FR2628740A3 - Sepn. of enantiomers of di:substd. ethanol - by carbamate formation using phenyl:ethyl isocyanate - Google Patents
Sepn. of enantiomers of di:substd. ethanol - by carbamate formation using phenyl:ethyl isocyanate Download PDFInfo
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- FR2628740A3 FR2628740A3 FR8904835A FR8904835A FR2628740A3 FR 2628740 A3 FR2628740 A3 FR 2628740A3 FR 8904835 A FR8904835 A FR 8904835A FR 8904835 A FR8904835 A FR 8904835A FR 2628740 A3 FR2628740 A3 FR 2628740A3
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- phenyl
- ethanol
- piperidyl
- methyl
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 title claims abstract 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 title abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 title 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 15
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims abstract description 9
- 238000001640 fractional crystallisation Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 22
- -1 [[(4-fluoro-phenyl) methyl] piperidyl] ethanol Chemical compound 0.000 claims description 21
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 4
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- JJSCUXAFAJEQGB-UHFFFAOYSA-N 1-isocyanatoethylbenzene Chemical compound O=C=NC(C)C1=CC=CC=C1 JJSCUXAFAJEQGB-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002253 anti-ischaemic effect Effects 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- GGUSQTSTQSHJAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanol Chemical compound C=1C=C(Cl)C=CC=1C(O)CN(CC1)CCC1CC1=CC=C(F)C=C1 GGUSQTSTQSHJAH-UHFFFAOYSA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MADORZDTLHDDEN-UHFFFAOYSA-N 1-piperidin-1-ylethanol Chemical compound CC(O)N1CCCCC1 MADORZDTLHDDEN-UHFFFAOYSA-N 0.000 description 2
- HACRKYQRZABURO-UHFFFAOYSA-N 2-phenylethyl isocyanate Chemical compound O=C=NCCC1=CC=CC=C1 HACRKYQRZABURO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- UVUOBXZEGYPBOV-UHFFFAOYSA-N 2-[2-[(4-fluorophenyl)methyl]piperidin-1-yl]ethanol Chemical compound FC1=CC=C(C=C1)CC1N(CCCC1)CCO UVUOBXZEGYPBOV-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- KZMHCQUAMFYNRF-UHFFFAOYSA-N phenyl n-ethylcarbamate Chemical compound CCNC(=O)OC1=CC=CC=C1 KZMHCQUAMFYNRF-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention a pour objet un procédé de préparation des énantiomères du (chloro-4 phényl)-l [[(fluoro-4 phenyl)- méthyl]-4 pipéridyl-1]-2 éthanol.The present invention relates to a process for the preparation of enantiomers of (4-chloro-phenyl) -1 [[(4-fluorophenyl) methyl] -1-piperidyl] ethanol.
Le (chloro-4 phényl)-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthanol, de formule
est décrit dans le brevet européen N 0109317. Il s'agit d'un composé utilisable comme substance active de médicaments anti-ischémiques cérébraux. Ses enantiomères, dont l'existence est due à la présence d'un atome de carbone chiral dans la molécule, peuvent être préparés à partir du racémate selon le procédé décrit ci-après.4- (4-chlorophenyl) -4 - [[(4-fluorophenyl) methyl] piperidyl] ethanol, of formula
is described in European Patent No. 0109317. It is a compound that can be used as an active substance of cerebral anti-ischemic drugs. Its enantiomers, whose existence is due to the presence of a chiral carbon atom in the molecule, can be prepared from the racemate according to the method described below.
Le procédé selon l'invention consiste à faire réagir le (chloro-4 phényl)-l [[(fluoro-4 phényl)méthyl]-4 pipéri dyl-iJ-2 éthanol racémique avec l'enantiomère S(-) de l'isocyanate de phényl-l éthyle, ce qui donne un mélange de deux carbamates diastéréoisomères A et B. On en sépare le diaste réoisomère A par cristallisation fractionnée, et on le traite au moyen d'hydrure de lithium et d'aluminium, obtenant ainsi l'énantiomere (+) du (chloro-4 phényl)-l [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthanol.The process according to the invention consists in reacting racemic (4-chloro-4-phenyl) -l [[(4-fluoro-phenyl) methyl] piperidyl-ethanol with the S (-) enantiomer of the phenyl-1-ethyl isocyanate to give a mixture of two diastereoisomeric carbamates A and B. The diastereoisomeric diastereomer A is separated by fractional crystallization and treated with lithium aluminum hydride, thereby obtaining (+) enantiomer of 4-chloro-phenyl-1 - [[(4-fluorophenyl) methyl] -2-piperidyl] ethanol.
