AU721257B2 - Process for preparing 4-aryl-piperidine derivatives - Google Patents
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- AU721257B2 AU721257B2 AU56845/96A AU5684596A AU721257B2 AU 721257 B2 AU721257 B2 AU 721257B2 AU 56845/96 A AU56845/96 A AU 56845/96A AU 5684596 A AU5684596 A AU 5684596A AU 721257 B2 AU721257 B2 AU 721257B2
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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
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Description
WO 96/36636 PCT/DK96/00185 -1- Process for preparing 4-aryl-piperidine derivatives The present invention relates to a novel process for preparing 4-arylpiperidine 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-piperidines of the general formula A:
O
.0 0
(A)
wherein R' represents hydrogen, alkyl having 1-4 carbon atoms and F may be in any of the available positions.
WO 96/36636 PCT/DK96/00185 -2- US Patent No. 4,585,777 and US Patent No. 4,593,036 describes a compound of the following formula B:
F
OCH
(B)
N
CH
3 The compounds of formula A and B are described as inhibitors of reuptake of 5-hydroxytryptamine (5-HT) which induces a potentiation of HT induced neurotransmission. 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. 4,007,196 has been found to be of special value especially in the treatment of depressions. This compound is known as paroxetine and has the following formula C:
F
9 rr0 Paroxetine WO 96/36636 PCT/DK96/00185 -3- 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 antidepressant 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 Plenge, E. T. Mellerup, T. Honore, and P. L. Honor6, 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-hydroxymethyl-1-methyl-4-phenylpiperidine 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 ,5151-4 (1983)]: X x 020 N D1 D2 CH3
CH
The synthesis of intermediate D1 has been described in several publications. In one method (Scheme E) arecoline, by a Grignard reaction is transformed into a mixture of the four different isomers of methyl 4phenyl-nipecotinic acid which by reduction can be transformed into (E3) [USP 4,007,196]: WO 96/36636 PCT/DK96/00185 -4- .OCH3
CH
El
S
E2 CY E2 I
CH
3 The Grignard reaction involves the use of ether solvents and is furthermore complicated by the use of the toxic starting material arecoline.
In another method (USP 4,902,801 and WO 94/21609) the intermediary D1 is prepared by reduction of the imide 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: x 0 H CONHMe
CO
2 Me Reduction
CH
F3 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 a-methylstyrene Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic WO 96/36636 PCT/K96/00185 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. 77 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 1702-1705 (1956);P. Sohar, J. Lazar, and G. Bernath, Chem. Ber., 118, 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. Pharmacol. Mol. Pharm, 208, 273-286, (1991); S. P. Markey and N. R.
Schnuff, Medicinal Res. Rev.6.386, (1986)]. 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 K.
Youngster, P. K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929- 934, (1987)], scheme G: X G2 x G3 I CH 3 NH2 SCH G1
N
I I HC
HC
X=H: MPTP x
X
G4 0 Red OH
OH
N
N
HC
CH.
WO 96/36636 PCT/D)K96/00185 -6- Since Paroxetine is one of four possible isomers, the use of the practically 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-l-methyl-4phenylpiperidine and the corresponding 4 -fluorophenyl-analog.
By the present invention easily available starting materials, by a procedure which is carried out in aqueous medium, are reacted to give a compound of formula VIII, wherein R' can be C 2 5 -alkyl, phenyl-C 1 5 -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 tetrahydropyridine (III) derivative into the pure enantiomers which are subsequently reduced either catalytically or by LiAIH 4 to give the entiomeric pure (VII) and (-)-trans 1-alkyl-4-phenyl-3-hydroxymethylpiperidine (VI) derivatives, which both are transformed to pure (-)-trans-1alkyl-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-piperidine derivatives (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, (Vill) reacting a primary amine of formula (I)
C.
eq C C CCC C
C
C.
C C C C C C C
CC
C 0 C C
C
*C.i
C
*CCC
C
C
.qq.
C
C
C..
C. C
C.
C.
