FR2694555A1 - 1-(4-chloro 2-hydroxyphenyl) 2-(4-(4-fluorophenyl methyl) piperidine 1-yl) ethanol enantiomer sepn. - by converting racemate to 1-(4-chloro 2-methoxymethyl phenyl) deriv., reacting with 1-phenylethyl isocyanate and sepg. carbamate(s) - Google Patents

1-(4-chloro 2-hydroxyphenyl) 2-(4-(4-fluorophenyl methyl) piperidine 1-yl) ethanol enantiomer sepn. - by converting racemate to 1-(4-chloro 2-methoxymethyl phenyl) deriv., reacting with 1-phenylethyl isocyanate and sepg. carbamate(s) Download PDF

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FR2694555A1
FR2694555A1 FR9209712A FR9209712A FR2694555A1 FR 2694555 A1 FR2694555 A1 FR 2694555A1 FR 9209712 A FR9209712 A FR 9209712A FR 9209712 A FR9209712 A FR 9209712A FR 2694555 A1 FR2694555 A1 FR 2694555A1
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

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Abstract

Enantiomers of 1-(4-chloro-2-hydroxy phenyl)-2-(4-(4-fluoro phenyl) methyl)piperidin-1-yl) ethanol (I) are separated from racemic (I) by conversion to the 2-methoxy methyl ether, reaction with an enantiomer of 1-phenyl ethyl isocyanate, separation of the resultant carbamates, and release of (I). USE - (I) is known (FR 91.01088) to be useful in the treatment of degenerative cerebral disorders. In an example, 4.15g racemic (I) was stirred with 100ml dichloromethane, 100ml water, 5ml NaOH (d = 1.33), 2 spatulasful of tetrabutyl ammonium hydrogen sulphate and 870 microlitres chloromethyl methyl ester (II). After 1 hour 10 minutes a further 500 microlitres of (II) was added, then, after 50 minutes, a further 500 microlitres (II). The product (III) was extracted into chloroform and dried. 4.57g (III) 250ml toluene, and 1.6ml S(-) 1-phenyl ethyl isocyanate were heated together for 7 hours at 100 deg.C. A further 1ml of the isocyanate was added and heating continued for a further 7 hours. This gave 9g crude product which was purified by chromatography on silica gel to give 1.15g diastereoisomer A and 3g mixture of diastereoisomers A and B. Recrystallisation from ethanol gave 630mg diastereoisomer A. 1.8g Diastereoisomer A, 100ml DMF and 1.8g sodium methane thiolate were heated at 100 deg C for 31/2 hours then purified to give 520mg of pure (+) (I), specific rotation (D line, 25 deg C) = +4 deg (c = 0.5; DMF).

Description

La présente invention a pour objet un procédé de préparation des énantiomères du 1-(4-chloro-2-hydroxyphényl)-2-[4-t(4- fluorophényl)méthyl]-pipéridin-1-yl]éthanol. The present invention relates to a process for the preparation of enantiomers of 1- (4-chloro-2-hydroxyphenyl) -2- [4-t (4-fluorophenyl) methyl] -piperidin-1-yl] ethanol.

Le 1-(4-chloro-2-hydroxyphényl)-2-[4-t(4-fluorophényl)mé- thyl]pipéridin-l-yl]éthanol, de formule

Figure img00010001

est décrit dans la demande de brevet français nO 91.01088. Ce composé est utilisé, comme substance active de médicaments, dans le traitement et la prévention de désordres cérébraux dégénératifs. Ses énantiomères peuvent être préparés à partir du racémate selon le procédé décrit ci-après.1- (4-chloro-2-hydroxyphenyl) -2- [4-t (4-fluorophenyl) methyl] piperidin-1-yl] ethanol, of formula
Figure img00010001

is described in French patent application No. 91.01088. This compound is used, as an active substance in drugs, in the treatment and prevention of degenerative brain disorders. Its enantiomers can be prepared from the racemate according to the method described below.

Le procédé selon l'invention consiste à faire réagir le 1-(4chloro-2-hydroxyphényl)-2-[4-[(4-fluorophényl)méthyl]pipéridin-l-yl]éthanol racémique avec le chlorométhyl méthyléther, ce qui donne le 1-(4-chloro-2-méthoxyméthoxyphényl)-2-[4-[(4- fluorophényl) méthyl] pipéridin-l-yl] éthanol. The process according to the invention consists in reacting the 1- (4-chloro-2-hydroxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] racemic ethanol with chloromethyl methyl ether, which gives 1- (4-chloro-2-methoxymethoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol.