On traite ensuite le mélange des carbamates A et B, riche en diastéréoisomère B, issu des eaux mères de la cristallisation fractionnée, au moyen d'hydrure de lithium et d'aluminium, obtenant ainsi l'énantiomère (-) du (chloro-4 phényl)-l [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthanol optiquement impur.The mixture of carbamates A and B, rich in diastereoisomer B, obtained from the mother liquors of the fractional crystallization, is then treated with lithium aluminum hydride, thus obtaining the (-) enantiomer of (chloro-4) phenyl) -1 [[(4-fluorophenyl) methyl] piperidyl] -2 ethanol optically impure.
On fait réagir celui-ci avec l'énantiomère R(+) de l'isocyanate de phényl-1 éthyle, ce qui fournit un mélange de deux carbamates diastéréoisomères A' et B' (antipodes respectifs des carbamates diastéréoisomères A et B précédemment obtenus). On sépare le diastéréoisomère A' par cristallisation fractionnée, et on le traite au moyen d'hydrure de lithium et d'aluminium, obtenant ainsi l'énantiomère (-) du (chloro-4 phényl)-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthanol.This is reacted with the R (+) enantiomer of 1-phenylethyl isocyanate, which provides a mixture of two diastereoisomeric carbamates A 'and B' (respective antipodes of the previously obtained diastereoisomeric carbamates A and B). . The diastereoisomer A 'is separated by fractional crystallization, and treated with lithium aluminum hydride, thereby obtaining the (-) enantiomer of (4-chloro-phenyl) -1 [[(4-fluorophenyl) ) methyl] -4-piperidyl-2-ethanol.
L'exemple suivant illustre le procédé selon l'invention.The following example illustrates the process according to the invention.
a) < Phényl-1 éthyl)carbamate de (chloro-4 phényl)-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthyle.a) 1- (4-Chloro-phenyl) -1 - [(4-fluorophenyl) methyl] -4-piperidyl] ethyl] phenyl-1-ethyl-carbamate.
Dans un ballon de 1000 ml muni d'un réfrigérant à reflux et d'une garde à chlorure de calcium, on introduit 8,00 g (0,054 mole) de S(-) isocyanate de phenyl-1 ethyle, 250 ml de toluène sec et 18,45 g (0,053 mole) de (chloro-4 phényl)-1 [t (fluoro-4 phényl)méthyl]-4 pipéridyl-1 -2 éthanol. On chauffe le mélange au reflux pendant 8h et on le laisse revenir à température ambiante. On répète ensuite deux fois la manipulation suivante : addition de 5,0 g (0,034 mole) de
S(-) isocyanate de phényl-1 éthyle, chauffage au reflux pendant 8h, et retour à la température ambiante.In a 1000 ml flask equipped with a reflux condenser and a guard containing calcium chloride, 8.00 g (0.054 mol) of S (-) 1-phenylethyl isocyanate, 250 ml of dry toluene are introduced. and 18.45 g (0.053 mol) of 4- (4-chlorophenyl) -4- (4-fluoro-phenyl) methyl] piperidyl ethanol. The mixture is refluxed for 8h and allowed to warm to room temperature. The following procedure is then repeated twice: addition of 5.0 g (0.034 mol) of
S (-) phenyl-1 ethyl isocyanate, refluxed for 8h, and returned to room temperature.
Ensuite on évapore le toluène, et on purifie le résidu par chromatographie sur colonne de silice avec un mélange 9/1 de dichlorométhane/éthanol, ce qui donne une huile, qu'on triture dans 180 ml d'un mélange 1/2 d'éther diéthylique/éther de pétrole. On obtient ainsi 24,12 g de mélange de diastéréoisomères A et B sous forme de solide blanc.The toluene is then evaporated off and the residue is purified by chromatography on a silica column with a 9/1 mixture of dichloromethane / ethanol, which gives an oil, which is triturated in 180 ml of a 1/2 mixture of diethyl ether / petroleum ether. 24.12 g of mixture of diastereoisomers A and B are thus obtained in the form of a white solid.
b) Diastéréoisomère A du (phényl-1 éthyl)carbamate de (chloro-4 phényl)-1 [t [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1 ]-2 éthyle.b) Diastereoisomer A of (4-chlorophenyl) -1- [1 - [(4-fluorophenyl) methyl] -4-piperidyl] ethyl (1-phenylethyl) carbamate.
