CA1265522A - (+)-trans-3-¬(4-methoxyphenoxy)-methyl|-1- methyl-4-phenylperidine (+)-mandelate - Google Patents
(+)-trans-3-¬(4-methoxyphenoxy)-methyl|-1- methyl-4-phenylperidine (+)-mandelateInfo
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- CA1265522A CA1265522A CA000576252A CA576252A CA1265522A CA 1265522 A CA1265522 A CA 1265522A CA 000576252 A CA000576252 A CA 000576252A CA 576252 A CA576252 A CA 576252A CA 1265522 A CA1265522 A CA 1265522A
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- methyl
- trans
- methoxyphenoxy
- phenylpiperidine
- mixture
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Abstract
ABSTR~CT OF THE DISCLOSURE
A process for the optical resolution of the enantio-mers of trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl-4-phenyl-piperidine, which involves reaction with an enantiomer of mandelic acid to form a mixture of diastereomeric compounds, precipitating one of the diastereoisomers, and converting it to the desirable free (+)-trans isomer, as well as the key diastereomeric isomer intermediate, is disclosed.
A process for the optical resolution of the enantio-mers of trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl-4-phenyl-piperidine, which involves reaction with an enantiomer of mandelic acid to form a mixture of diastereomeric compounds, precipitating one of the diastereoisomers, and converting it to the desirable free (+)-trans isomer, as well as the key diastereomeric isomer intermediate, is disclosed.
Description
~2655~2 OPtical Resolution of Racemic Femoxetine The present invention relates to a new process for the optical resolution of racemic trans-3-~(4-methoxyphenoxy) -methyl~ methyl-4-phenylpiperidine into its optical pure forms, of which the (~)-enantiomer is the antidepressive drug femoxetine having the structural formula ~H3 (~),trans ~ CH -O ~ O-CH3 ~3 .
A conventional procedure for the optical resolution of a racemate into its optical active components comprises reacting the racemate with ~n optical compound to form two diastereomeric compounds, which because of their different physical properties can be separated by fractionated crystallization from a solvent, in which the solubility of the two compounds is different.
The preliminary step of the procedure for the optical resolution of a racemic compound by employing an optical active resolving agent usually comprises a step of mixing equimolar amounts of the racemate and the resolving agent each dissolved in a suitable solvent or mixing a hot solution of the racemate with an equimolar amount of the resolving agent. Following dissolution of the reactants the solution is allowed to cool to a temperature at which only one of the diastereomers precipitates. The optical active component of the racemate to be resolved is then recovered from the precipitated diastereomer by well known procedures.
. . : ~ . ,
A conventional procedure for the optical resolution of a racemate into its optical active components comprises reacting the racemate with ~n optical compound to form two diastereomeric compounds, which because of their different physical properties can be separated by fractionated crystallization from a solvent, in which the solubility of the two compounds is different.
The preliminary step of the procedure for the optical resolution of a racemic compound by employing an optical active resolving agent usually comprises a step of mixing equimolar amounts of the racemate and the resolving agent each dissolved in a suitable solvent or mixing a hot solution of the racemate with an equimolar amount of the resolving agent. Following dissolution of the reactants the solution is allowed to cool to a temperature at which only one of the diastereomers precipitates. The optical active component of the racemate to be resolved is then recovered from the precipitated diastereomer by well known procedures.
. . : ~ . ,
- 2 -~2~iS522 British patent specification No~ 1 422 263 discloses a process for the optical resolution of various racemates of 3-substituted-4-phenylpiperidine compounds including trans-3-C(4-methoxyphenoxy)-methyll-1-methyl-4-phenyl-piperidine using (-)-dibenzoyltartaric acid as the resolving agent. The process is examplified by the optical resolution of racemic trans-3-methoxymethyl-1--methyl-4-phenylpiperidine.
However, the optical resolution of a mixture of the enantiomers of trans-3-r(4-methoxyphenoxy)-methyl~
-methyl-4-phenylpiperidine using (-l-dibenzoyltartaric acid as the resolving agent suffers from the defects that the yield obtained is-only about 47~ of the theo-retical value, that the precipitated (+)-trans-3- r(4--methoxyphenoxy)-methylJ-1-methyl-4-phenylpiperidine, (-)-dibenzoyltartrate is impure, and that (-~-dibenzoyl-tartaric acid is relatively costly. The high cost of the (-)-dibenzoyltartaric acid makes it desirable to recover it from the precipitated diastereomeric compound, but this has turned out to be difficult. Therefore the prior art process is of little value for commercial production of femoxetine.