On fait ensuite réagir ce composé avec l'énantiomère S(-) de l'isocyanate de 1-phényléthyle, on sépare l'un des carbamates diastéréoisomères du mélange des deux carbamates diastéréoisomères obtenu, par chromatographie et cristallisation dans l'éthanol, et on traite le carbamate diastéréoisomère isolé, avec le méthanethiolate de sodium, pour obtenir l'énantiomère(+) du 1- (4-chloro-2-hydroxyphényl) -2-[4- [(4-f luorophényl) - méthyl]pipéridin-l-yl]éthanol, puis on fait réagir le 1-(4 chloro-2-méthOxyméthoxyphényl)-2-[4-[(4-fluorophényl)méthyl]- pipéridin-l-yl]éthanol avec l'énantiomère R(+) de l'isocyanate de 1-phényléthyle, on sépare l'un des carbamates diasté réoisomères du mélange des deux carbamates diastéréoisomères obtenu, par chromatographie et cristallisation dans l'éthanol, et on traite le carbamate diastéréoisomère isolé, avec le méthanethiolate de sodium, pour obtenir l'énantiomère (-) du l-(4-chloro-2-hydroxyphényl) -2-[4-[ (4-f luorophényl)mé- thyl]pipéridin-1-yl]éthanol.This compound is then reacted with the S (-) enantiomer of 1-phenylethyl isocyanate, one of the diastereoisomeric carbamates is separated from the mixture of the two diastereoisomeric carbamates obtained, by chromatography and crystallization from ethanol, and treats the isolated diastereoisomeric carbamate with sodium methanethiolate to obtain the (+) enantiomer of 1- (4-chloro-2-hydroxyphenyl) -2- [4- [(4-f luorophenyl) - methyl] piperidin- l-yl] ethanol, then reacting 1- (4 chloro-2-methOxymethoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] - piperidin-1-yl] ethanol with the R (+) enantiomer ) from 1-phenylethyl isocyanate, one of the reoisomeric diastere carbamates is separated from the mixture of the two diastereoisomeric carbamates obtained, by chromatography and crystallization from ethanol, and the isolated diastereoisomeric carbamate is treated with sodium methanethiolate, to obtain the (-) enantiomer of 1- (4-chloro-2-hydroxyphenyl) -2 - [4- [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol.

L'exemple suivant illustre le procédé selon l'invention.The following example illustrates the process according to the invention.

a) 1-(4-Chloro-2-méthoxyméthoxyphényl)-2-[4-[(4-fluorophé- nyl)méthyl]pipéridin-1-yl]éthanol.a) 1- (4-Chloro-2-methoxymethoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol.

Dans un ballon muni d'un agitateur magnétique, on introduit 4,15 g (11,5 mmoles) de 1-(4-chloro-2-hydroxyphényl)-2-[4- [(4-fluorophenyl)methyl]piperidin-1-yl]éthanol racémique, 100 ml de-dichlorométhane, 100 ml d'eau, 5 ml de lessive de soude (d = 1,33), 2 spatulées d'hydrogènosulfate de tétrabutyl ammonium et 870 ijl (11,5 mmoles) de chlorométhyl méthyléther. On agite le mélange pendant 1 h 10 mn, on rajoute 500 ul de chlorométhyl méthyléther puis on agite encore pendant 2 h avant de rajouter 500 u1 de chlorométhyl méthyléther. On agite encore pendant 50 mn, puis on décante et extrait une fois au chloroforme. On lave la phase chloroformique à l'eau, on la sèche sur sulfate de sodium puis on la filtre et on évapore le solvant à sec.4.15 g (11.5 mmol) of 1- (4-chloro-2-hydroxyphenyl) -2- [4- [(4-fluorophenyl) methyl] piperidin- are introduced into a flask fitted with a magnetic stirrer 1-yl] racemic ethanol, 100 ml of-dichloromethane, 100 ml of water, 5 ml of sodium hydroxide solution (d = 1.33), 2 spatulas of tetrabutyl ammonium hydrogen sulphate and 870 ijl (11.5 mmol) of chloromethyl methyl ether. The mixture is stirred for 1 h 10 min, 500 μl of chloromethyl methyl ether are added and then the mixture is stirred for 2 h before adding 500 μl of chloromethyl methyl ether. Stirred further for 50 min, then decanted and extracted once with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and then filtered and the solvent is evaporated to dryness.