C
CH
3
CH
2
NH
2 with a compound of formula (11)
F
to form a compound of formula III by crystallising the salt of a mixture of a compound of formula Ill and a suitable optically active acid, preferably (-)-O,O-ditoluoyl tartaric acid to form, upon purification of the basic component, an optically active compound of formula
IV,
[R:\LtBAA]08013.doc:tab
(IV)
CH
2
CH
3 which is able to rotate the plane of polarised light clockwise, and a mother liquid containing an optically active compound, which upon crystallisation in the presence of a suitable optically active acid, preferably (+)-O,O-ditoluoyl tartaric acid, and 5 purification of the basic component, forms a compound of formula V, .4 4- 4 4
S
0 *9 4 4* S 4 .4 4 4 i 4 9 *444 *4 0
CH
2
CH
3 which is able to rotate the plane of polarised light counterclockwise, by treatment of a compound of formula IV with LiAIH 4 or NaAIH 4 to form a compound of formula VI,
(VI)
CH
2
CH
3 by treatment of a compound of formula V with hydrogen in the presence of a metal catalyst which is metal on palladium, to give a compound of formula VII, [R:\LIBAA]08013.doc:tab
(VII)
by treatment of a compound of formula VI,
(VI)
e 0 0 06.: so*0 .00.0 00
CH
2
CH
3 with benzene sulfonyichloride, or another suitable reagent, which reacts with the 5hydroxy 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 which is sodium methanolate, to give a compound of formula ViII (Vill) -0 by treatment of a compound of formula VII, [R:\LIBAA]M81OA Aab
(VII)
I
CH
2
CH
3 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-methylenedioxyphenolate, prepared by treatment of 5 3,4-methylenedioxyphenol with a base which is sodium methanolate, to give a compound of formula VIII, 0O 0O 0 *e 0 0 S 0 0 0 0
S
*0 0 0 0 5000 r €o0 *O 0
S
00 S
S
6
(VIII)
-0 .0)
CH
2
CH
3 The invention also provides a process for the following preparation of a compound of formula IX by way of the following step: by treatment of a compound of formula VIII,
(VIII)
-0
CH
2
CH
3 with chlorethylchloroformate or another similar reagent, followed by decomposition .of the intermediary carbamate by methanol to form a compound of formula IX, [R:\LIBAA]0S013.doc:tab
IF
(DO)
NH 0 The present invention is illustrated by the following examples [K\LIBAA]08013.doc:tab 12 THIS PAGE HAS BEEN LEFT INTENTIONALLY
BLANK.
[R:\LAA]0813dc: WO 96/36636 PCT/DK96/00185 -13- EXAMPLE 1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1, 2 ,3,6-tetrahydropyridine hydrochloride Ethylamine hydrochloride (132.2 g) was dissolved in formaldehyde (500 ml, 37 and the mixture heated to 700C. 1-methyl-4'-fluorostyrene (200 ml) was added over 1 hour keeping the temperature about 700C.
After the styrene was added the mixture was refluxed at 96 0 C for 4 hours. The reaction mixture was cooled down to 800C and extracted with toluene (100 ml). The aqueous phase was evaporated at atmospheric pressure until the bottom temperature reached 1000C, and then hydrochloric acid was added (135 ml) and the reaction mixture refluxed for 20 hours. Toluene was added (120 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 (16 times 100 ml, 0.5 According to analysis on HPLC (Column: RP18; Eluent: methanol, water: 90,10 (triethylamine, phosphoric acid until pH Flow: 0.9 ml/min; Detector: UV 220 nm; RT 3.22 min) the fractions 3 to 15 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 (164 The oil was dissolved in 2-propanol (300 ml) and the hydrochloride of the title compound precipitated with concentrated hydrochloric acid.
Yield 86.4 g 24.8 M.p. 1920C. The product was identified by 1
H-
NMR and elemental analysis.
WO 96/36636 PCT/DK96/00185 -14- EXAMPLE 2 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1, 2 3 ,6-tetrahydropyridine -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1, 2 ,3,6-tetrahydropyridine 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 The oil (72 g) was dissolved in acetone (900 ml) with ditoluoyltartaric acid (59 g) at 50-60 0 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)-1,2,3,6tetrahydropyridine hemi-(-)-O,O'-ditoluoyltartrate M.p. 149-151 0
C.