Surprisingly it has now been found that an improved optical resolution of a mixture of the enantiomers of trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl-4-phenyl-piperidine can be effected by use of less than equimolar amounts of one of the enantiomers of mandelic acid or of a derivative thereof as the resolving agent in an organic solvent.
_ 7--t '~
~265522 Accordingly, the present invention provides an impr~ved process for the production o (+)-trans-3-((4-methoxy--phenoxy)-methyl)-1-methyl-4-phenylpiperidine fxom racemic trans-3-l(4 methoxyphenoxy)-methyl)-1-methyl-4-phenyl-piperidine, which comprises reacting said racemic trans-3-((4-methoxyphenoxy)-methyl)-1-methyl-4-phenylpiperidine with one of the enantiomers of mandelic acid or of a derivative thereof in less than stoichiometric amounts in an organic solvent to form two diastereomeric compounds in mixture with excess trans-3-((4-methoxyphenoxy)-methyl)--1-methyl-4-phenylpiperidine, and which process comprises, from this mixture, precipitating one of said diastereomeric compounds in high yield of ~he theoretical possible amount.
It is eviident that the present invention provides an exceptional example to separation of optical isomers by fractional crystallization as difference in solubilities of diastereomers rarely if ever is great enough to effect total separation with one crystallization (see J. March., Advanced Organic Chemistry, McGraw-Hill, Inc. (1977)).
In a preferred embodiment of the process according to the present invention said enantiomer of mandelic acid of a derivative thereof is reacted with a mixture of the enan-tiomers of trans-3-[(4-methoxyphenoxy)-methyl] -1-methyl-4--phenylpiperidine dissolved in a hot organic solvent.
In a preferred embodiment of the present invention one of said dlastereomeric compounds is precipitated by cooling the solution to a temperature at which only said diastereo-meric compound precipitates.
The organic solvent used as reaction medium is preferably an aromatic solvent including for example alkylated and halogenated derivatives, an aliphatic ester, an aliphatic alcohol or a mixture thereof. The organic solvent is most preferably toluene, ethyl acetate, met~yl isobutyl carbinol or mixtures thereof.
~26S522 The resolving agent is preferable (+)-mandelic acid or a derivative thereof, most preferably (+)-mandelic acid.
Derivatives of (+)-mandelic acid include derivatives which is halogenated, hydroxylated, nitrated, alkylated and alkoxylated. Most preferred derivatives are those which i5 halogenated. Most preferred halogenated deri-vatives are those whic~h is halogenated in 4 position of the phenyl group.
h~hen using (~)-mandelic acid as the resolving agent and toluene as the solvent the precipitation is preferably carried out by coolin~ the solution to a temperature between 0 and 30C.
The mixture of the enantiomers of trans-3-[(4-methoxyphenoxy)--methyl]-1-methyl-4-phenylpiperidine is preferably dissolved in 0.3 to 0.4 1 of toluene for each mol of trans-3-[(4--methoxyphenoxy)-methyl]-1-methyl-4-phenylpipe~ridine, and the toluene is preferably heated to a temperature between 50 and 75C.
The amount of (+)-mandelic acid is preferably from 0.5 to 0.6 mol for each mol of trans-3-[(4-methoxyphenoxy)-methyl]
-1-methyl-4-phenylpiperidine. Despite the small amount of the resolving agent used the yield of (+)-trans-3-~(4-methoxy-phenoxy)-methyl~-1-methyl-4-phenylpiperidine,(+)-mandelate is approximately 75% of the theoretical value and said mandelate is of a very high purity.
Not only does said preferred embodiments of the process require less than equimolar amounts of the t+)-mandelic acid, but it has also been found that the (+)-mandelic acid as well as racemic trans-3-[~4-methoxyphenoxy)-methyl]-1--methyl-4-phenylpiperidine left in the solution can easily be recovered and recycled, thus only leaving the (-)-trans-
However, the optical resolution of a mixture of the enantiomers of trans-3-r(4-methoxyphenoxy)-methyl~
-methyl-4-phenylpiperidine using (-l-dibenzoyltartaric acid as the resolving agent suffers from the defects that the yield obtained is-only about 47~ of the theo-retical value, that the precipitated (+)-trans-3- r(4--methoxyphenoxy)-methylJ-1-methyl-4-phenylpiperidine, (-)-dibenzoyltartrate is impure, and that (-~-dibenzoyl-tartaric acid is relatively costly. The high cost of the (-)-dibenzoyltartaric acid makes it desirable to recover it from the precipitated diastereomeric compound, but this has turned out to be difficult. Therefore the prior art process is of little value for commercial production of femoxetine.
