethyl acetate. Mp.: 149-151 °C. Total yield 93.0 %. 1HNMR (200 MHz, CDC13): δ 2.29 [s,5H]; 2.81 [s,6H]; 3.26 [m,2H]; 5.33 [t,1H]; 6.84 [d,2H]; 7,12 [d,2H]; 7.26 [s,5H]; 7.37 [d,2H]; 7.73 [d,2H]; 10.6 [s,2H] Example 3
N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethvO-phenoxyl-propyl- -aminel
One proceeds as described in Example 1 except that the toluene solution of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} obtained at the end of the reaction is evaporated in vacuo. Thus the desired title compound is obtained in pure form (purity 98 % by GC). Yield 57.4 g (89 %). The product is directly suitable for the preparation of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine}-p-toluenesulfonate. Example 4
N,N-dimethyl-{3-phenyl-3- (4-thfluoromethyl)-phenoxyl-propyl- -aminej
One proceeds as described in Example 1 except that in the place of potassium hydroxide 24.0 g (0.6 mole) of powdered sodium hydroxide is used and dimethyl sulfoxide is used in an amount of 130 ml rather than 120 ml. The reaction is carried out at 100°C for 12 hours. Thus 640 ml of a toluene solution are obtained which contains 56.3 g of N,N-dimethyl- -{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} according to GC. Yield 87 %. The solution may be directly converted into N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine}-p-toluenesulfonate by the method described in Example 2. Example 5
N,N-dimethyl-{3-phenyl-3-K4-trifluoromethvO-phenoxyl-propyl- -aminel
One proceeds as described in Example 1 except that on working up the reaction mixture toluene is replaced by a commercially available xylene mixture. Thus 620 ml of a xylene solution are obtained, which contains 55.8 g N,N- -dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine} by GC. Yield 86 %. The solution is directly suitable for the preparation of N,N-dimethyl-{3-phenyl-3-[(4-thfluoromethyl)- -phenoxy]-propyl-amine}-p-toluenesulfonate. Example 6
N,N-dimethyl-{3-phenyl-3-K4-trifluoromethyl)-phenoxy]-propyl- -aminej-p-toluenesulfonate
1.0 g (0.003 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 15 ml of isopropanol. To the solution 0.6 g (0.00315 mole) of p_-toluene sulfonic acid monohydrate are added. The reaction mixture is heated to boiling under stirring. The crystals precipitated on cooling are filtered and washed with a small amount of isopropanol. Thus 1.26 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyi)-phenoxy]- -propyl-amine}-p-toluenesulfonate are obtained, yield 85.1 %, mp.: 150-152°C. According to HPLC the purity of the product is higher than 99.5 %. The product is directly suitable for the preparation of fluoxetine. Example 7
N,N-dimethyl-l3-phenyl-3-f(4-trifluoromethyl)-phenoxy1-propyl- -aminej-p-toluenesulfonate
4.00 g (0.012 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 20 ml of ethanol whereupon to the solution 2.4 g (0.0126 mole) of r toluene-sulfonic acid monohydrate are added and the mixture is heated to boiling under stirring. The crystals precipitated on cooling are filtered and washed with a small amount of ethanol. Thus 4.90 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl- -amine}-p-toluenesulfonate are obtained, yield 82.5 %. Mp.: 150-152°C. The purity of the product is above 99.5 % by HPLC. The product may be directly used for the preparation of fluoxetine. Example 8
N,N-dimethyl-{3-phenyl-3-r(4-trifluoromethyl)-phenoxyl-propyl- -aminel-p-toluenesulfonate
2.0 g (0.006 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifiuoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 30 ml of ethyl acetate. To the solution 1.2 g (0.0063 mole) of p_-toluene-sulfonic acid monohydrate are added and the reaction mixture is heated to boiling under stirring. The crystals precipitated on cooling are filtered and washed with a small amount of ethyl acetate. Thus 2.75 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]- -propyl-amine}-p-toluenesulfonate are obtained, yield 92.6 %. Mp.: 150-152°C. The purity of the product is above 99.5 % by HPLC. The product is directly suitable for the preparation of fluoxetine. Example 9
N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy1-propyl- -aminej-p-toluenesulfonate
2.0 g (0.006 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 25 ml of toluene. To the solution 1.2 g (0.0063 mole) of β-toluene sulfonic acid monohydrate and 10 ml of isopropanol are added. The reaction mixture is heated to boiling. The crystals precipitated on cooling are filtered and washed with a small amount of toluene. Thus 2.84 g of N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]- -propyl-amine}-p-toluenesulfonate are obtained, yield 95.6 %. Mp.: 150-152°C. The purity of the product is above 99.5 % by HPLC. The product is directly suitable for the preparation of fluoxetine. Example 10
N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy1-propyl- -aminel-p-toluenesulfonate
2.0 g (0.006 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 30 ml of toluene. To the solution 1.2 g (0.0063 mole) of p_-toluene-sulfonic acid monohydrate are added. The reaction mixture is heated to boiling under stirring and then cooled to 0°C within an hour. The precipitated crystals are filtered and washed with a small amount of toluene. Thus 2.73 g of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine}-p-toluenesulfonate are obtained, yield 91.9 %, mp.: 150-152°C. The purity of the product is above 99.5 % by HPLC. The product may be directly used for the preparation of fluoxetine. Example 11
N,N-dimethyl-{3-phenyl-3-f(4-trifluoromethyl)-phenoxy1-propyl- -amine}-p-toluenesulfonate
1.0 g (0.003 mole) of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} prepared according to Example 3 are dissolved in 5 ml of xylene. To the solution 0.6 g (0.00315 mole) of p_-toluene sulfonic acid monohydrate are added. The reaction mixture is heated to 60°C under stirring. On cooling crystallization takes place. The precipitated crystals are filtered and washed with a small amount of xylene and ethyl acetate successively. Thus 1.3 g of N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p- -toluenesulfonate are obtained, yield 87.2 %, mp.: 148-150°C. The purity of the product is above 99.0 % by HPLC. The product may be directly used for the preparation of fluoxetine.