On obtient 5,1 g de produit brut.5.1 g of crude product are obtained.

b) Diastéréoisomère A du 1-phényléthylcarbamate de 1-(4 chloro-2-méthoxyméthoxyphényl)-2-[4-[(4-fluorophényl)méthyl]- pipéridin-1-yl]éthyle. b) Diastereoisomer A of 1- (4 chloro-2-methoxymethoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] -piperidin-1-yl] 1-phenylethylcarbamate.

Dans un ballon sous argon, on introduit 4,57 g du produit obtenu à l'étampe a), 250 ml de toluène sec et 1,6 ml de S(-) isocyanate de 1-phényléthyle. On chauffe le mélange à 1000C pendant 3 h 30 mn, on agite à la température ambiante pendant une nuit, puis on rajoute 1 ml de S(-)isocyanate de 1-phenyl- éthyle, on chauffe à 1000C pendant 7 h et on agite à la température ambiante pendant une nuit. On rajoute encore 1 ml de S(-)isocyanate de 1-phényléthyle, on chauffe à 1000C pendant 7 heures puis on évapore le solvant à sec. On obtient 9 g de produit brut que l'on chromatographie sur gel de silice avec un mélange 70/30 de chloroforme et d'éther. On récupère ainsi 1,15 g de diastéréoisomère A pur et 3 g de mélange des diastéréoisomères A et B.Après recristallisation du mélange dans de l'éthanol, on isole 630 mg de diastéréoisomère A pur.4.57 g of the product obtained in stamp a), 250 ml of dry toluene and 1.6 ml of 1-phenylethyl isocyanate are introduced into a flask under argon. The mixture is heated at 1000C for 3 h 30 min, stirred at room temperature overnight, then 1 ml of 1-phenylethyl S (-) isocyanate is added, the mixture is heated at 1000C for 7 h and stirred at room temperature overnight. Another 1 ml of 1 (phenylethyl) isocyanate is added, the mixture is heated at 1000C for 7 hours and then the solvent is evaporated to dryness. 9 g of crude product are obtained which are chromatographed on silica gel with a 70/30 mixture of chloroform and ether. 1.15 g of pure diastereoisomer A and 3 g of mixture of diastereoisomers A and B are thus recovered. After recrystallization of the mixture from ethanol, 630 mg of pure diastereoisomer A is isolated.

c) Enantiomère (+) du 1-(4-chloro-2-hydroxyphényl)-2-[4-[ (4- fluorophényl)méthyl]pipéridin-1-yl]éthanol. c) (+) Enantiomer of 1- (4-chloro-2-hydroxyphenyl) -2- [4- [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol.

Dans up ballon sous argon, muni d'un agitateur magnétique, on introduit 1,8 g (3,2 mmoles) du diastéréoisomère A obtenu à l'étape b), 100 ml de diméthylformamide sec et 1,8 g de méthanethiolate de sodium. On chauffe le mélange à 1000C pendant 3 h 30 mn puis on laisse refroidir et on ajoute de la glace et de l'eau. On extrait deux fois à l'éther, on lave la phase éthérée deux fois à l'eau, on la sèche sur sulfate de sodium, on la filtre et on évapore le solvant à sec.1.8 g (3.2 mmol) of the diastereoisomer A obtained in step b), 100 ml of dry dimethylformamide and 1.8 g of sodium methanethiolate are introduced into an argon flask fitted with a magnetic stirrer . The mixture is heated to 1000C for 3 h 30 min then allowed to cool and ice and water are added. Extraction is carried out twice with ether, the ethereal phase is washed twice with water, dried over sodium sulphate, filtered and the solvent is evaporated to dryness.

Après dissolution du résidu dans un mélange de chloroforme et de méthanol, on recristallise dans le méthanol pour obtenir finalement 590 mg de produit.After dissolving the residue in a mixture of chloroform and methanol, recrystallization from methanol to finally obtain 590 mg of product.