Surprisingly it has now been found that an improved optical resolution of a mixture of the enantiomers of trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl-4-phenyl-piperidine can be effected by use of less than equimolar amounts of one of the enantiomers of mandelic acid or of a derivative thereof as the resolving agent in an organic solvent.
_ 7--t '~
~265522 Accordingly, the present invention provides an impr~ved process for the production o (+)-trans-3-((4-methoxy--phenoxy)-methyl)-1-methyl-4-phenylpiperidine fxom racemic trans-3-l(4 methoxyphenoxy)-methyl)-1-methyl-4-phenyl-piperidine, which comprises reacting said racemic trans-3-((4-methoxyphenoxy)-methyl)-1-methyl-4-phenylpiperidine with one of the enantiomers of mandelic acid or of a derivative thereof in less than stoichiometric amounts in an organic solvent to form two diastereomeric compounds in mixture with excess trans-3-((4-methoxyphenoxy)-methyl)--1-methyl-4-phenylpiperidine, and which process comprises, from this mixture, precipitating one of said diastereomeric compounds in high yield of ~he theoretical possible amount.
It is eviident that the present invention provides an exceptional example to separation of optical isomers by fractional crystallization as difference in solubilities of diastereomers rarely if ever is great enough to effect total separation with one crystallization (see J. March., Advanced Organic Chemistry, McGraw-Hill, Inc. (1977)).
In a preferred embodiment of the process according to the present invention said enantiomer of mandelic acid of a derivative thereof is reacted with a mixture of the enan-tiomers of trans-3-[(4-methoxyphenoxy)-methyl] -1-methyl-4--phenylpiperidine dissolved in a hot organic solvent.
In a preferred embodiment of the present invention one of said dlastereomeric compounds is precipitated by cooling the solution to a temperature at which only said diastereo-meric compound precipitates.
The organic solvent used as reaction medium is preferably an aromatic solvent including for example alkylated and halogenated derivatives, an aliphatic ester, an aliphatic alcohol or a mixture thereof. The organic solvent is most preferably toluene, ethyl acetate, met~yl isobutyl carbinol or mixtures thereof.
~26S522 The resolving agent is preferable (+)-mandelic acid or a derivative thereof, most preferably (+)-mandelic acid.
Derivatives of (+)-mandelic acid include derivatives which is halogenated, hydroxylated, nitrated, alkylated and alkoxylated. Most preferred derivatives are those which i5 halogenated. Most preferred halogenated deri-vatives are those whic~h is halogenated in 4 position of the phenyl group.
h~hen using (~)-mandelic acid as the resolving agent and toluene as the solvent the precipitation is preferably carried out by coolin~ the solution to a temperature between 0 and 30C.
The mixture of the enantiomers of trans-3-[(4-methoxyphenoxy)--methyl]-1-methyl-4-phenylpiperidine is preferably dissolved in 0.3 to 0.4 1 of toluene for each mol of trans-3-[(4--methoxyphenoxy)-methyl]-1-methyl-4-phenylpipe~ridine, and the toluene is preferably heated to a temperature between 50 and 75C.
The amount of (+)-mandelic acid is preferably from 0.5 to 0.6 mol for each mol of trans-3-[(4-methoxyphenoxy)-methyl]
-1-methyl-4-phenylpiperidine. Despite the small amount of the resolving agent used the yield of (+)-trans-3-~(4-methoxy-phenoxy)-methyl~-1-methyl-4-phenylpiperidine,(+)-mandelate is approximately 75% of the theoretical value and said mandelate is of a very high purity.
Not only does said preferred embodiments of the process require less than equimolar amounts of the t+)-mandelic acid, but it has also been found that the (+)-mandelic acid as well as racemic trans-3-[~4-methoxyphenoxy)-methyl]-1--methyl-4-phenylpiperidine left in the solution can easily be recovered and recycled, thus only leaving the (-)-trans-
-3-[(4-methoxyphenoxy)-methyl~-1-methyl-4~phenylpiperidine as waste product.
The following examples illustrate the invention:
EXAMPLE 1.
-116.4 kg (383.7 mol) of racemic trans-3-~(4-methoxyphenoxy)--methyl~ methyl-4-phenylpiperidine was dissolved in 10Q l of toluene. The solution was stirred while the temperature was raised to 60C. 31.2 kg (205.5 mol) of (~)-mandelic acid was added and the mixture was stirred at 60C until .
the mixture was clear. The solution was allowed to cool to room temperature. The temperature of the mixture was then reduced to 10C while stirring during the next 15 hours. The mixture was then centrifuged and the precipitate was washed with toluene and iso-propanol. The yield was 64.8 ky (75% of the theoretical value) of (~)-trans-3-~(4--methoxyphenoxy)-methyl]-1-methyl-4-phenylpiperidine, (+)-mandelate, m.p. 126-30C, ~a]D + 90.2 ~C = 2 in 96% ethanol). Recrystallization of said mandelate salt did not change the value of ,aJ 20.
50 kg of ~+)-trans-3- [(4-methoxyphenoxy)-methyl]-1-methyl-
The following examples illustrate the invention:
EXAMPLE 1.
-116.4 kg (383.7 mol) of racemic trans-3-~(4-methoxyphenoxy)--methyl~ methyl-4-phenylpiperidine was dissolved in 10Q l of toluene. The solution was stirred while the temperature was raised to 60C. 31.2 kg (205.5 mol) of (~)-mandelic acid was added and the mixture was stirred at 60C until .
the mixture was clear. The solution was allowed to cool to room temperature. The temperature of the mixture was then reduced to 10C while stirring during the next 15 hours. The mixture was then centrifuged and the precipitate was washed with toluene and iso-propanol. The yield was 64.8 ky (75% of the theoretical value) of (~)-trans-3-~(4--methoxyphenoxy)-methyl]-1-methyl-4-phenylpiperidine, (+)-mandelate, m.p. 126-30C, ~a]D + 90.2 ~C = 2 in 96% ethanol). Recrystallization of said mandelate salt did not change the value of ,aJ 20.
50 kg of ~+)-trans-3- [(4-methoxyphenoxy)-methyl]-1-methyl-
-4-phenylpiperidine,(+)-mandelate was mixed with 27.5 l of distilled water, 67.5 l of toluene and 6.1 l of 50% w/w NaOH. The toluene phase was separated and stirred w$th 3.3 kg of potassium carbonate and filtered. 10 1 of conce~-trated hydrochloric acid and 45 l of isopropanol was mixed with the toluene phase and the mixture was evaporated.
The residue was recrystallized from iso-propanol to give 33.8 kg (90%) o~ ~)-trans-3-~4 methoxyphenoxy)-methyl]-1--methyl-4-phenylpiperidine as the hydrochloride. M.p. 189-90C, -~20 = 75 3 ~C = 5 in H2O)-~265522 EXAMPLES 2-5.
In a similar manner but by use of different solvents and different mandelic acid derivatives in an amount counting for 55% of the racemic trans-3-~4-methoxyphenoxy)-methyl~
-1-methyl-4-phenylpiperidine the experiment were repeated.
The table below shows the overall yield of the salt of ~ trans-3- [(4-methoxyphenoxy)-methyl~-1-methyl-4-phenyl-piperidine Ifemoxetine) and (+)-mandelic acid or a deri-vative thereof.
- Overall yi~ld of the ~ - salt of femoxetine and (+)-~andelic acid or a derivative thereof Ex. Solvent Resolving agent _ (%) 2 toluene ~ 2-hydroxy-2-(4-fluoro- 74.0 phenyl)-acetic acid 3 toluene (~)-2-hydroxy-2-(4-chloro- 66.5 phenyl)-acetic acid 4 ethyl (+)-2-hydroxy-2-phenyl- 67.5 acetate ~cetic acid MIBC* (~-2-hydroxy-2-phenyl- 59.0 acetic acid ~ MIBC = methyl iso-~utyl carbinol The results thus obtained clearly show that the present invention provides an improved process for the production of femoxetine in that the yield of the salt of femoxetlne and (+)-mandelic acid or a derivative thereof is 65-75%
of the theoretical value compared to 47% obtained by the known methods. Furthermore said salt of femoxetine and ~ mandelic acid or a derivative thereof is of very high purity.
15~0 g (48.2 mmol) of racemic trans-3((4-methoxyphenoxy)--methyl)-1-methyl-4-phenylpiperidine was dissolved in 11.5 ml of toluene. The solution was stirred while the temperature was raised to 60C. 6.55 g (43.1 mmol) of (+)-mandelic acid was added and the mixture was stirred at 60C until the m~xture was-clear~ The solutisn was allowed to cool to room temperature. The temperature of the mixture was then reduced to 10C and the mixture was left at this temperature for the next 15 hours. The mixture was then filtered and the precipitate was washed with toluene and iso-propanol. The yield was 6.1 y (55% of the theoretical value) of (+)-trans-3-((4-methoxy-phenoxy)-methyl)-1-methyl-4-phenylpiperidine,(+)-mandelate, m.p. 121C, a D + 81.6 (C = 2 in 96% ethanol~.