On fait recristalliser 24,0 g du mélange obtenu dans l'étape a) dans 80 ml d'éthanol absolu, en ensemençant la solution surnageante avec un cristal de diastéréoisomère A pur, et on la laisse revenir à température ambiante pendant 3h. On sépare le diastéréoisomère A par filtration, ce qui fournit 7,32 g d'aiguilles blanches, qu'on utilise telles quelles dans l'étape suivante.24.0 g of the mixture obtained in step a) are recrystallized from 80 ml of absolute ethanol, by seeding the supernatant solution with a pure diastereoisomeric A crystal, and allowed to return to room temperature for 3 hours. The diastereoisomer A is separated by filtration, which gives 7.32 g of white needles, which are used as they are in the next step.
Point de fusion : 104-1080C. [a]D5 21150 (c=1,036 ; cHcl3)
Enfin on récupère le mélange de diastéréoisomères (B > A) brut par évaporation des eaux-mères, ce qui laisse 16,65 g de résidu. [a25--33,60 (c=1,048 ; CHCl3).Melting point: 104-1080C. [a] D5 21150 (c = 1.036; cHCl3)
Finally, the mixture of crude diastereoisomers (B> A) is recovered by evaporation of the mother liquors, leaving 16.65 g of residue. [? 25? 33.60 (c = 1.048, CHCl?).
c) Enantiomère (+) du (chloro-4 phényl)-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1 J-2 éthanol.c) (+) (4-Chloro-phenyl) -1 [[(4-fluorophenyl) methyl] -4-piperidyl] -2-ethanol enantiomer.
Dans un ballon tricol de 1000 ml muni d'une ampoule à introduction, d'un réfrigérant à reflux et d'une garde à chlorure de calcium, on introduit 0,96 g (0,025 mole) d'hydrure de lithium et d'aluminium et 120 ml de tétrahydrofuranne. On agite la suspension à température ambiante, et on ajoute, en 15mn, une solution de 6,0 g du diastéréoisomère A, obtenu dans l'étape b), dans 100 ml de tétrahydrofuranne. On agite le mélange pendant 1h à température ambiante, on le refroidit avec un bain de glace, et on détruit l'excès hydrure de lithium et d'aluminium en ajoutant lentement 100 ml d'eau.In a 1000 ml three-necked flask equipped with an introduction funnel, a reflux condenser and a calcium chloride guard, 0.96 g (0.025 mol) of lithium aluminum hydride are introduced. and 120 ml of tetrahydrofuran. The suspension is stirred at room temperature and a solution of 6.0 g of the diastereoisomer A obtained in step b) in 100 ml of tetrahydrofuran is added over 15 minutes. The mixture is stirred for 1 hour at room temperature, cooled with an ice bath, and the excess lithium aluminum hydride is destroyed by slowly adding 100 ml of water.
On extrait le mélange trois fois avec 300 ml d'acétate d'éthyle, on sèche la phase organique sur sulfate de sodium, on évapore le solvant, et on recristallise le résidu dans 40 ml d'éthanol absolu. On isole finalement 3,03 g d'énantiomère (+) pur.The mixture is extracted three times with 300 ml of ethyl acetate, the organic phase is dried over sodium sulphate, the solvent is evaporated off and the residue is recrystallized in 40 ml of absolute ethanol. Finally, 3.03 g of pure (+) enantiomer is finally isolated.
Point de fusion : 141-142,50C.Melting point: 141-142.50C.
[a]25 = +48,20 (c = 0,998 ; CHC13). [?] = +48.20 (c = 0.998, CHCl3).
d) Enantiomère (-) optiquement impur du (chloro-4 phényl)-1 [f (f luoro-4 phényl)méthyl]-4 pipéridyl-1 -2 éthanol.d) Optically impure (-) (4-chlorophenyl) -1- (4-fluorophenyl) methyl] -4-piperidyl ethanol enantiomer.
Dans un ballon tricol de 2000 ml muni d'une ampoule à introduction, d'un réfrigérant à reflux et d'une garde à chlorure de calcium, on introduit 2,56 g (0,067 mole) d'hydrure de lithium et d'aluminium et 250 ml de tétrahydrofuranne. On agite la suspension à température ambiante, et on ajoute, en 75mon, une solution de 16,0 g du mélange de diastéréoisomères (B > A) brut, obtenu dans l'étape b), dans 250 ml de tétrahydrofuranne. On agite le mélange pendant 1h à température ambiante, on le refroidit avec un bain de glace, et on détruit l'excès d'hydrure de lithium et d'aluminium en ajoutant lentement 200 ml d'eau.In a three-necked 2000 ml flask equipped with an introduction funnel, a reflux condenser and a calcium chloride guard, 2.56 g (0.067 mol) of lithium aluminum hydride are introduced. and 250 ml of tetrahydrofuran. The suspension is stirred at room temperature, and a solution of 16.0 g of the crude diastereoisomeric mixture (B> A) obtained in step b) in 250 ml of tetrahydrofuran is added in 75 ml. The mixture is stirred for 1 hour at room temperature, cooled with an ice bath, and the excess lithium aluminum hydride is destroyed by slowly adding 200 ml of water.
On extrait le mélange avec 200 ml, puis deux fois 300 ml, d'acétate d'éthyle, on sèche la phase organique sur sulfate de sodium, on évapore le solvant, et on recristallise le résidu dans 100 ml d'éthanol absolu. On isole ainsi 9,22 g d'énantiomère (-) optiquement Impur.The mixture is extracted with 200 ml and then twice 300 ml of ethyl acetate, the organic phase is dried over sodium sulfate, the solvent is evaporated off and the residue is recrystallized from 100 ml of absolute ethanol. 9.22 g of (-) optically impure enantiomer are thus isolated.
Point de fusion : 131-1320C. [ ]25=-15,6 (c=1,008 ; CHCl3) e) Diastéréoisomère A' du (phényl-1 éthyl)carbamate de (chloro-4 phényl )-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1]-2 éthyle.Melting point: 131-1320C. [] 25 = -15.6 (c = 1.008, CHCl 3) e) 4-Dichloro-4-phenyl-1-phenyl-4-phenyl-1-phenyl-4 - [(4-fluorophenyl) methyl] -4-piperidyl diastereoisomer -1] -2 ethyl.
Dans un ballon de 250 ml muni d'un réfrigérant à reflux et d'une garde à chlorure de calcium, on introduit 4,84 g (0,033 mole) de R(+) isocyanate de phényl-1 éthyle, 100 ml de toluène sec et 9,0 g (0,026 mole) d'énantiomère (-) optiquement impur obtenu dans l'étape d).In a 250 ml flask equipped with a reflux condenser and a calcium chloride guard, 4.84 g (0.033 mol) of 1-phenyl-1-ethyl R (+) isocyanate, 100 ml of dry toluene are introduced. and 9.0 g (0.026 mol) of optically impure enantiomer (-) obtained in step d).
On chauffe le mélange au reflux pendant 8h, on le laisse revenir à température ambiante, on ajoute 1,0 g (0,007 mole) de R(+) isocyanate de phényl-1 éthyle, et on chauffe au reflux pendant encore 4h. On laisse refroidir le mélange, on évapore le toluène, et on purifie le résidu par chromatographie sur colonne de silice avec un mélange 9/1 de dichlorométhane/acétone.The mixture was refluxed for 8 h, allowed to warm to room temperature, 1.0 g (0.007 mole) of 1-phenylethyl 1-isocyanate (R) and refluxed for a further 4 hours. The mixture is allowed to cool, toluene is evaporated, and the residue is purified by chromatography on a silica column with a 9/1 mixture of dichloromethane / acetone.
On obtient 13,67 g de solide blanc qui, après recristallisation dans 42 ml d'éthanol absolu, fournit 7,04 g-d'aiguilles blanches.13.67 g of white solid are obtained which, after recrystallization from 42 ml of absolute ethanol, gives 7.04 g of white needles.
Point de fusion : 105-1100C. [a]D5=,20,80 (c=1,082 ; CHCl3) f) Enantiomère (-) du (chloro-4 phényl)-1 [[(fluoro-4 phényl)méthyl]-4 pipéridyl-1 )-2 éthanol.Melting point: 105-1100C. [a] D5 =, 20.80 (c = 1.082, CHCl3) f) Enantiomer (-) of (4-chlorophenyl) -1 [[(4-fluorophenyl) methyl] -4-piperidyl] -2 ethanol .
Dans un ballon tricol de 1000 ml muni d'une ampoule à introduction, d'un réfrigérant à reflux et d'une garde à chlorure de calcium, on introduit 0,96 g (0,025 mole) d'hydrure de lithium et d'aluminium et 120 ml de tétrahydrofuranne. On agite la suspension à température ambiante, et on ajoute, en 15mn, une solution de 6,0 g du diastéréoisomère A', obtenu dans l'étape e), dans 100 ml-de tétrahydrofuranne. On agite le mélange pendant 1h à température ambiante, on le refroidit avec un bain de glace, et on détruit l'excès d'hydrure de lithium et d'aluminium en ajoutant lentement 100 ml d'eau.In a 1000 ml three-necked flask equipped with an introduction funnel, a reflux condenser and a calcium chloride guard, 0.96 g (0.025 mol) of lithium aluminum hydride are introduced. and 120 ml of tetrahydrofuran. The suspension is stirred at room temperature, and a solution of 6.0 g of the diastereoisomer A ', obtained in step e), in 100 ml of tetrahydrofuran is added over 15 minutes. The mixture is stirred for 1 hour at room temperature, cooled with an ice bath, and the excess lithium aluminum hydride is destroyed by slowly adding 100 ml of water.
On extrait le mélange trois fois avec 300 ml d'acétate d'éthyle, on sèche la phase organique sur sulfate de sodium, on évapore le solvant, et on recristallise le résidu dans 50 ml d'éthanol absolu. On isole finalement 3,33 g d'énantiomère (-) pur.The mixture is extracted three times with 300 ml of ethyl acetate, the organic phase is dried over sodium sulphate, the solvent is evaporated off and the residue is recrystallized in 50 ml of absolute ethanol. Finally, 3.33 g of pure (-) enantiomer is finally isolated.
Point de fusion : 141,5-142,50C.Melting point: 141.5-142.50C.
[α]D25 = -47,5 (c = 0,984 ; CHC13). [α] D25 = -47.5 (c = 0.984, CHCl3).
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8904835A FR2628740B3 (en) | 1989-04-12 | 1989-04-12 | PROCESS FOR THE PREPARATION OF (CHLORO-4 PHENYL) -1 (((FLUORO-4 PHENYL) METHYL) -4 PIPERIDYL-1) -2-ETHANOL ENANTIOMERS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8904835A FR2628740B3 (en) | 1989-04-12 | 1989-04-12 | PROCESS FOR THE PREPARATION OF (CHLORO-4 PHENYL) -1 (((FLUORO-4 PHENYL) METHYL) -4 PIPERIDYL-1) -2-ETHANOL ENANTIOMERS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2628740A3 true FR2628740A3 (en) | 1989-09-22 |
| FR2628740B3 FR2628740B3 (en) | 1990-01-19 |
Family
ID=9380638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8904835A Expired - Lifetime FR2628740B3 (en) | 1989-04-12 | 1989-04-12 | PROCESS FOR THE PREPARATION OF (CHLORO-4 PHENYL) -1 (((FLUORO-4 PHENYL) METHYL) -4 PIPERIDYL-1) -2-ETHANOL ENANTIOMERS |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2628740B3 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2694555A1 (en) * | 1992-08-05 | 1994-02-11 | Synthelabo | 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) |
| FR2696741A1 (en) * | 1992-10-12 | 1994-04-15 | Synthelabo | New 1-phenyl-2-piperidino:ethanol derivs. - are useful as anticonvulsants, agents for treating brain disorders, neurodegenerative diseases, schizophrenia etc. |
| EP0692472A1 (en) | 1994-07-13 | 1996-01-17 | Synthelabo | Alpha-(4-chlorophenyl)- 4-(4-fluorophenylmethyl)-piperidine-1 -ethanol esters, their preparation and therapeutical use |
| WO2001085169A3 (en) * | 2000-05-10 | 2002-03-28 | Alcon Universal Ltd | R-eliprodil for treating glaucoma |
| US6538008B1 (en) | 1998-03-06 | 2003-03-25 | Merck Sharpe & Dohme Limited | Combination of a selective NMDA NR2B antagonist and an opioid analgesic |
-
1989
- 1989-04-12 FR FR8904835A patent/FR2628740B3/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2694555A1 (en) * | 1992-08-05 | 1994-02-11 | Synthelabo | 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) |
| FR2696741A1 (en) * | 1992-10-12 | 1994-04-15 | Synthelabo | New 1-phenyl-2-piperidino:ethanol derivs. - are useful as anticonvulsants, agents for treating brain disorders, neurodegenerative diseases, schizophrenia etc. |
| 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 |
| US6538008B1 (en) | 1998-03-06 | 2003-03-25 | Merck Sharpe & Dohme Limited | Combination of a selective NMDA NR2B antagonist and an opioid analgesic |
| WO2001085169A3 (en) * | 2000-05-10 | 2002-03-28 | Alcon Universal Ltd | R-eliprodil for treating glaucoma |
| WO2001085152A3 (en) * | 2000-05-10 | 2002-03-28 | Alcon Universal Ltd | R-eliprodil for treating glaucoma |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2628740B3 (en) | 1990-01-19 |
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