The free base was liberated from the O,0'-ditoluoyltartrate by dissolving in a mixture of toluene (100 ml) and water (100 ml), made pH 11 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 0 C, a ]20 -127.2' (c 1 in methanol).
The identity was confirmed by 1 H-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) 11.5 min, isomer) 10.1 min).
WO 96/36636 PCT/DK96/00185 EXAMPLE 3 (+)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)- 1,2,3,6-tetrahydropyridine, The mother liquor from precipitation of (-)-l-ethyl-3-hydroxymethyl-4-(4fuorophenyl)-1,2,3,6-tetrahydropyridine hemi-(-)-0,0'-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 The oil was dissolved in acetone (900 ml) with (+)-O,0'-ditoluoyltartaric acid (59 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-ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6tetrahydropyridine hemi-( +)-O,O'-ditoluoyltartrate, M.p. 146-147 0
C.
The free base was liberated from the (+)-O,0'-ditoluoyltartrate by dissolving in a mixture of toluene (100 ml), water (100 ml) and sodium hydroxide at pH 11. 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 0 C, [a]D 20 104.1 (c 1 in methanol).
The identity was confirmed by 'H-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) 11.5 min, isomer) 10.1 min).
WO 96/36636 PCT/DK96/00185 -16- EXAMPLE 4 -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 (12.7 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 separated, the aqueous phase extracted with another portion of toluene 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 Evaporation of the mother liquor and crystallisation from ethanol gave another crop of crystals (3.1 g).
Yield 21.5 g, M.p. 215-217 0 C, [a]D 20 82.1 (c 1 abs. ethanol) The identity of the product was confirmed by and 3 C-NMR and elemental analysis.
The enantiomeric purity of the product was verified by Chiral HPLC to be better than 99 Chiral HPLC: Column: Chiradex f-Cyclodextrin Merck); Eluent: methanol, buffer: 15, 85 (10 mM (disodiumhydrogenphosphate/sodiumdihydrogenphosphate, pH Flow: 1.0 ml/min. Detector: UV 215 or 270 nm; RT((-)-trans-isomer)) 9.1 min, RT((+)-trans-isomer)) 11.5 min, RT((-)-cis-isomer)) 13.5 min, )-cis-isomer)) 15.8 min.
6 i 'd WO 96/36636 PCT/DK96/00185 17- EXAMPLE (+)-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 0 C for 1 hour and then cooled to 20 0 C. To this mixture was added a solution of (+)-1-ethyl- 3 -hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6tetrahydropyridine (20 g) in tetrahydrofuran (40 ml) over 1 hour. The mixture was stirred at 50 0 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 0 C. The mixture was extracted twice with toluene (100 ml and 50 ml). The extract was dried over potassium carbonate and evaporated 21 The crude, slightly sticky, product was recrystallized from heptane (40 ml) and a little ethyl acetate.
Yield 14.8 g, M.p. 75-85 0 C, [a]D 20 29.9 c 1 abs. ethanol) The identity was confirmed by 'H-NMR and elemental analysis. The enantiomeric purity was controlled by Chiral HPLC to be better than 99.8 Chiral HPLC: Column: Chiradex f-Cyclodextrin Merck); Eluent: methanol, buffer: 15, 85 (10 mM (disodium hydrogen phosphate/sodium dihydrogen phosphate, pH Flow: 1.0 ml/min. Detector: UV 215 or 270 nm; RT((-)-trans-isomer)) 9.1 min, RT((+)-trans-isomer)) 11.5 min, RT((-)-cis-isomer)) 13.5 min, RT((+)-cis-isomer)) 15.8 min.