Claims

What we claim is,
1. N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)- -phenoxy]-propyl-amine}-p-toluenesulfonate of the Formula
Figure imgf000020_0001
2. Process for the preparation of N,N-dimethyl-{3- -phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p- -toluenesulfonate of the Formula
Figure imgf000020_0002
which comprises reacting N,N-dimethyl-(3-hydroxy-3-phenyl- -propyl)-amine of the Formula
Figure imgf000020_0003
with an alkali hydroxide in dimethyl sulfoxide as medium, condensing the alkali salt obtained with a 1-halogeno-4- -(trifluoromethyl)-benzene of the Formula X
VII
C 3
(wherein X stands for chlorine or fluorine), adding an aromatic organic solvent and an aqueous solution of an inorganic salt to the reaction mixture, and thereafter forming the salt of the Formula I from the solution of N,N-dimethyl-{3-phenyl-3-[(4- -trifluoromethyl)-phenoxy]-propyl-amine} in the aromatic organic solvent, if desired after removal of the aromatic organic solvent, by reacting with β-toluene sulfonic acid or the monohydrate thereof.
3. Process according to Claim 2 which comprises using as compound of the general Formula VII 1-chloro-4- -(trifluoromethyl)-benzene, in which X stands for chlorine.
4. Process according to Claim 2 or 3 which comprises using potassium hydroxide or sodium hydroxide as alkali hydroxide.
5. Process according to Claim 4 which comprises using potassium hydroxide.
6. Process according to Claim 2 which comprises using benzene, toluene, o-, m- or p_-xylene, a commercially available xylene mixture, chloro benzene, 1 ,2-dichloro- -benzene, o-chloro-xylene, m-chloro-xylene or p_-chloro xylene as aromatic organic solvent.
7. Process according to Claim 6 which comprises using toluene as aromatic organic solvent.
8. Process according to Claim 2 which comprises using an aqueous solution of an alkali halide, ammonium halide, alkali sulfate or ammonium sulfate as aqueous solution of an inorganic salt.
9. Process according to Claim 8 which comprises using an aqueous solution of sodium chloride, sodium sulfate, ammonium sulfate, potassium sulfate, sodium chloride or ammonium chloride.
10. Process according to Claim 9 which comprises using an aqueous sodium chloride solution.
11. Process according to any of Claims 2-10 which comprises adding to the reaction mixture obtained on reacting the alkali salt of the compound of the Formula IV with the compound of the Formula VII at first the aromatic organic solvent and thereafter the aqueous solution of the inorganic salt.
12. Process according to any of Claims 2-11 which comprises separating the aromatic organic solvent phase containing N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]- -propyl-amine} from the aqueous solution of the inorganic salt and adding p_-toluene sulfonic acid or the monohydrate thereof to said organic phase.
13. Process according to any of Claims 2-11 which comprises evaporating the aromatic organic solvent phase which contains N,N-dimethyl-{3-phenyl-3-[(4-thfluoromethyl)- -phenoxy]-propyl-amine}, dissolving the residue in an organic solvent and adding p_-toluene sulfonic acid or the monohydrate thereof.
14. Process according to Claim 13 which comprises using an aliphatic alcohol or ester as organic solvent.
15. Process according to Claim 14 which comprises using isopropanol, ethanol or ethyl acetate as organic solvent.
PCT/HU1999/000068 1998-10-13 1999-10-13 Pharmaceutical intermediate for the synthesis of fluoxetine and a process for the preparation thereof Ceased WO2000021917A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (1)

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Publication number Priority date Publication date Assignee Title
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect

Patent Citations (1)

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US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect

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Title
E.J. COREY AND G.A. REICHARD: "Enantioselective and Practical Synthesis of R- and S-Fluoxetines", TETRAHEDRON LETTERS., vol. 30, no. 39, 1989, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 5207 - 5210, XP002131425, ISSN: 0040-4039 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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