Une impureté ayant été décelée, on purifie le produit. Pour cela, on introduit 580 mg du produit obtenu précédemment, dans un tricol sous argon, muni d'un agitateur magnétique. On ajoute 20 ml d'acide acétique et 24,5 mg de perborate de sodium, puis on chauffe le mélange à 500C pendant 1 h 30 mn et on le laisse revenir à la température ambiante. On concentre l'acide acétique sous vide puis on reprend le résidu dans de l'eau et on alcalinise avec de l'ammoniaque. On extrait trois fois au chloroforme, puis on lave la phase organique une fois à l'eau, on la sèche sur sulfate de sodium, on la filtre et on évapore le solvant à sec.An impurity having been detected, the product is purified. For this, 580 mg of the product obtained above is introduced into a three-necked flask under argon, equipped with a magnetic stirrer. 20 ml of acetic acid and 24.5 mg of sodium perborate are added, then the mixture is heated to 500 ° C. for 1 h 30 min and is allowed to return to room temperature. The acetic acid is concentrated in vacuo, then the residue is taken up in water and basified with ammonia. Extraction is carried out three times with chloroform, then the organic phase is washed once with water, it is dried over sodium sulfate, it is filtered and the solvent is evaporated to dryness.

On chromatographie ensuite le résidu sur gel de silice avec un mélange 97/3 de chloroforme et de méthanol puis on dissout le produit obtenu dans un mélange de chloroforme et de méthanol.The residue is then chromatographed on silica gel with a 97/3 mixture of chloroform and methanol and then the product obtained is dissolved in a mixture of chloroform and methanol.

Par recristallisation dans le méthanol, on obtient 520 mg d'énantiomère (+) pur.By recrystallization from methanol, 520 mg of pure (+) enantiomer are obtained.

Point de fusion : 185-1860C. Melting point: 185-1860C.

[α]D25 = + 4 (c = 0,5 ; DMF).  [α] D25 = + 4 (c = 0.5; DMF).

d) Diastéréoisomère A' du 1-phényléthylcarbamate de 1-(4 chloro-2-méthoxyméthoxyphényl)-2-[4-[(4-fluorophényl)méthyl]- pipéridin-1 -yl J éthyle. d) Diastereoisomer A 'of 1- (4 chloro-2-methoxymethoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] -piperidin-1-yl ethyl 1-phenylethylcarbamate.

Dans un ballon sous argon, on introduit 7,1 g du produit obtenu à l'étape a), 300 ml de toluène sec et 2,7 ml de R(+) isocyanate de 1-phényléthyle. On chauffe à 1000C pendant 7 h puis on agite à.la température ambiante pendant une nuit. On rajoute ensuite 1,2 ml de R(+)isocyanate de 1-phényléthyle et on chauffe à 1000C pendant 7 h, puis on agite à la température ambiante pendant une nuit.7.1 g of the product obtained in step a), 300 ml of dry toluene and 2.7 ml of 1-phenylethyl isocyanate R are introduced into an argon flask. The mixture is heated at 1000C for 7 h and then stirred at room temperature overnight. 1.2 ml of 1-phenylethyl isocyanate R (+) is then added and the mixture is heated at 1000C for 7 h, then stirred at room temperature overnight.

On rajoute encore 1,5 ml de R(+) isocyanate de 1-phényléthyle et on chauffe de nouveau à 1000C pendant 7 h, puis on évapore le solvant à sec. On obtient 13 g de produit brut que l'on chromatographie sur gel de silice avec un mélange 70/30 de chloroforme et d'éther.A further 1.5 ml of 1-phenylethyl isocyanate R (+) is added and the mixture is again heated at 1000C for 7 h, then the solvent is evaporated to dryness. 13 g of crude product are obtained which is chromatographed on silica gel with a 70/30 mixture of chloroform and ether.

On récupère ainsi 3,2 g de diastéréoisomère A' pur, 1 g de diastéréoisomère B' pur et 4,5 g de mélange des diastéréoisomères A' et B'.3.2 g of pure diastereoisomer A 'are thus recovered, 1 g of pure diastereoisomer B' and 4.5 g of mixture of diastereoisomers A 'and B'.

Après recristallisation du mélange dans de l'éthanol, on isole 900 mg de diastéréoisomère A' pur.After recrystallization of the mixture from ethanol, 900 mg of pure diastereoisomer A 'are isolated.

e) Enantiomère (-) du 1-(4-chloro-2-hydroxyphényl)-2-[4-[(4- fluorophényl)méthyl]pipéridin-1-yl]éthanol. e) (-) Enantiomer of 1- (4-chloro-2-hydroxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol.

Dans un ballon sous argon, muni d'un agitateur magnétique, on introduit les 4,1 g (7,4 mmoles) de diastéréoisomère A' obtenu à l'étape d), 150 ml de diméthylformamide sec et 3,62 g de méthanethiolate de sodium. On chauffe le mélange à 1000C pendant 2 h 30 mn puis on laisse refroidir et on ajoute de la glace et de l'eau. On extrait deux fois à l'éther, on lave la phase éthérée deux fois à l'eau, on la sèche sur sulfate de magnésium, on la filtre puis on évapore le solvant à sec.4.1 g (7.4 mmol) of diastereoisomer A 'obtained in step d), 150 ml of dry dimethylformamide and 3.62 g of methanethiolate are introduced into an argon flask fitted with a magnetic stirrer sodium. The mixture is heated to 1000C for 2 h 30 min then allowed to cool and ice and water are added. It is extracted twice with ether, the ethereal phase is washed twice with water, it is dried over magnesium sulphate, it is filtered and the solvent is evaporated to dryness.

Après dissolution du résidu dans un mélange de chloroforme et de méthanol, on recristallise dans le méthanol pour obtenir finalement 720 mg de produit.After dissolving the residue in a mixture of chloroform and methanol, recrystallization from methanol to finally obtain 720 mg of product.

Une impureté ayant été décelée, on purifie le produit. Pour cela, on introduit 650 mg du produit obtenu précédemment, dans un tricol sous argon, muni d'un agitateur magnétique. On ajoute 10 ml d'acide acétique et 30 mg de perborate de sodium. On chauffe le mélange à 500C pendant 1 h 15 mn puis on le laisse refroidir. On évapore l'acide acétique sous vide puis on reprend le résidu dans de l'eau et on alcalinise avec de l'ammoniaque. On extrait trois fois au chloroforme, puis on lave la phase organique une fois à l'eau, on la sèche sur sulfate de sodium, on la filtre et on évapore le solvant à sec.An impurity having been detected, the product is purified. For this, 650 mg of the product obtained above is introduced into a three-necked flask under argon, fitted with a magnetic stirrer. 10 ml of acetic acid and 30 mg of sodium perborate are added. The mixture is heated to 500C for 1 h 15 min and then allowed to cool. The acetic acid is evaporated in vacuo, then the residue is taken up in water and basified with ammonia. Extraction is carried out three times with chloroform, then the organic phase is washed once with water, it is dried over sodium sulfate, it is filtered and the solvent is evaporated to dryness.

On chromatographie ensuite le résidu sur gel de silice avec un mélange 97/3 de chloroforme et de méthanol, puis on dissout le produit obtenu dans un mélange de chloroforme et de méthanol. Par recristallisation dans le méthanol, on obtient 605 mg d'énantiomère (-) pur.The residue is then chromatographed on silica gel with a 97/3 mixture of chloroform and methanol, then the product obtained is dissolved in a mixture of chloroform and methanol. By recrystallization from methanol, 605 mg of pure (-) enantiomer are obtained.

Point de fusion = 185 - 1860C. Melting point = 185 - 1860C.

,25 = 30 (c = 0,5 ; DMF).  , 25 = 30 (c = 0.5; DMF).

Claims (1)

Revendication Claim Procédé de préparation des énantiomères du 1-(4-chloro-2 hydroxyphényl) -2-E 4-E (4-fluorophényl )méthyl J pipéridin-1 - yl]éthanol, caractérisé en ce qu'on fait réagir le l-(4-chlo ro-2-hydroxyphényl)-2-[4-[(4-fluorophényl)méthyl]pipéridin-1- yl]éthanol racémique avec le chlorométhyl méthyléther, puis on fait réagir le 1-(4-chloro-2-méthoxyméthoxyphényl)-2-[4- [(4-fluorophényl)méthyl]pipéridin-1-yl]éthanol obtenu avec leProcess for the preparation of enantiomers of 1- (4-chloro-2 hydroxyphenyl) -2-E 4-E (4-fluorophenyl) methyl J piperidin-1 - yl] ethanol, characterized in that the l- ( 4-chlo ro-2-hydroxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1- yl] racemic ethanol with chloromethyl methyl ether, then reacting 1- (4-chloro-2- methoxymethoxyphenyl) -2- [4- [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol obtained with S(-)isocyanate de 1-phényléthyle, on sépare l'un des deux carbamates diastéréoisomères obtenus, par chromatographie et cristallisation dans l'éthanol, et on traite le carbamate diastéréoisomère ainsi isolé avec le méthane thiolate de sodium pour obtenir l'énantiomère (+) du 1-(4-chloro-2-hydroxyphényl)-2-[4-[(4-fluorophényl)méthyl]pipéridin-1-yl]é- thanol, puis on fait réagir le 1-(4-chloro-2-méthoxymétoxyphényl)-2-[4-[(4-fluorophényl)méthyl]pipéridin-1-yl]éthanol avec le R(+)isocyanate de 1-phényléthyle, on sépare l'un des deux carbamates diastéréoisomères obtenus, par chromatographie et cristallisation dans l'éthanol, et on traite le carbamate diastéréoisomère ainsi isolé avec le méthanethiolate de sdium pour obtenir l'énantiomère(-) du 1-(4-chloro-2 hydroxyphényl)-2-[4-[(4-fluorophényl)méthyl]pipéridin-1- yl]éthanol. S (-) 1-phenylethyl isocyanate, one of the two diastereoisomeric carbamates obtained is separated by chromatography and crystallization from ethanol, and the diastereoisomeric carbamate thus isolated is treated with sodium methane thiolate to obtain the enantiomer ( +) 1- (4-chloro-2-hydroxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol, then react the 1- (4-chloro- 2-methoxymetoxyphenyl) -2- [4 - [(4-fluorophenyl) methyl] piperidin-1-yl] ethanol with R (+) isocyanate of 1-phenylethyl, separating one of the two diastereoisomeric carbamates obtained by chromatography and crystallization from ethanol, and the diastereoisomeric carbamate thus isolated is treated with sdium methanethiolate to obtain the (-) enantiomer of 1- (4-2-chloro-hydroxyphenyl) -2- [4 - [(4-fluorophenyl ) methyl] piperidin-1-yl] ethanol.
FR9209712A 1992-08-05 1992-08-05 1-(4-chloro 2-hydroxyphenyl) 2-(4-(4-fluorophenyl methyl) piperidine 1-yl) ethanol enantiomer sepn. - by converting racemate to 1-(4-chloro 2-methoxymethyl phenyl) deriv., reacting with 1-phenylethyl isocyanate and sepg. carbamate(s) Pending FR2694555A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0692472A1 (en) * 1994-07-13 1996-01-17 Synthelabo Alpha-(4-chlorophenyl)- 4-(4-fluorophenylmethyl)-piperidine-1 -ethanol esters, their preparation and therapeutical use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0109317A2 (en) * 1982-10-13 1984-05-23 Synthelabo Phenyl-1-piperidino-2-propanol derivatives, their preparation and medicaments containing them
FR2628740A3 (en) * 1989-04-12 1989-09-22 Synthelabo Sepn. of enantiomers of di:substd. ethanol - by carbamate formation using phenyl:ethyl isocyanate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0109317A2 (en) * 1982-10-13 1984-05-23 Synthelabo Phenyl-1-piperidino-2-propanol derivatives, their preparation and medicaments containing them
FR2628740A3 (en) * 1989-04-12 1989-09-22 Synthelabo Sepn. of enantiomers of di:substd. ethanol - by carbamate formation using phenyl:ethyl isocyanate

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0692472A1 (en) * 1994-07-13 1996-01-17 Synthelabo Alpha-(4-chlorophenyl)- 4-(4-fluorophenylmethyl)-piperidine-1 -ethanol esters, their preparation and therapeutical use
FR2722497A1 (en) * 1994-07-13 1996-01-19 Synthelabo ALPHA-4-CHLOROPHENYL) -4- (4-FLUOROPHENYL) METHYL) PIPERIDINE-1-ETHANOL ESTERS, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US5620990A (en) * 1994-07-13 1997-04-15 Synthelabo Alpha-(4-chlorophenyl)-4-[(4-fluorphenyl)-methyl]piperidine-1-ethanol esters, their preparation and their therapeutic application

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