WO 96/36636 PCT/DK96/00185 -18- EXAMPLE 6 (-)-trans-1-Ethyl- 4 4 -fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride (+)-cis-1-Ethyl- 3 -hydroxymethyl-4-(4-fluorophenyl)-piperidine hydrochloride (21 g) was dissolved in a mixture of toluene (50 ml), water 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 The oil was dissolved in toluene (86 ml) and sodium hydroxide (17.2 g, 32.5 was added. Benzene sulfonylchloride (16.6 g) was added over 1 hour keeping the temperature between 20 and 30 0 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 ml), the organic phase separated and evaporated to a viscous oil (29.5 The oil was dissolved in acetone (100 ml) and precipitated as the hydrochloride salt of the title compound with concentrated hydrochloric acid (10 ml). Yield 16.4 g, M.p. 244-246 0 C, 2 0 72.8 (c 1 abs. ethanol).
The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was established by Chiral HPLC to better than 99.5 Chiral HPLC: Column: f-Cyclodextrin, Chiradex (Merck); Eluent: methanol,buffer: 46, 60 triethylamine pH =4.1 adjusted with acetic acid); Detector; UV 290 nm; RT ((+)-trans-isomer) 10.2 min; RT trans-isomer) 12.0 min.
4 4 WO 96/36636 PCT/DK96/00185 -19- EXAMPLE 7 (-)-trans-l-Ethyl- 4 4 -fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-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 50C and benzenesulfonyl chloride (14.1 g) was added over 2 hours keeping the stated temperature during the addition. The temperature was raised to 10 0 C over 15 min.
and water was added (40 ml) and the mixture stirred for 15 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined extract was dried over magnesium sulfate and evaporated to an oil.
The oil was dissolved in dimethylformamide (60 ml) together with 3,4methylenedioxyphenol (10 g) and the solution was heated to 450C. 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 0 C, 72.2 c 1 abs.
ethanol).
The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC Chiral HPLC: Column: 6-Cyclodextrin, Chiradex (Merck); Eluent: methanol, buffer: 46, 60 1% triethylamine pH 4.1 adjusted with acetic WO 96/36636 PCT/DK96/00185 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-methylenedioxyphenoxymethyl)-piperidine hydrochloride (15.4 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 (11.5 The oil (4.75 g) was redissolved in dry toluene ml), cooled to -10 0 C. 1-Chloroethylchloroformate (2.85 g) in dry toluene ml) was added over 15 min.at -10 0 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 11. 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 The oil was dissolved in ethanol (15 ml) with L(+)-tartaric acid (2.37 The tartrate of the title compound was crystallized by cooling and could be filtered off and dried. Yield 6.2 g, M.p. 174-176 0
C.
The identity was confirmed by 1 H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC to be better than 99.5 WO 96/36636 PCT/DK96/00185 21 Chiral HPLC: Column: Chiral-AGP (Chromtech); Eluent: 2 -p ropanol: buffer, 5:95 (10 mM sodium acetate, pH Flow 1.0 mI/min, Detector: UV 290 nm; RT((+)-isomer) =8.7 min and RT((-)-isomer) 12.5 min.
Claims (4)
1. A process for the preparation of a compound of formula (VIII): (VIII) -0 ,o I U"2CI-1 reacting a primary amine of formula (I) a a *aa. a a a a.. a a CH 3 CH 2 NH 2 with a compound of formula (II) F 0o to form a compound of formula III (I) (II) (Il) by crystallising 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, [R:\LIBAA]08013.doc:tab (IV) CH 2 CH 3 which is able to rotate the plane of polarised light clockwise, and a mother liquid containing an optically active compound, which upon crystallisation in the presence of an optically active acid, and purification of the basic component, forms a compound of formula V, q a a a a "OH CH 2 CH 3 which is able to rotate the plane of polarised light counterclockwise, and by treatment of a compound of formula IV with LiAIH 4 or NaAIH 4 to form a compound of formula VI, (VI) CH 2 CH 3 by treatment of a compound of formula V with hydrogen in the presence of a metal catalyst which is metal on palladium, to give a compound of formula VII, [R:\LIBAA]08013.doc:tab (V II) by treatment of a compound of formula VI, NOI *0 a a. a a a a. a a CH 2 CH 3 with benzene sulfonylchioride, which reacts with the hydroxy group to transform it 5into a leaving group, which subsequently can be removed by treatment with 3,4- methylenedioxyphenolate, prepared by treatment of 3 ,4-methylened ioxyphenol with a base which is sodium methanolate, to give a compound of formula ViII (Vill) WH 2 CH 3 by treatment of a compound of formula VII, [R:\LIBAA]08013.doc~ab F (VII) OH N CH 2 CH 3 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-methylenedioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base which is sodium methanolate, to give a compound of formula VIII, F (VIII) N O CH 2 CH 3
2. A process according to claim 1 wherein the reaction to form a compound .of formula Ill (step is carried out at 700C. 10
3. A process according to claim 1 or claim 2 wherein the optically active acid in step is (+)-O,O-di-toluoyl tartaric acid.
