WO1996036636A1 - Process for preparing 4-aryl-piperidine derivatives - Google Patents

Process for preparing 4-aryl-piperidine derivatives Download PDF

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Publication number
WO1996036636A1
WO1996036636A1 PCT/DK1996/000185 DK9600185W WO9636636A1 WO 1996036636 A1 WO1996036636 A1 WO 1996036636A1 DK 9600185 W DK9600185 W DK 9600185W WO 9636636 A1 WO9636636 A1 WO 9636636A1
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Prior art keywords
compound
formula
treatment
alkyl
defined above
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Application number
PCT/DK1996/000185
Other languages
French (fr)
Inventor
John Bondo Hansen
Svend Treppendahl
Mogens Engelstoft
Bjørn BENTZEN
Søren LEHMANN
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Novo Nordisk A/S
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Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU56845/96A priority Critical patent/AU721257B2/en
Priority to EP96914861A priority patent/EP0828735A1/en
Priority to NZ307479A priority patent/NZ307479A/en
Priority to JP8534464A priority patent/JPH11505229A/en
Priority to BR9608471A priority patent/BR9608471A/en
Publication of WO1996036636A1 publication Critical patent/WO1996036636A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel process for preparing 4-aryl- piperidine derivatives.
  • R 1 represents hydrogen, alkyl having 1 -4 carbon atoms and F may be in any of the available positions.
  • US Patent No. 4,585,777 and US Patent No. 4, 593,036 describes a compound of the following formula B:
  • the compounds of formula A and B are described as inhibitors of reup- take of 5-hydroxytryptamine (5-HT) which induces a potentiation of 5- HT induced neurotransmission.
  • 5-HT 5-hydroxytryptamine
  • Paroxetine which is the pure enantiomer (3S,4R)-4-(4-fluorophenyl)-3- (3,4-methylenedioxyphenoxymethyl)piperidine has been found to be a potent inhibitor of serotonin reuptake and to be an effective antide- pressant in man [ S. M. Holliday and G. L. Plosker, Drugs and Aging 3: 278-299 (1993)].
  • the pharmacological activity resides in this isomer and the corresponding stereoisomer is considerably less potent with respect to inhibition of 5-HT uptake in vitro [P. Plenge, E. T. Mellerup, T. Honore, and P. L. Honore, J. Pharm. Pharmacol. 39: 877-882 (1987)].
  • the Grignard reaction involves the use of ether solvents and is further ⁇ more complicated by the use of the toxic starting material arecoline.
  • the intermediary D1 is prepared by reduction of the imide (F2), prepared from benzaldehyde and methyl N-methylamidomalonate.
  • the reduction involves the use of lithium aluminium hydride, aluminium hydride or diborane using ether solvents like diethyl ether, tetrahydrofurane and dimethoxyethane, scheme F:
  • the intermediate D1 is prepared by reacting methylamine, formaldehyde and ⁇ -methylstyrene (G 1 ). Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic compound 1 -methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) [USP 2,748, 140, C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 11 5698-5700 (1955); C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc.
  • MPTP has in primates and in humans been found to cause anatomical and behavioral changes analogous to those of Parkinson's disease [M. Gerlach, P. Riederer, H. Przuntek, and M. B. H. Youdin, EUR. J. Pharma ⁇ col. Mol. Pharm, 208, 273-286, (1991 ); S. P. Markey and N. R. Schnuff, Medicinal Res. /?ev.6.386, ( 1 986)]. It is known that the 1 -methyl group causes MPTP to be toxic and that substitution of the methyl group with longer alkyl groups will abolish the toxicity [S. K. Youngster, P. K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929- 934, (1987)], scheme G:
  • Paroxetine is one of four possible isomers, the use of the practi ⁇ cally and economically best procedure for the isolation of this isomer is of high importance.
  • the procedure will involve the use of the appropriate isomer of D1 in combination with the use of the right conditions for reaction as well as separations by recrystallizations using optically active acids, e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid.
  • optically active acids e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid.
  • R 1 can be C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, preferentially ethyl.
  • R 1 can be C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, preferentially ethyl.
  • the intermediary 1 -alkyl-1 ,2,3,6-tetrahydro-4-phenylpyridine will in comparison with MPTP be non-toxic as described in:S. K. Youngster, P.
  • the present invention provides a process for the preparation of a compound of formula VIII,
  • R is C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, by
  • R 1 is C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, with a compound of formula (II)
  • X is halogen, preferably F, to form a compound of formula
  • R 1 and X are as defined above, c) by treatment of a compound of formula IV, wherein R 1 and X are as defined above with metal hydrides, preferably LiAIH 4 or NaAIH 4 , to form a compound of formula VI,
  • R 1 and X are as defined above, with benzene sulfonylchloride, or another suitable reagent, which reacts with the hydroxy group to trans ⁇ form it into a leaving group, which subsequently can be removed by treatment with 3,4-methylene dioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, preferably sodium methanolate to give a compound of formula VIII,
  • R 1 and X are as defined above with chlorethylchloroformate or another similar reagent, followed by decomposition of the intermediary carbamate by methanol to form a compound of formula IX,
  • Ethylamine hydrochloride 132.2 g was dissolved in formaldehyde (500 ml, 37 %) and the mixture heated to 70°C. 1 -methyl-4'-fluorostyrene (200 ml) was added over 1 hour keeping the temperature about 70°C.
  • the phases were separated and the toluene phase extracted with hydrochloric acid (1 6 times 100 ml, 0.5 M).
  • hydrochloric acid 1 6 times 100 ml, 0.5 M.
  • the toluene phases were pooled and evaporated to an oil (1 64 g). The oil was dissolved in 2-propanol (300 ml) and the hydrochloride of the title compound precipitated with con ⁇ centrated hydrochloric acid.
  • the aqueous phase was extracted with another portion of toluene (50 ml).
  • the combined toluene extract was washed with water (50 ml), dried over potassium carbonate and evaporated.
  • the aqueous phase was separated and extracted with another portion of toluene (100 ml) .
  • the combined toluene phase was dried over potassium carbonate and evaporated to an oil (47 g).
  • the oil was dissolved in acetone (900 ml) with ( + )-O,O'-ditoluoyltartaric acid (59 g).
  • Formic acid ( 2.2 g) was added and the mixture stirred until next day.
  • the precipitate was filtered off, washed with acetone and dried.
  • the aqueous phase was extracted with another portion of toluene (50 ml), washed with water (50 ml) and evaporated.
  • Lithium aluminium hydride (3 g) and sodium hydride 60 % (3 g) was dispersed in dry tetrahydrofuran (80 ml). The mixture was heated at 60°C for 1 hour and then cooled to 20°C. To this mixture was added a solution of ( + )-1 -ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 , 2,3,6- tetrahydropyridine (20 g) in tetrahydrofuran (40 ml) over 1 hour. The mixture was stirred at 50°C for 1 hour.
  • Benzene sulfonyl ⁇ chloride (16.6 g) was added over 1 hour keeping the temperature between 20 and 30°C with external cooling with ice and water. After the addition the reaction mixture was stirred at ambient temperature for 3 hours. Water was added (50 ml) and the toluene phase was separated. A solution of 3,4-methylenedioxyphenol (17 g) in methylisobutylcarbinol (4-methyl-2-pentanol) (90 ml) was added to the toluene phase together with sodium hydroxide (17.2 g, 32.5 %). The mixture was refluxed for 4 hours and stirred overnight at ambient temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for the preparation of a compound of formula (VIII), wherein R1 is C¿2-5?-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl.

Description

Process for preparing 4-aryl-piperidine derivatives
The present invention relates to a novel process for preparing 4-aryl- piperidine derivatives.
US Patent No. 4,007,196 describes certain compounds which are described as possessing anti-depressant activity.
The compounds of that invention relates to 3-substituted 4-aryl-piperidi nes of the general formula A:
Figure imgf000003_0001
wherein R1 represents hydrogen, alkyl having 1 -4 carbon atoms and F may be in any of the available positions. US Patent No. 4,585,777 and US Patent No. 4, 593,036 describes a compound of the following formula B:
Figure imgf000004_0001
The compounds of formula A and B are described as inhibitors of reup- take of 5-hydroxytryptamine (5-HT) which induces a potentiation of 5- HT induced neurotransmission. [D. R. Thomas, D. R. Nelson, and A. M. Johnson, Neuropsychopharmacol. 93: 193-200 (1987)]. Since several disorders is thought to be caused by an imbalance in 5-HT levels the compounds could be used as pharmaceutical agents for the treatment of central and peripheral diseases.
One particular compound disclosed in US Patent No. 4,007, 1 96 has been found to be of special value especially in the treatment of depres¬ sions. This compound is known as paroxetine and has the following formula C:
Figure imgf000004_0002
36636
Paroxetine, which is the pure enantiomer (3S,4R)-4-(4-fluorophenyl)-3- (3,4-methylenedioxyphenoxymethyl)piperidine has been found to be a potent inhibitor of serotonin reuptake and to be an effective antide- pressant in man [ S. M. Holliday and G. L. Plosker, Drugs and Aging 3: 278-299 (1993)]. The pharmacological activity resides in this isomer and the corresponding stereoisomer is considerably less potent with respect to inhibition of 5-HT uptake in vitro [P. Plenge, E. T. Mellerup, T. Honore, and P. L. Honore, J. Pharm. Pharmacol. 39: 877-882 (1987)].
Several methods for the synthesis of analogues of Paroxetine have been described. The pivotal component in the synthesis is the 3-hydroxy- methyl-1 -methyl-4-phenylpiperidine (D1 ), which in several steps can be transformed into the desired compounds as described in USP 4,007, 196, USP 4,585, 777, USP 4,593,036, and J. A. Christensen, M. Engelstoft, K. Schaumbaurg, H. Schou, and F. Watjen, Tet. Lett. 24 ,51 51 -4
(1 983)]:
Figure imgf000005_0001
The synthesis of intermediate D1 has been described in several publica¬ tions. In one method (Scheme E) arecoline, by a Grignard reaction is transformed into a mixture of the four different isomers of methyl 4- phenyl-nipecotinic acid (E2), which by reduction can be transformed into (E3) [USP 4,007, 196] :
Figure imgf000006_0001
The Grignard reaction involves the use of ether solvents and is further¬ more complicated by the use of the toxic starting material arecoline.
In another method (USP 4,902,801 and WO 94/21 609) the intermediary D1 is prepared by reduction of the imide (F2), prepared from benzaldehyde and methyl N-methylamidomalonate. The reduction involves the use of lithium aluminium hydride, aluminium hydride or diborane using ether solvents like diethyl ether, tetrahydrofurane and dimethoxyethane, scheme F:
Figure imgf000006_0002
In another method (USP 2,748, 140, USP 4,007, 196; USP 4,593,036; USP 4,585,777) the intermediate D1 is prepared by reacting methylamine, formaldehyde and σ-methylstyrene (G 1 ). Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic compound 1 -methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) [USP 2,748, 140, C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 11 5698-5700 (1955); C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 78 425-428 (1956); C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 78 1 702-1 705 (1 956);P. Sohar, J. Lazar, and G. Bernath, Chem. Ber. , 1 18, 551 -559, (1985)].
MPTP has in primates and in humans been found to cause anatomical and behavioral changes analogous to those of Parkinson's disease [M. Gerlach, P. Riederer, H. Przuntek, and M. B. H. Youdin, EUR. J. Pharma¬ col. Mol. Pharm, 208, 273-286, (1991 ); S. P. Markey and N. R. Schnuff, Medicinal Res. /?ev.6.386, ( 1 986)]. It is known that the 1 -methyl group causes MPTP to be toxic and that substitution of the methyl group with longer alkyl groups will abolish the toxicity [S. K. Youngster, P. K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929- 934, (1987)], scheme G:
Figure imgf000007_0001
Since Paroxetine is one of four possible isomers, the use of the practi¬ cally and economically best procedure for the isolation of this isomer is of high importance. The procedure will involve the use of the appropriate isomer of D1 in combination with the use of the right conditions for reaction as well as separations by recrystallizations using optically active acids, e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid. These transformations have been described using 3-hydroxymethyl-1 -methyl-4- phenylpiperidine and the corresponding 4-fluorophenyl-analog.
By the present invention easily available starting materials, by a pro¬ cedure which is carried out in aqueous medium, are reacted to give a compound of formula VIII, wherein R1 can be C2.5-alkyl, phenyl-C^-alkyl, or substituted phenyl-C^-alkyl, preferentially ethyl. Using this method the intermediary 1 -alkyl-1 ,2,3,6-tetrahydro-4-phenylpyridine will in comparison with MPTP be non-toxic as described in:S. K. Youngster, P.
K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929-934, (1987). Furthermore in the present invention by separating the racemic tetrahy- dropyridine (III) derivative into the pure enantiomers which are subsequently reduced either catalytically or by LiAIH4 to give the entio- meric pure ( + )-cis- (VII) and (-)-trans 1 -alkyl-4-phenyl-3-hydroxymethylpi- peridine (VI) derivatives, which both are transformed to pure (-)-trans-l - alkyl-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-piperidine deriva¬ tives (VIII), an economically route for the synthesis of a compound of formula IX, using both possible enatiomers, is obtained.
The transformation of either VII or VI to pure VIII is described in J. A. Christensen, M. Engelstoft, K. Schaumbaurg, H. Schou, and F. Watjen, Tet. Lett. 24 ,5151 -4 (1983)].
Accordingly, the present invention provides a process for the preparation of a compound of formula VIII,
Figure imgf000009_0001
wherein R is C2.5-alkyl, phenyl-C^-alkyl, or substituted phenyl-C^-alkyl, by
a) reacting an primary amine of formula (I)
R1-NH, (I)
wherein R1 is C2.5-alkyl, phenyl-C^-alkyl, or substituted phenyl-C^-alkyl, with a compound of formula (II)
Figure imgf000009_0002
wherein X is halogen, preferably F, to form a compound of formula
Figure imgf000009_0003
wherein X and R1 are as defined above, and
b) by crystallizing the salt of a mixture of a compound of formula III and a suitable optically active acid, preferably (-)-0,0-ditoluoyltartaric acid to form, upon purification of the basic component, an optically active compound of formula IV,
Figure imgf000010_0001
which is able to rotate the plane of polarized light clockwise, and a mother liquid containing an optically active compound which upon crystallization in the presence of a suitable optically active acid, prefer¬ ably ( + )-0,0-ditoluoyl tartaric acid, and purification of the basic compo¬ nent, forms a compound of formula V, which is able to rotate the plane of polarized light counterclockwise:
Figure imgf000010_0002
wherein R1 and X are as defined above, c) by treatment of a compound of formula IV, wherein R1 and X are as defined above with metal hydrides, preferably LiAIH4 or NaAIH4, to form a compound of formula VI,
Figure imgf000011_0001
wherein R1 and X are as defined above,
d) by treatment of a compound of formula V, wherein R1 and X are as defined above with hydrogen in the presence of a suitable metal catalyst, preferably palladium on carbon to give a compound of formula VII,
Figure imgf000011_0002
wherein R1 and X are as defined above. by treatment of a compound of formula VI,
Figure imgf000012_0001
with benzene sulfonylchloride, or another suitable reagent, which reacts with the hydroxy group to transform it into a leaving group, which subsequently can be removed by treatment with 3,4-methylenedioxyphe- nolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, preferably sodium methanolate, to give a compound of formula VIII
Figure imgf000012_0002
wherein R1 and X are defined as above, f) by treatment of a compound of formula VII,
Figure imgf000013_0001
wherein R1 and X are as defined above, with benzene sulfonylchloride, or another suitable reagent, which reacts with the hydroxy group to trans¬ form it into a leaving group, which subsequently can be removed by treatment with 3,4-methylene dioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, preferably sodium methanolate to give a compound of formula VIII,
Figure imgf000013_0002
wherein R and X are as defined above, g) by treatment of a compound of formula VIII,
Figure imgf000014_0001
wherein R1 and X are as defined above with chlorethylchloroformate or another similar reagent, followed by decomposition of the intermediary carbamate by methanol to form a compound of formula IX,
Figure imgf000014_0002
wherein X is as defined above.
The present invention is illustrated by the following examples: EXAMPLE 1
( + ,-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyri- dine hydrochloride
Ethylamine hydrochloride (132.2 g) was dissolved in formaldehyde (500 ml, 37 %) and the mixture heated to 70°C. 1 -methyl-4'-fluorostyrene (200 ml) was added over 1 hour keeping the temperature about 70°C.
After the styrene was added the mixture was refluxed at 96°C for 4 hours. The reaction mixture was cooled down to 80°C and extracted with toluene (100 ml) . The aqueous phase was evaporated at atmos¬ pheric pressure until the bottom temperature reached 100°C, and then hydrochloric acid was added (135 ml) and the reaction mixture refluxed for 20 hours. Toluene was added (1 20 ml) and aqueous ammonia (25 %) until pH = 5.5. The phases were separated and the aqueous phase extracted with more toluene (240 ml) and made pH = 9.3 with aqueous ammonia. The phases were separated and the toluene phase extracted with hydrochloric acid (1 6 times 100 ml, 0.5 M). According to analysis on HPLC (Column: RP18; Eluent: methanol, water: 90, 10 (triethylamine, phosphoric acid until pH = 7); Flow: 0.9 ml/min; Detector: UV 220 nm; RT = 3.22 min) the fractions 3 to 1 5 were pooled, treated with filter aid, made pH = 9.0 with sodium hydroxide and extracted twice with toluene (200 ml and 100 ml). The toluene phases were pooled and evaporated to an oil (1 64 g). The oil was dissolved in 2-propanol (300 ml) and the hydrochloride of the title compound precipitated with con¬ centrated hydrochloric acid.
Yield 86.4 g ( 24.8 %), M.p. 192°C. The product was identified by 1H-
NMR and elemental analysis. EXAMPLE 2
(-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine
( + ,-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyri- dine hydrochloride (84.6 g) was dissolved in a mixture of water ( 100 ml) and toluene (250 ml) and the aqueous phase made pH = 10 with sodium hydroxide. The toluene phase was separated . The aqueous phase extracted with another portion of toluene (50 ml). The combined toluene phase was dried over potassium carbonate and evaporated to an oil (76.5 g). The oil (72 g) was dissolved in acetone (900 ml) with (-)-O,O'- ditoluoyltartaric acid (59 g) at 50-60°C. Formic acid (7.1 g) was added to the mixture. The mixture was cooled down to room temperature and the precipitate filtered off.
Yield 47.3 g of (-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 , 2,3,6- tetrahydropyridine hemi-(-)-O,O'-ditoluoyltartrate M.p. 149-1 51 °C.
The free base was liberated from the O,O'-ditoluoyltartrate by dissolving in a mixture of toluene (100 ml) and water (100 ml), made pH = 1 1 with sodium hydroxide. The aqueous phase was extracted with another portion of toluene (50 ml). The combined toluene extract was washed with water (50 ml), dried over potassium carbonate and evaporated.
Yield 24.9 g, M.p. 70-75 °C, [ a ]20 D = -1 27.2 ° (c = 1 % in methanol) .
The identity was confirmed by 1H-NMR and elemental analysis. The enantiomeric purity was confirmed by Chiral HPLC to be better than 99 %. Chiral HPLC: (Column: Cycloband I 2000-SN (Astec); Eluent: acetonitrile, methanol, acetic acid, triethylamine: 100, 5, 0.3, 0.2; Flow: 0.8 ml/min, Detector: UV 240 nm, RT(( + )-isomer) = 1 1 .5 min, RT((-)- isomer) = 10.1 min). EXAMPLE 3
( + )-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyri- dine,
The mother liquor from precipitation of (-)-1 -ethyl-3-hydroxymethyl-4-(4- fuorophenyl)-1 ,2,3,6-tetrahydropyridine hemi-(-)-O,O'-ditoluoyltartrate was evaporated and dissolved in a mixture of toluene (200 ml) water (100 ml) and sodium hydroxide added until pH = 10. The aqueous phase was separated and extracted with another portion of toluene (100 ml) . The combined toluene phase was dried over potassium carbonate and evaporated to an oil (47 g). The oil was dissolved in acetone (900 ml) with ( + )-O,O'-ditoluoyltartaric acid (59 g). Formic acid ( 2.2 g) was added and the mixture stirred until next day.
The precipitate was filtered off, washed with acetone and dried.
Yield 52.8 g of ( + )-1 -ethyi-3-hydroxymethyl-4-(4-fluorophenyl)-1 , 2,3,6- tetrahydropyridine hemi-( + )-O,O'-ditoluoyltartrate, M.p. 146-147°C.
The free base was liberated from the ( + )-O,O'-ditoluoyltartrate by dissolving in a mixture of toluene (100 ml), water (100 ml) and sodium hydroxide at pH = 1 1 . The aqueous phase was extracted with another portion of toluene (50 ml), washed with water (50 ml) and evaporated.
Yield 32.4 g, M.p. 55-70°C, [σ]D 20 = 104.1 ° (c = 1 % in methanol) . The identity was confirmed by 1H-NMR and elemental analysis. The enantiomeric purity was determined by Chiral HPLC to be 97.5 % Chiral HPLC: (Column: Cycloband I 2000-SN ( Astec); Eluent: acetonitrile, methanol, acetic acid, triethylamine: 100, 5, 0.3, 0.2; Flow:
0.8 ml/min, Detector: UV 240 nm, RT(( + )-isomer) = 1 1 .5 min, RT((-)- isomer) = 10.1 min). EXAMPLE 4
( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine hydrochloride
(-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine (24.9 g) was dissolved in a mixture of ethanol (100 ml), acetic acid ( 1 2.7 ml) and water (50 ml). Palladium on carbon (2 g, 10 % Pd, 50 % wet) was added and the mixture hydrogenated at atmospheric pressure at room temperature for 28 hours. Toluene ( 200 ml) was added and sodium hydroxide added until pH = 12. The toluene phase was sepa¬ rated, the aqueous phase extracted with another portion of toluene (50 ml). The combined toluene phase was dried over potassium carbonate and evaporated. The oil was dissolved in acetone (70 ml) and the hydrochloride of the title compound precipitated with concentrated hydrochloric acid (10 ml) (18.4 g). Evaporation of the mother liquor and crystallisation from ethanol gave another crop of crystals (3.1 g).
Yield 21 .5 g, M.p. 215-21 7°C, [σ]D 20 = 82.1 ° (c = 1 %, abs. ethanol)
The identity of the product was confirmed by 1 H- and 13C-NMR and elemental analysis.
The enantiomeric purity of the product was verified by Chiral HPLC to be better than 99 %.
Chiral HPLC: Column: Chiradex /?-Cyclodextrin ( Merck); Eluent: metha¬ nol, buffer: 1 5, 85 ( 10 mM (disodiumhydrogenphosphate/sodiumdihydro- genphosphate, pH = 6)); Flow: 1 .0 ml/min. Detector: UV 215 or 270 nm; RT((-)-trans-isomer)) = 9.1 min, RT(( + )-trans-isomer)) = 1 1 .5 min,
RT((-)-cis-isomer)) = 13.5 min, RT(( + )-cis-isomer)) = 1 5.8 min. EXAMPLE 5
( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine — —
Lithium aluminium hydride (3 g) and sodium hydride 60 % (3 g) was dispersed in dry tetrahydrofuran (80 ml). The mixture was heated at 60°C for 1 hour and then cooled to 20°C. To this mixture was added a solution of ( + )-1 -ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 , 2,3,6- tetrahydropyridine (20 g) in tetrahydrofuran (40 ml) over 1 hour. The mixture was stirred at 50°C for 1 hour. The mixture was then added to a solution of ( + )-tartaric acid (24 g) and sodium hydroxide (20 g) in water (100 ml) at a temperature below 25 °C. The mixture was extracted twice with toluene (100 ml and 50 ml) . The extract was dried over potassium carbonate and evaporated ( 21 g). The crude, slightly sticky, product was recrystallized from heptane (40 ml) and a little ethyl acetate.
Yield 14.8 g, M.p. 75-85°C, [σ]D 20 = 29.9 ° ( c = 1 %, abs. ethanol)
The identity was confirmed by 1H-NMR and elemental analysis. The enantiomeric purity was controlled by Chiral HPLC to be better than 99.8 %.
Chiral HPLC: Column: Chiradex ?-Cyclodextrin ( Merck); Eluent: metha¬ nol, buffer: 1 5, 85 (10 mM (disodium hydrogen phosphate/sodium dihydrogen phosphate, pH = 6)); Flow: 1 .0 ml/min. Detector: UV 21 5 or 270 nm; RT((-)-trans-isomer)) = 9.1 min, RT(( + )-trans-isomer)) = 1 1 .5 min, RT((-)-cis-isomer)) = 13.5 min, RT(( + )-cis-isomer)) = 1 5.8 min. EXAMPLE 6
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme- thyl)-piperidine hydrochloride
( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine hydrochloride (21 g) was dissolved in a mixture of toluene (50 ml), water (50 ml) and sodium hydroxide (7 ml, 32.5 %). The aqueous phase was separated and extracted with another portion of toluene (30 ml). The combined toluene extract was dried over potassium carbonate and evaporated to an oil (17.2 g). The oil was dissolved in toluene (86 ml) and sodium hydroxide (17.2 g, 32.5 %) was added. Benzene sulfonyl¬ chloride (16.6 g) was added over 1 hour keeping the temperature between 20 and 30°C with external cooling with ice and water. After the addition the reaction mixture was stirred at ambient temperature for 3 hours. Water was added (50 ml) and the toluene phase was separated. A solution of 3,4-methylenedioxyphenol (17 g) in methylisobutylcarbinol (4-methyl-2-pentanol) (90 ml) was added to the toluene phase together with sodium hydroxide (17.2 g, 32.5 %). The mixture was refluxed for 4 hours and stirred overnight at ambient temperature. Water was added (50 ml), the organic phase separated and evaporated to a viscous oil (29.5 g). The oil was dissolved in acetone (100 ml) and precipitated as the hydrochloride salt of the title compound with concentrated hydro- chloric acid (10 ml). Yield 16.4 g, M.p. 244-246°C, [σ]D 20 = - 72.8 ° (c
= 1 %, abs. ethanol).
The identity was confirmed by "Η-NMR and elemental analysis. The enantiomeric purity was established by Chiral HPLC to better than 99.5 %. Chiral HPLC: Column: β-Cyclodextrin, Chiradex (Merck); Eluent: methanol, buffer: 46, 60 (1 % triethylamine pH = 4.1 adjusted with acetic acid); Detector; UV 290 nm; RT (( + )-trans-isomer) = 10.2 min; RT ((-)- trans-isomer) = 12.0 min. EXAMPLE 7
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme- thyl)-piperidine hydrochloride _____
( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine ( 14.4 g) and triethylamine (14.4 ml) was dissolved in dichloromethane (26 ml) . The solution was cooled to between -10 to 5 °C and benzenesulfonyl chloride (14.1 g) was added over 2 hours keeping the stated temperature during the addition. The temperature was raised to 10°C over 1 5 min. and water was added (40 ml) and the mixture stirred for 1 5 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined extract was dried over mag- nesium sulfate and evaporated to an oil.
The oil was dissolved in dimethylformamide (60 ml) together with 3,4- methylenedioxyphenol (10 g) and the solution was heated to 45 °C. A solution of sodium methanolate (prepared from 2.3 g sodium dissolved in 30 ml methanol evaporated to dryness) in dimethylformamide (30 ml) was added over 15 min to the solution of sulfoester and phenol. The reaction mixture was stirred for 2 hours at 45 °C. Water was added (200 ml) and the mixture extracted twice with toluene ( 100 ml and 50 ml) . The extract was evaporated to a viscous oil (25.8 g) .
The oil (20.8 g) was dissolved in acetone (66 ml) and the hydrochloride of the title compound crystallized with concentrated hydrochloric acid (6.6 ml) . Yield 19.9 g, M.p. 242-243°C, [σ] = - 72.2 ' ( c = 1 %, abs. ethanol). The identity was confirmed by 1H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC Chiral HPLC: Column: /?-Cyclodextrin, Chiradex (Merck); Eluent: metha¬ nol, buffer: 46, 60 ( 1 % triethylamine pH = 4.1 adjusted with acetic acid); Flow: 1 .0 ml/min; Detector; UV 290 nm; RT (( + )-trans-isomer) = 10.2 min; RT ((-)-trans-isomer) = 12.0 min.
EXAMPLE 8
(-)-trans-4-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)- piperidine hydrochloride
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme- thyl)-piperidine hydrochloride ( 1 5.4 g) was dissolved in a mixture of toluene (100 ml), water (50 ml) and sodium hydroxide (3.5 ml, 32.5 %). The toluene phase was separated. The aqueous phase extracted with another portion of toluene (50 ml). The extracts was combined and dried over potassium carbonate. The dry toluene solution was evaporated to give an oil (1 1 .5 g). The oil (4.75 g) was redissolved in dry toluene (50 ml), cooled to -10°C. 1 -Chloroethylchloroformate (2.85 g) in dry toluene (20 ml) was added over 15 min. at -10°C. The mixture was heated slowly to reflux and refluxed for 1 hour. The reaction mixture was evaporated to an oil, dissolved in methanol (50 ml) and refluxed for 1 hour. The mixture was evaporated to an oil and dissolved in a mixture of toluene (30 ml) and water (20 ml) and sodium hydroxide (32 %) was added until pH = 1 1 . The phases were separated and the aqueous phase extracted with another portion of toluene (30 ml). The combined toluene extract was dried over potassium carbonate and evaporated to an oil.
(5.2 g). The oil was dissolved in ethanol (1 5 ml) with L( + )-tartaric acid (2.37 g) . The tartrate of the title compound was crystallized by cooling and could be filtered off and dried. Yield 6.2 g, M.p. 1 74-1 76°C.
The identity was confirmed by 1H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC to be better than 99.5 %. Chiral HPLC: Column: Chiral-AGP (Chromtech); Eluent: 2-propanol:buffer, 5:95 ( 10 mM sodium acetate, pH = 5.2); Flow : 1 .0 ml/min, Detector: UV 290 nm; RT(( + )-isomer) = 8.7 min and RT((-)-isomer) = 1 2.5 min.

Claims

A process for the preparation of a compound of formula (VIII):
Figure imgf000024_0001
wherein R1 is C2.5-alkyl, phenyl-C^-alkyl, or substituted phenyl-C^-alkyl, by
a) reacting an primary amine of formula (I)
R1-NH, (I)
wherein R1 is C2.5-alkyl, phenyl-C^-alkyl, or substituted phenyl-C^-alkyl, with a compound of formula (II)
Figure imgf000024_0002
wherein X is halogen, preferably F, to form a compound of formula
Figure imgf000025_0001
wherein X and R1 are as defined above, and
b) by crystallizing the salt of a mixture of a compound of formula III and an optically active acid to form, upon purification of the basic component, an optically active compound of formula IV,
Figure imgf000025_0002
which is able to rotate the plane of polarized light clockwise, and a mother liquid containing an optically active compound, which upon crystallization in the presence of an optically active acid, and purification of the basic component, forms a compound of formula V,
Figure imgf000026_0001
which is able to rotate the plane of polarized light counterclockwise, and wherein R1 and X are as defined above,
c) by treatment of a compound of formula IV, wherein R1 and X are as defined above with a metal hydride to form a compound of formula
VI,
Figure imgf000026_0002
wherein R1 and X are as defined above,
d) by treatment of a compound of formula V, wherein R1 and X are as defin needd aabboovvee wwiitthh hhyyddrrooggeenn in the presence of a metal catalyst, to give a compound of formula VII,
Figure imgf000027_0001
wherein R1 and X are as defined above.
by treatment of a compound of formula VI,
Figure imgf000027_0002
with benzene sulfonylchloride, which reacts with the hydroxy group to transform it into a leaving group, which subsequently can be removed by treatment with 3,4-methylenedioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, to give a compound of formula VIII
(VIII )
Λ-CO wherein R1 and X are defined as above,
f) by treatment of a compound of formula VII,
Figure imgf000028_0001
wherein R1 and X are as defined above, with benzene sulfonylchloride, or another suitable reagent, which reacts with the hydroxy group to trans¬ form it into a leaving group, which subsequently can be removed by treatment with 3,4-methylenedioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, to give a compound of formula VIII,
Figure imgf000028_0002
wherein R1 and X are as defined above.
2. A process according to claim 1 wherein the reaction to form a compound of formula III (step a)) is carried out at 70°C.
3. A process according to claim 1 wherein the optically active acid in step b) is ( + )-0,0-di-toluoyl tartaric acid.
4. A process according to claim 1 wherein the metal hydride in step c) is LiAIH4 or NaAIH4.
5. A process according to claim 1 wherein the metal catalyst in step d) is palladium on carbon.
6. A process according to claim 1 , wherein the base used for preparing 3,4-methylenedioxyphenolate in step e) and f) is sodium methanolate.
PCT/DK1996/000185 1995-05-17 1996-04-25 Process for preparing 4-aryl-piperidine derivatives WO1996036636A1 (en)

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NZ307479A NZ307479A (en) 1995-05-17 1996-04-25 A process for preparing 4-(4-halo substituted phenyl)-3-(3,4-methylenedioxy phenoxy methyl)piperidine derivatives
JP8534464A JPH11505229A (en) 1995-05-17 1996-04-25 Method for producing 4-aryl-piperidine derivatives
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WO1997024323A1 (en) * 1995-12-28 1997-07-10 Chirotech Technology Process for the preparation of optically enriched 4-aryl-3-hydromethyl substituted piperidines to be used as intermediates in the synthesis of paroxetine
WO1997031915A1 (en) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NEW PROCESS FOR PREPARING (-)-TRANS-N-p-FLUOROBENZOYLMETHYL-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]-PIPERIDINE
EP0812827A1 (en) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation
WO1998052920A1 (en) * 1997-05-17 1998-11-26 Knoll Aktiengesellschaft Chemical process for the reduction of 1-substituted -3-hydroxymethyl-4- (4-fluorophenyl)tetrahydropyridines
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
WO2000032591A1 (en) * 1998-11-28 2000-06-08 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride
WO2000039090A1 (en) * 1998-12-29 2000-07-06 Smithkline Beecham Plc Process for the preparation of paroxetine acetate and analogues thereof
WO2000050422A1 (en) * 1999-02-23 2000-08-31 Recordati S.A. Chemical And Pharmaceutical Company Process for the production of paroxetine
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof
US6172233B1 (en) 1997-01-15 2001-01-09 Smithkline Beecham Plc Process for making paroxetine
EP1074550A1 (en) * 1999-08-02 2001-02-07 CHEMI S.p.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivatives
WO2001032178A1 (en) * 1999-10-29 2001-05-10 Novo Nordisk A/S Use of 3,4-substituted piperidines
WO2002006275A1 (en) * 2000-07-17 2002-01-24 Smithkline Beecham P.L.C. Novel processes for the preparation of 4-phenylpiperidine derivatives
WO2002018338A1 (en) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Process for the racemisation of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine
WO2002018337A1 (en) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Process for the racemisation of an intermediate useful in the preparation of paroxetine
WO2002028834A1 (en) * 2000-10-06 2002-04-11 Smithkline Beecham P.L.C. Process for the preparation of aryl-piperidine carbinols and intermediates thereof
WO2002053537A1 (en) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Process for preparing (±) trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
EP1242378A1 (en) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Novel processes
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
US6521758B2 (en) 2000-05-12 2003-02-18 Synthon Bv Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-carbinols
US6657062B1 (en) * 1996-07-08 2003-12-02 Richter Gedeon Vegyesseti Gyar Rt. N-benzylpiperidine and tetrahydropyridine derivatives
WO2015071831A1 (en) * 2013-11-18 2015-05-21 Piramal Enterprises Limited An improved process for minimising the formation of dehalogenated byproducts

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Cited By (38)

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WO1997024323A1 (en) * 1995-12-28 1997-07-10 Chirotech Technology Process for the preparation of optically enriched 4-aryl-3-hydromethyl substituted piperidines to be used as intermediates in the synthesis of paroxetine
WO1997031915A1 (en) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NEW PROCESS FOR PREPARING (-)-TRANS-N-p-FLUOROBENZOYLMETHYL-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]-PIPERIDINE
US6476227B1 (en) 1996-06-13 2002-11-05 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
EP0812827A1 (en) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation
US6610851B1 (en) 1996-06-13 2003-08-26 Sumika Fine Chemicals Co., Ltd. Process for preparing a piperidine derivative
US5948914A (en) * 1996-06-13 1999-09-07 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
US6815548B2 (en) 1996-06-13 2004-11-09 Sumika Fine Chemicals Co., Ltd. Process for preparing a piperidine derivative
US6657062B1 (en) * 1996-07-08 2003-12-02 Richter Gedeon Vegyesseti Gyar Rt. N-benzylpiperidine and tetrahydropyridine derivatives
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof
US6172233B1 (en) 1997-01-15 2001-01-09 Smithkline Beecham Plc Process for making paroxetine
US6326496B1 (en) 1997-05-17 2001-12-04 Knoll Aktiengesellschaft Process for preparing an intermediate in the production of paroxetine
CN1121386C (en) * 1997-05-17 2003-09-17 克诺尔有限公司 Chemical process for reduction of 1-substituted-3--hydroxymethyl-4-(4-fluorophenyl) tetrahydropyridines
WO1998052920A1 (en) * 1997-05-17 1998-11-26 Knoll Aktiengesellschaft Chemical process for the reduction of 1-substituted -3-hydroxymethyl-4- (4-fluorophenyl)tetrahydropyridines
US6716985B2 (en) 1997-05-29 2004-04-06 Smithkline Beecham P.L.C. Process for making paroxetine
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
US7598271B1 (en) 1997-06-10 2009-10-06 Noven Therapeutics, Llc Crystalline paroxetine methane sulfonate
US6900327B2 (en) 1997-06-10 2005-05-31 Synthon Bct Technologies, Llc 4-phenylpiperidine compounds
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
WO2000032591A1 (en) * 1998-11-28 2000-06-08 Smithkline Beecham Plc Process for the preparation of paroxetine hydrochloride
WO2000039090A1 (en) * 1998-12-29 2000-07-06 Smithkline Beecham Plc Process for the preparation of paroxetine acetate and analogues thereof
US6583287B1 (en) 1999-02-23 2003-06-24 Recordati S.A. Chemical And Pharmaceutical Company Process for the production of paroxetine
JP2002537394A (en) * 1999-02-23 2002-11-05 レコーダチ エス．エイ．ケミカル アンド ファルマチェウティカル カンパニー Method for producing paroxetine
WO2000050422A1 (en) * 1999-02-23 2000-08-31 Recordati S.A. Chemical And Pharmaceutical Company Process for the production of paroxetine
US6444822B1 (en) 1999-08-02 2002-09-03 Chemi S.P.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivative
EP1074550A1 (en) * 1999-08-02 2001-02-07 CHEMI S.p.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivatives
WO2001032178A1 (en) * 1999-10-29 2001-05-10 Novo Nordisk A/S Use of 3,4-substituted piperidines
EP1242378A1 (en) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Novel processes
EP1242378A4 (en) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Novel processes
US6521758B2 (en) 2000-05-12 2003-02-18 Synthon Bv Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-carbinols
WO2002006275A1 (en) * 2000-07-17 2002-01-24 Smithkline Beecham P.L.C. Novel processes for the preparation of 4-phenylpiperidine derivatives
WO2002018338A1 (en) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Process for the racemisation of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine
WO2002018337A1 (en) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Process for the racemisation of an intermediate useful in the preparation of paroxetine
US6949650B2 (en) 2000-08-30 2005-09-27 Aesica Pharmaceuticals Ltd. Process for the racemization of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2-3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine
WO2002028834A1 (en) * 2000-10-06 2002-04-11 Smithkline Beecham P.L.C. Process for the preparation of aryl-piperidine carbinols and intermediates thereof
US6881845B2 (en) 2001-01-04 2005-04-19 Ferrer Internacional, S.A. Process for preparing (±)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2002053537A1 (en) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Process for preparing (±) trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2015071831A1 (en) * 2013-11-18 2015-05-21 Piramal Enterprises Limited An improved process for minimising the formation of dehalogenated byproducts

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