12~;5S~Z
_ a) 20 g (64 mmol) of racemic trans-3-~(4-methoxyphenoxy~--methyl~ methyl-4-phenylpiperiaine and 22 g (62 mmol~
of (-)-dibenzoyl tartaric acid $s dissolved in 200 ml of ethanol. The mixture is evaporated under vacuum.
The residue is optimally recrystallized from 50 ml methanol to yield.16.2 g of product. M.p. 84.1-84.6~C
[~D0 0.38 (c = 5 in 99~ ethanol).
b) 1~ g of the product of a is mixed with 20 ml of 4M
NaOH~ 40 ml of water and 100 ml of ether. The organi~
phase is dried with potassium carbonat, filtered and evaporated under vacuum to give 4.2 g of product. The product is dissolved -n 75 ml of iso-propanol. 1 ml of konc. hydrochloric acid is added and the mixture is evaporated to give 4.7 g of product. M.p. 182.7-184.2C.
1.9 g of this product is recrystallized from 6 ml of iso-propanol to give 1.4 g of (+)-trans-3-C(4-methoxy-phenoxy)-methyl~ methyl-4-phenylpiperidine as the hydrochloride. M.p. 189.4C 20 7S.6 (c = 5 in H2O) Overall yield of the hydrochloride is 47% of theoretical amount.
126ss22 EXAMPLE 8.
The toluene solution of example 1 from which (+)-trans--3-~(4-methoxyphenoxy)-methyl-J-1-methyl-4-phenylpiperidine (~)-mandelate is precipitated is mixed with 13 1 of 9 M
a~ueous NaOH and 14 l of water. The mixture is stirred and ~e aqueous phase is mixed with the aqueous phase of example 1 and heated to 40C. To this mixture is added 23 l of conc. hydrochloric acid ensuring that pH
is around 1.5. The mixture is cooled and stirred. When the temperature is around 10C the precipitate is separated and washed 1 time with 10 l of water giving 26.5 kg of (~)-mandelic acid. M.p. 130-3C.
Yield of theoretical amount is 85%. - -
The residue was recrystallized from iso-propanol to give 33.8 kg (90%) o~ ~)-trans-3-~4 methoxyphenoxy)-methyl]-1--methyl-4-phenylpiperidine as the hydrochloride. M.p. 189-90C, -~20 = 75 3 ~C = 5 in H2O)-~265522 EXAMPLES 2-5.
In a similar manner but by use of different solvents and different mandelic acid derivatives in an amount counting for 55% of the racemic trans-3-~4-methoxyphenoxy)-methyl~
-1-methyl-4-phenylpiperidine the experiment were repeated.
The table below shows the overall yield of the salt of ~ trans-3- [(4-methoxyphenoxy)-methyl~-1-methyl-4-phenyl-piperidine Ifemoxetine) and (+)-mandelic acid or a deri-vative thereof.
- Overall yi~ld of the ~ - salt of femoxetine and (+)-~andelic acid or a derivative thereof Ex. Solvent Resolving agent _ (%) 2 toluene ~ 2-hydroxy-2-(4-fluoro- 74.0 phenyl)-acetic acid 3 toluene (~)-2-hydroxy-2-(4-chloro- 66.5 phenyl)-acetic acid 4 ethyl (+)-2-hydroxy-2-phenyl- 67.5 acetate ~cetic acid MIBC* (~-2-hydroxy-2-phenyl- 59.0 acetic acid ~ MIBC = methyl iso-~utyl carbinol The results thus obtained clearly show that the present invention provides an improved process for the production of femoxetine in that the yield of the salt of femoxetlne and (+)-mandelic acid or a derivative thereof is 65-75%
of the theoretical value compared to 47% obtained by the known methods. Furthermore said salt of femoxetine and ~ mandelic acid or a derivative thereof is of very high purity.
15~0 g (48.2 mmol) of racemic trans-3((4-methoxyphenoxy)--methyl)-1-methyl-4-phenylpiperidine was dissolved in 11.5 ml of toluene. The solution was stirred while the temperature was raised to 60C. 6.55 g (43.1 mmol) of (+)-mandelic acid was added and the mixture was stirred at 60C until the m~xture was-clear~ The solutisn was allowed to cool to room temperature. The temperature of the mixture was then reduced to 10C and the mixture was left at this temperature for the next 15 hours. The mixture was then filtered and the precipitate was washed with toluene and iso-propanol. The yield was 6.1 y (55% of the theoretical value) of (+)-trans-3-((4-methoxy-phenoxy)-methyl)-1-methyl-4-phenylpiperidine,(+)-mandelate, m.p. 121C, a D + 81.6 (C = 2 in 96% ethanol~.
12~;5S~Z
_ a) 20 g (64 mmol) of racemic trans-3-~(4-methoxyphenoxy~--methyl~ methyl-4-phenylpiperiaine and 22 g (62 mmol~
of (-)-dibenzoyl tartaric acid $s dissolved in 200 ml of ethanol. The mixture is evaporated under vacuum.
The residue is optimally recrystallized from 50 ml methanol to yield.16.2 g of product. M.p. 84.1-84.6~C
[~D0 0.38 (c = 5 in 99~ ethanol).
b) 1~ g of the product of a is mixed with 20 ml of 4M
NaOH~ 40 ml of water and 100 ml of ether. The organi~
phase is dried with potassium carbonat, filtered and evaporated under vacuum to give 4.2 g of product. The product is dissolved -n 75 ml of iso-propanol. 1 ml of konc. hydrochloric acid is added and the mixture is evaporated to give 4.7 g of product. M.p. 182.7-184.2C.
1.9 g of this product is recrystallized from 6 ml of iso-propanol to give 1.4 g of (+)-trans-3-C(4-methoxy-phenoxy)-methyl~ methyl-4-phenylpiperidine as the hydrochloride. M.p. 189.4C 20 7S.6 (c = 5 in H2O) Overall yield of the hydrochloride is 47% of theoretical amount.
126ss22 EXAMPLE 8.
The toluene solution of example 1 from which (+)-trans--3-~(4-methoxyphenoxy)-methyl-J-1-methyl-4-phenylpiperidine (~)-mandelate is precipitated is mixed with 13 1 of 9 M
a~ueous NaOH and 14 l of water. The mixture is stirred and ~e aqueous phase is mixed with the aqueous phase of example 1 and heated to 40C. To this mixture is added 23 l of conc. hydrochloric acid ensuring that pH
is around 1.5. The mixture is cooled and stirred. When the temperature is around 10C the precipitate is separated and washed 1 time with 10 l of water giving 26.5 kg of (~)-mandelic acid. M.p. 130-3C.
Yield of theoretical amount is 85%. - -
Claims (4)
-
- THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
- PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
(+)-trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl- - 4-phenylpiperidine (+)-mandelate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000576252A CA1265522A (en) | 1983-03-07 | 1988-08-31 | (+)-trans-3-¬(4-methoxyphenoxy)-methyl|-1- methyl-4-phenylperidine (+)-mandelate |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK111583A DK149624C (en) | 1983-03-07 | 1983-03-07 | PROCEDURE FOR THE PREPARATION OF (+) - TRANS-3 - (((4-METHOXYPHENOXY) -METHYL) -1-METHYL-4-PHENYLPIPERIDINE OR A PHARMACEUTICAL ACCEPTABLE SALT FROM A MIXTURE OF ENANTIOMY |
| DK1115 | 1983-03-07 | ||
| CA000448829A CA1257599A (en) | 1983-03-07 | 1984-03-05 | -trans-3-[(4-methoxyphenoxy)-methyl]-1- methyl-4-phenylpiperidines |
| CA000576252A CA1265522A (en) | 1983-03-07 | 1988-08-31 | (+)-trans-3-¬(4-methoxyphenoxy)-methyl|-1- methyl-4-phenylperidine (+)-mandelate |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000448829A Division CA1257599A (en) | 1983-03-07 | 1984-03-05 | -trans-3-[(4-methoxyphenoxy)-methyl]-1- methyl-4-phenylpiperidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1265522A true CA1265522A (en) | 1990-02-06 |
Family
ID=25670316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576252A Expired - Lifetime CA1265522A (en) | 1983-03-07 | 1988-08-31 | (+)-trans-3-¬(4-methoxyphenoxy)-methyl|-1- methyl-4-phenylperidine (+)-mandelate |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1265522A (en) |
-
1988
- 1988-08-31 CA CA000576252A patent/CA1265522A/en not_active Expired - Lifetime
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