4. A process for preparing a 4-arylpiperidine derivative, substantially as hereinbefore described with reference to any one of the Examples. A 4-arylpiperidine derivative prepared by the process of any one of claims 1 to 4. Dated 27 April, 2000 Novo Nordisk A/S Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R\LIBAA]08013.doc:tab
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK56395 | 1995-05-17 | ||
| DK563/95 | 1995-05-17 | ||
| PCT/DK1996/000185 WO1996036636A1 (en) | 1995-05-17 | 1996-04-25 | Process for preparing 4-aryl-piperidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5684596A AU5684596A (en) | 1996-11-29 |
| AU721257B2 true AU721257B2 (en) | 2000-06-29 |
Family
ID=8094959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU56845/96A Ceased AU721257B2 (en) | 1995-05-17 | 1996-04-25 | Process for preparing 4-aryl-piperidine derivatives |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0828735A1 (en) |
| JP (1) | JPH11505229A (en) |
| CN (1) | CN1068597C (en) |
| AU (1) | AU721257B2 (en) |
| BR (1) | BR9608471A (en) |
| CA (1) | CA2220963A1 (en) |
| HU (1) | HUP9900318A3 (en) |
| IL (1) | IL118294A0 (en) |
| NZ (1) | NZ307479A (en) |
| WO (1) | WO1996036636A1 (en) |
| ZA (1) | ZA963951B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9526645D0 (en) * | 1995-12-28 | 1996-02-28 | Chiroscience Ltd | Stereoselective synthesis |
| ES2117557B1 (en) * | 1996-02-29 | 1999-07-01 | Ferrer Int | NEW PROCEDURE FOR OBTAINING (-) - TRANS -N-P-FLUOROBENZOILMETIL-4- (P-FLUOROFENIL) -3- ((3,4- (METHYLENDIOXI) PHENOXI) METHYL) -PIPERIDINE. |
| EP0812827B1 (en) * | 1996-06-13 | 2009-09-02 | Sumitomo Chemical Company, Limited | Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation |
| HU221921B1 (en) * | 1996-07-08 | 2003-02-28 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzyl-piperidine or tetrahydro-pyridine derivatives and processes for producing them |
| GB9623359D0 (en) * | 1996-11-09 | 1997-01-08 | Smithkline Beecham Plc | Novel process |
| GB9700690D0 (en) | 1997-01-15 | 1997-03-05 | Smithkline Beecham Plc | Novel process |
| GB9710004D0 (en) * | 1997-05-17 | 1997-07-09 | Knoll Ag | Chemical process |
| AP9901698A0 (en) | 1997-05-29 | 1999-12-31 | Smithkline Beecham Corp | Novel process. |
| EP0994872B9 (en) | 1997-06-10 | 2001-12-05 | Synthon B.V. | 4-phenylpiperidine compounds |
| CH689805A8 (en) * | 1998-07-02 | 2000-02-29 | Smithkline Beecham Plc | Paroxetine methanesulfonate, process for its preparation and pharmaceutical compositions containing it. |
| GB9826175D0 (en) * | 1998-11-28 | 1999-01-20 | Smithkline Beecham Plc | Novel process |
| GB9828767D0 (en) * | 1998-12-29 | 1999-02-17 | Smithkline Beecham Plc | Novel process |
| IT1308629B1 (en) * | 1999-02-23 | 2002-01-09 | Recordati Chem Pharm | PROCESS FOR THE PRODUCTION OF PAROXETIN. |
| IT1313702B1 (en) * | 1999-08-02 | 2002-09-09 | Chemi Spa | PROCESS FOR THE PREPARATION OF 3-SUBSTITUTED DERIVATIVES OF 4-PHENYL-PIPERIDINS. |
| AU1018801A (en) * | 1999-10-29 | 2001-05-14 | Novo Nordisk A/S | Use of 3,4-substituted piperidines |
| GB9930577D0 (en) * | 1999-12-23 | 2000-02-16 | Smithkline Beecham Plc | Novel process |
| CZ20023694A3 (en) | 2000-05-12 | 2003-05-14 | Synthon B. V. | Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-methanols |
| EP1301508A1 (en) * | 2000-07-17 | 2003-04-16 | Smithkline Beecham Plc | Novel processes for the preparation of 4-phenylpiperidine derivatives |
| GB0021145D0 (en) * | 2000-08-30 | 2000-10-11 | Knoll Ag | Chemical process |
| GB0021147D0 (en) * | 2000-08-30 | 2000-10-11 | Knoll Ag | Chemical process |
| AU2001211337A1 (en) * | 2000-10-06 | 2002-04-15 | Smithkline Beecham Plc | Process for the preparation of aryl-piperidine carbinols and intermediates thereof |
| JP2004520333A (en) | 2001-01-04 | 2004-07-08 | フエルレル インターナショナル，ソシエダッド アノニマ | A method for producing (±) -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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| US4593036A (en) * | 1984-02-07 | 1986-06-03 | A/S Ferrosan | (-)-Trans-4-(4-fluorophenyl)-3-[(4-methoxyphenoxy)methyl]-1-methylpiperidine useful as 5-HT potentiator |
| IE66332B1 (en) * | 1986-11-03 | 1995-12-27 | Novo Nordisk As | Piperidine compounds and their preparation and use |
| DK715988D0 (en) * | 1988-12-22 | 1988-12-22 | Ferrosan As | ETHERIFICATION AND DEALKYLING OF PIPERIDINE DERIVATIVES AND INTERMEDIATES |
-
1996
- 1996-04-25 HU HU9900318A patent/HUP9900318A3/en unknown
- 1996-04-25 AU AU56845/96A patent/AU721257B2/en not_active Ceased
- 1996-04-25 BR BR9608471A patent/BR9608471A/en not_active Application Discontinuation
- 1996-04-25 JP JP8534464A patent/JPH11505229A/en active Pending
- 1996-04-25 EP EP96914861A patent/EP0828735A1/en not_active Ceased
- 1996-04-25 CN CN96193942A patent/CN1068597C/en not_active Expired - Fee Related
- 1996-04-25 NZ NZ307479A patent/NZ307479A/en unknown
- 1996-04-25 WO PCT/DK1996/000185 patent/WO1996036636A1/en not_active Application Discontinuation
- 1996-04-25 CA CA002220963A patent/CA2220963A1/en not_active Abandoned
- 1996-05-16 IL IL11829496A patent/IL118294A0/en unknown
- 1996-05-17 ZA ZA963951A patent/ZA963951B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA963951B (en) | 1997-01-21 |
| CN1068597C (en) | 2001-07-18 |
| BR9608471A (en) | 1998-12-29 |
| NZ307479A (en) | 1999-08-30 |
| JPH11505229A (en) | 1999-05-18 |
| AU5684596A (en) | 1996-11-29 |
| IL118294A0 (en) | 1996-09-12 |
| HUP9900318A2 (en) | 1999-09-28 |
| WO1996036636A1 (en) | 1996-11-21 |
| HUP9900318A3 (en) | 2001-09-28 |
| CA2220963A1 (en) | 1996-11-21 |
| CN1184476A (en) | 1998-06-10 |
| EP0828735A1 (en) | 1998-03-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |