CA2220963A1 - Process for preparing 4-aryl-piperidine derivatives - Google Patents
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- CA2220963A1 CA2220963A1 CA002220963A CA2220963A CA2220963A1 CA 2220963 A1 CA2220963 A1 CA 2220963A1 CA 002220963 A CA002220963 A CA 002220963A CA 2220963 A CA2220963 A CA 2220963A CA 2220963 A1 CA2220963 A1 CA 2220963A1
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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
Abstract
A process for the preparation of a compound of formula (VIII), wherein R1 is C2-5-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl.
Description
5 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-15 nes of the general formula A:
~ (A) 25 wherein R' represents hydrogen, alkyl having 1-4 carbon atoms and F
may be in any of the available positions.
W 096/36636 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:
,1~
~ ~J ( 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. [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. 4,007,196 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:
F
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-15 nes of the general formula A:
~ (A) 25 wherein R' represents hydrogen, alkyl having 1-4 carbon atoms and F
may be in any of the available positions.
W 096/36636 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:
,1~
~ ~J ( 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. [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. 4,007,196 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:
F
2~ c~\ ~ J~~' (C) H Paroxetine CA 02220963 l997-ll-l3 W 096/36636 PCT~DX~6/00185 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 ~nd ,4ging 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. Honoré, and P. L. Honoré, J. Ph~rm 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 ,5151-4 (1983)]:
20 ~ /Z
1~ Dl ~ D2 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]:
W O 96/36636 PCT~DK96/00185 ~ ~ o'CH3 ~ o,C~
El 3 E2 CK3 E3 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 W0 94/21609) the intermediary 15 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:
X
J CO~Me O~0~ Re:Zuctio~
In another method (USP 2,748,140, USP 4,007,196; USP 4,593,036;
USP 4,585,777J the intermediate D1 is prepared by reacting methylamine, formaldehyde and a-methylstyrene (G1). Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic , ¦ CA 02220963 l997-ll-l3 PCT~DKg6/00185 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. Pharma-col. Mol. Pharm, 208, 273-286, (1991); S. P. Markey and N. R.
Schnuff, MedicinalRes. Rev.6.386, (1986)].1t 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:
x G2 X G3 _1 ~ IJ~
- ~ X=H: MPTP
X X
~3 G4 ~3 G5 ¦ Red OH ~ ~OH
=
W 096/36636 PCT~DK~6/00185 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 5 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.
10 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 Vlll, wherein R1 can be C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C1 5-alkyl, preferentially ethyl. Using this method the intermediary 1 -alkyl- 1 ,2,3, 6-tetrahydro-4-phenylpyridine will in 15 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 (Ill~ derivative into the pure enantiomers which are subsequently reduced either catalytically or by LiAlH4 to give the entio-20 meric pure (+)-cis- (Vll) and (-)-trans 1-alkyl-4-phenyl-3-hydroxymethylpi-peridine (Vl) derivatives, which both are transformed to pure (-)-trans-1-alkyl-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-piperidine deriva-tives (Vlll), an economically route for the synthesis of a compound of formula IX, using both possible enatiomers, is obtained.
The transformation of either Vll or Vl to pure Vlll is described in J. A.
Christensen, M. Engelstoft, K. Schaumbaurg, H. Schou, and F. Wàtjen, Tet. Lett. 24,5151-4 (1983)].
30 Accordingly, the present invention provides a process for the preparation of a compound of formula Vlll, PCT~DK96/0018 ( VI I I ) Rl wherein R1 is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl, 10 by a) reacting an primary amine of formula ~I) R'-NH2 (1) wherein Rl is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl, with a compound of formula (Il) ~\
~J (II) ,,~
25 wherein X is halogen, preferably F, to form a compound of formula lll X
~ (III) ~OH
N
W 096/36636 PCT~DK96/00185 wherein X and R' are as defined above, and b) by crystallizing the salt of a mixture of a compound of formula lll and a suitable optically active acid, preferably (-)~O,O-ditoluoyltartaric ~ 5 acid to form, upon purification of the basic component, an optically ~ active compound of formula IV, ~ (IV) '\ OH
N
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 ( + )-O,O-ditoluoyl tartaric acid, and purification of the basic compo-20 nent, forms a compound of formula V, which is able to rotate the planeof polarized light counterclockwise:
~ (V) ~ ~--OE
N
wherein R' and X are as defined above, PCT~DK96/00185 _ 9 _ c) by treatment of a compound of formula lV, wherein R' and X are as defined above with metal hydrides, preferably LiAlH4 or NaAlH4, to form a compound of formula Vl, X
(VI ) ~ OH
wherein R1 and X are as defined above, 15 dJ by treatment of a compound of formula V, wherein R' 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 Vll, X
l (VII ) J OH
N
l1 wherein R' and X are as defined above.
e) by treatment of a compound of formula Vl, S ~ (VI) "~'~OH
N
Rl 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, 15 preferably sodium methanolate, to give a compound of formula Vlll 1~3 ~ (VIII ) ""~o_~ o>
N
R
25 wherein R1 and X are defined as above, f) by trea~ment of a compound of formula Vll, ~ (VII) ~~ OH
wherein R' 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 15 3,4-methylenedioxyphenol with a base, preferably sodium methanolate to give a compound of formula Vlll, ~ ~0 (VIII) wherein R1 and X are as defined above, g) by treatment of a compound of formula Vlll, ~ (VIII) o~ ~
N
R
wherein R' 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, 1 5 ~
~ o ( IX) NX
wherein X is as defined above.
25 The present invention is illustrated by the following examples:
CA 02220963 l997~ l3 W 096/36636 PCT~DK~6/0018 ( + ,-)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-5 dine hydrochloride Ethylamine hydrochloride (132.2 9) was dissolved in formaldehyde (500 ml, 37 ~/0) 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 (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 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 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 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 'H-NMR and elemental analysis.
CA 02220963 l997-ll-l3 W O 96/36636 PCTADK~6/0018 (-)-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 (-)-0,0'-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-(-)-0,0'-ditoluoyltartrate M.p. 149-151 ~C.
The free base was liberated from the 0,0'-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~C, [ ~ ]20D = -127.2~ (c = 1 % in methanol).
The identity was confirmed by 'H-NMR and elemental analysis. The enantiomeric purity was confirmed by Chiral HPLC to be better than 99 %. Chiral HPLC: (Column: Cycloband 1 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, RT((-)-isomer) = 10.1 min).
CA 02220963 l997-ll-l3 W 096/36636 PCT~DK~6/00185 a ( + )-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-_ ~ 5 dlne, The mother liquor from precipitation of (-)-1-ethyl-3-hydroxymethyl-4-(4-fuorophenyl)-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 9). The oil was dissolved in acetone (900 ml) with ( ~)-0,0'-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-ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hemi-( + )-0,0'-ditoluoyltartrate, M.p. 146-147~C.
The free base was liberated from the ( + )-0,0 '-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), v~ashed with water (50 ml) and evaporated.
Yield 3~.4 g, M.p. 55-70~C, [~]D20 = 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 1 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, RT((-)-isomer) = 10.1 min).
-CA 02220963 l997-ll-l3 ( + )-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 (12.7 ml) and water (50 ml). Palladium on carbon ~2 9, 10 % Pd, 50 %
10 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 15 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 9). 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~C, [a]D20 = 82.1 ~ (c = 1 ~/0, abs. ethanol) The identity of the product was confirmed by 'H- and '3C-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: 15, 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)) = 11.5 min, RT((-)-cis-isomer)) = 13.5 min, RT((+)-cis-isomer)) = 15.8 min.
W 096/36636 PCT~D~96100185 - 17 -( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine Lithium aluminium hydride (3 9) 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)-1,2,3,6-10 tetrahydropyridine (Z0 g) in tetrahydrofuran (40 ml) over 1 hour. Themixture was stirred at 50~C for 1 hour. The mixture was then added to a solution of (+)-tartaric acid (24 9) 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 15 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 9, M.p. 75-85~C, [a]D20 = 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 %.
25 Chiral HPLC: Column: Chiradex ,B-Cyclodextrin ( Merck); Eluent: metha-nol, buffer: 15, 85 (10 mM (disodium hydrogen phosphate/sodium dihydrogen phosphate, pH = 6)); 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.
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-thyl)-piperidine hydrochloride ( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine hydrochloride (21 9) 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 9, 32.5 %) was added. Benzene sulfonyl-chloride (16.6 9) 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 9) in methylisobutylcarbinol (4-methyl-2-pentanol) (90 ml) was added to the toluene phase together with sodium hydroxide (17.2 9, 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 9). 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 9, M.p. 244-246~C, [a]D20 = 72.8 ~ (c = 1 %, abs. ethanol).
The identity was confirmed by 1H-NMR and elemental analysis.
The enantiomeric purity was established by Chiral HPLC to better than 99.5 %. Chiral HPLC: Column:,~-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) = 1Z.0 min.
, W 096/36636 PCT~DK~610018 (-)-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 9) was added over 2 hours keeping the stated temperature during the addition. The temperature was raised to 10~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 mag-15 nesium sulfate and evaporated to an oil.
The oil was dissolved in dimethylformamide (60 ml) together with 3,4-methylenedioxyphenol (10 9) and the solution was heated to 45~C. A
solution of sodium methanolate (prepared from 2.3 9 sodium dissolved in 20 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 ~0 ml) .
The extract was evaporated to a viscous oil (25.8 9).
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 9, M.p. 242-243~C, [~] = - 72.2 ~ ( c = 1 %, abs.
ethanol) .
30 The identity was confirmed by 'H-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 , CA 02220963 l997-ll-l3 PCTAD~96/00185 acid); Flow: 1.0 ml/min; Detector; UV 290 nm; RT ((+)-trans-isomer) =
10.2 min; RT ((-)-trans-isomer) = 12.0 min.
(-)-trans-4-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride (-)-trans-1-Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-thyl)-piperidine hydrochioride (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 15 over potassium carbonate. The dry toluene solution was evaporated to give an oil (11.5 9). The oil (4.75 9) was redissolved in dry toluene (50 ml), cooled to -10~C. 1-Chloroethylchloroformate (2.85 9) in dry toluene (20 ml) was added over 15 min.àt-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 = 11. The phases were separated and the aqueous phase extracted with another portion of toluene (30 ml). The combined toluene 25 extract was dried over potassium carbonate and evaporated to an oil.
(5.2 9). The oil was dissolved in ethanol (15 ml) with L(+)-tartaric acid (2.37 9). The tartrate of the title compound was crystallized by cooling and could be filtered off and dried. Yield 6.2 9, M.p. 174-176~C.
30 The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC to be better than 99.5 %.
CA 02220963 l997-ll-13 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) = 12.5 min.
1';
~'5 :30
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. Honoré, and P. L. Honoré, J. Ph~rm 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 ,5151-4 (1983)]:
20 ~ /Z
1~ Dl ~ D2 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]:
W O 96/36636 PCT~DK96/00185 ~ ~ o'CH3 ~ o,C~
El 3 E2 CK3 E3 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 W0 94/21609) the intermediary 15 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:
X
J CO~Me O~0~ Re:Zuctio~
In another method (USP 2,748,140, USP 4,007,196; USP 4,593,036;
USP 4,585,777J the intermediate D1 is prepared by reacting methylamine, formaldehyde and a-methylstyrene (G1). Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic , ¦ CA 02220963 l997-ll-l3 PCT~DKg6/00185 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. Pharma-col. Mol. Pharm, 208, 273-286, (1991); S. P. Markey and N. R.
Schnuff, MedicinalRes. Rev.6.386, (1986)].1t 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:
x G2 X G3 _1 ~ IJ~
- ~ X=H: MPTP
X X
~3 G4 ~3 G5 ¦ Red OH ~ ~OH
=
W 096/36636 PCT~DK~6/00185 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 5 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.
10 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 Vlll, wherein R1 can be C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C1 5-alkyl, preferentially ethyl. Using this method the intermediary 1 -alkyl- 1 ,2,3, 6-tetrahydro-4-phenylpyridine will in 15 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 (Ill~ derivative into the pure enantiomers which are subsequently reduced either catalytically or by LiAlH4 to give the entio-20 meric pure (+)-cis- (Vll) and (-)-trans 1-alkyl-4-phenyl-3-hydroxymethylpi-peridine (Vl) derivatives, which both are transformed to pure (-)-trans-1-alkyl-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-piperidine deriva-tives (Vlll), an economically route for the synthesis of a compound of formula IX, using both possible enatiomers, is obtained.
The transformation of either Vll or Vl to pure Vlll is described in J. A.
Christensen, M. Engelstoft, K. Schaumbaurg, H. Schou, and F. Wàtjen, Tet. Lett. 24,5151-4 (1983)].
30 Accordingly, the present invention provides a process for the preparation of a compound of formula Vlll, PCT~DK96/0018 ( VI I I ) Rl wherein R1 is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl, 10 by a) reacting an primary amine of formula ~I) R'-NH2 (1) wherein Rl is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl, with a compound of formula (Il) ~\
~J (II) ,,~
25 wherein X is halogen, preferably F, to form a compound of formula lll X
~ (III) ~OH
N
W 096/36636 PCT~DK96/00185 wherein X and R' are as defined above, and b) by crystallizing the salt of a mixture of a compound of formula lll and a suitable optically active acid, preferably (-)~O,O-ditoluoyltartaric ~ 5 acid to form, upon purification of the basic component, an optically ~ active compound of formula IV, ~ (IV) '\ OH
N
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 ( + )-O,O-ditoluoyl tartaric acid, and purification of the basic compo-20 nent, forms a compound of formula V, which is able to rotate the planeof polarized light counterclockwise:
~ (V) ~ ~--OE
N
wherein R' and X are as defined above, PCT~DK96/00185 _ 9 _ c) by treatment of a compound of formula lV, wherein R' and X are as defined above with metal hydrides, preferably LiAlH4 or NaAlH4, to form a compound of formula Vl, X
(VI ) ~ OH
wherein R1 and X are as defined above, 15 dJ by treatment of a compound of formula V, wherein R' 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 Vll, X
l (VII ) J OH
N
l1 wherein R' and X are as defined above.
e) by treatment of a compound of formula Vl, S ~ (VI) "~'~OH
N
Rl 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, 15 preferably sodium methanolate, to give a compound of formula Vlll 1~3 ~ (VIII ) ""~o_~ o>
N
R
25 wherein R1 and X are defined as above, f) by trea~ment of a compound of formula Vll, ~ (VII) ~~ OH
wherein R' 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 15 3,4-methylenedioxyphenol with a base, preferably sodium methanolate to give a compound of formula Vlll, ~ ~0 (VIII) wherein R1 and X are as defined above, g) by treatment of a compound of formula Vlll, ~ (VIII) o~ ~
N
R
wherein R' 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, 1 5 ~
~ o ( IX) NX
wherein X is as defined above.
25 The present invention is illustrated by the following examples:
CA 02220963 l997~ l3 W 096/36636 PCT~DK~6/0018 ( + ,-)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-5 dine hydrochloride Ethylamine hydrochloride (132.2 9) was dissolved in formaldehyde (500 ml, 37 ~/0) 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 (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 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 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 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 'H-NMR and elemental analysis.
CA 02220963 l997-ll-l3 W O 96/36636 PCTADK~6/0018 (-)-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 (-)-0,0'-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-(-)-0,0'-ditoluoyltartrate M.p. 149-151 ~C.
The free base was liberated from the 0,0'-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~C, [ ~ ]20D = -127.2~ (c = 1 % in methanol).
The identity was confirmed by 'H-NMR and elemental analysis. The enantiomeric purity was confirmed by Chiral HPLC to be better than 99 %. Chiral HPLC: (Column: Cycloband 1 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, RT((-)-isomer) = 10.1 min).
CA 02220963 l997-ll-l3 W 096/36636 PCT~DK~6/00185 a ( + )-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-_ ~ 5 dlne, The mother liquor from precipitation of (-)-1-ethyl-3-hydroxymethyl-4-(4-fuorophenyl)-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 9). The oil was dissolved in acetone (900 ml) with ( ~)-0,0'-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-ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hemi-( + )-0,0'-ditoluoyltartrate, M.p. 146-147~C.
The free base was liberated from the ( + )-0,0 '-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), v~ashed with water (50 ml) and evaporated.
Yield 3~.4 g, M.p. 55-70~C, [~]D20 = 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 1 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, RT((-)-isomer) = 10.1 min).
-CA 02220963 l997-ll-l3 ( + )-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 (12.7 ml) and water (50 ml). Palladium on carbon ~2 9, 10 % Pd, 50 %
10 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 15 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 9). 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~C, [a]D20 = 82.1 ~ (c = 1 ~/0, abs. ethanol) The identity of the product was confirmed by 'H- and '3C-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: 15, 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)) = 11.5 min, RT((-)-cis-isomer)) = 13.5 min, RT((+)-cis-isomer)) = 15.8 min.
W 096/36636 PCT~D~96100185 - 17 -( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine Lithium aluminium hydride (3 9) 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)-1,2,3,6-10 tetrahydropyridine (Z0 g) in tetrahydrofuran (40 ml) over 1 hour. Themixture was stirred at 50~C for 1 hour. The mixture was then added to a solution of (+)-tartaric acid (24 9) 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 15 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 9, M.p. 75-85~C, [a]D20 = 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 %.
25 Chiral HPLC: Column: Chiradex ,B-Cyclodextrin ( Merck); Eluent: metha-nol, buffer: 15, 85 (10 mM (disodium hydrogen phosphate/sodium dihydrogen phosphate, pH = 6)); 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.
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-thyl)-piperidine hydrochloride ( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine hydrochloride (21 9) 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 9, 32.5 %) was added. Benzene sulfonyl-chloride (16.6 9) 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 9) in methylisobutylcarbinol (4-methyl-2-pentanol) (90 ml) was added to the toluene phase together with sodium hydroxide (17.2 9, 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 9). 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 9, M.p. 244-246~C, [a]D20 = 72.8 ~ (c = 1 %, abs. ethanol).
The identity was confirmed by 1H-NMR and elemental analysis.
The enantiomeric purity was established by Chiral HPLC to better than 99.5 %. Chiral HPLC: Column:,~-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) = 1Z.0 min.
, W 096/36636 PCT~DK~610018 (-)-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 9) was added over 2 hours keeping the stated temperature during the addition. The temperature was raised to 10~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 mag-15 nesium sulfate and evaporated to an oil.
The oil was dissolved in dimethylformamide (60 ml) together with 3,4-methylenedioxyphenol (10 9) and the solution was heated to 45~C. A
solution of sodium methanolate (prepared from 2.3 9 sodium dissolved in 20 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 ~0 ml) .
The extract was evaporated to a viscous oil (25.8 9).
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 9, M.p. 242-243~C, [~] = - 72.2 ~ ( c = 1 %, abs.
ethanol) .
30 The identity was confirmed by 'H-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 , CA 02220963 l997-ll-l3 PCTAD~96/00185 acid); Flow: 1.0 ml/min; Detector; UV 290 nm; RT ((+)-trans-isomer) =
10.2 min; RT ((-)-trans-isomer) = 12.0 min.
(-)-trans-4-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride (-)-trans-1-Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-thyl)-piperidine hydrochioride (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 15 over potassium carbonate. The dry toluene solution was evaporated to give an oil (11.5 9). The oil (4.75 9) was redissolved in dry toluene (50 ml), cooled to -10~C. 1-Chloroethylchloroformate (2.85 9) in dry toluene (20 ml) was added over 15 min.àt-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 = 11. The phases were separated and the aqueous phase extracted with another portion of toluene (30 ml). The combined toluene 25 extract was dried over potassium carbonate and evaporated to an oil.
(5.2 9). The oil was dissolved in ethanol (15 ml) with L(+)-tartaric acid (2.37 9). The tartrate of the title compound was crystallized by cooling and could be filtered off and dried. Yield 6.2 9, M.p. 174-176~C.
30 The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC to be better than 99.5 %.
CA 02220963 l997-ll-13 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) = 12.5 min.
1';
~'5 :30
Claims (6)
1. A process for the preparation of a compound of formula (VIII):
(VIII) wherein R1 is C2-5-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl, by a) reacting an primary amine of formula (I) R1-NH2 (1) wherein R1 is C2-5-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl, with a compound of formula (II) (II) wherein X is halogen, preferably F, to form a compound of formula III
(III) 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, (IV) 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, (V) 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, (VI) 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 metal catalyst, to give a compound of formula VII, (VII) wherein R1 and X are as defined above, e) by treatment of a compound of formula VI, (VI) 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) wherein R1 and X are defined as above, f) by treatment of a compound of formula VII, (VII) wherein R1 and X are as defined above, 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, to give a compound of formula VIII, (VIII) wherein R1 and X are as defined above.
(VIII) wherein R1 is C2-5-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl, by a) reacting an primary amine of formula (I) R1-NH2 (1) wherein R1 is C2-5-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl, with a compound of formula (II) (II) wherein X is halogen, preferably F, to form a compound of formula III
(III) 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, (IV) 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, (V) 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, (VI) 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 metal catalyst, to give a compound of formula VII, (VII) wherein R1 and X are as defined above, e) by treatment of a compound of formula VI, (VI) 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) wherein R1 and X are defined as above, f) by treatment of a compound of formula VII, (VII) wherein R1 and X are as defined above, 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, to give a compound of formula VIII, (VIII) 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 LiAlH4 or NaAlH4.
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK56395 | 1995-05-17 | ||
| DK0563/95 | 1995-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2220963A1 true CA2220963A1 (en) | 1996-11-21 |
Family
ID=8094959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002220963A Abandoned CA2220963A1 (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. |
| ES2331937T3 (en) * | 1996-06-13 | 2010-01-20 | Sumitomo Chemical Company, Limited | DERIVATIVES OF PIPERIDINE AS INTERMEDIARIES FOR THE PREPARATION OF PAROXETINE AND PROCEDURE FOR PREPARING THEMSELVES. |
| 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 |
| BR9809687A (en) | 1997-05-29 | 2000-07-11 | Smithkline Beecham Corp | New process |
| US5874447A (en) | 1997-06-10 | 1999-02-23 | Synthon B. V. | 4-Phenylpiperidine compounds for treating depression |
| 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. |
| WO2001032178A1 (en) * | 1999-10-29 | 2001-05-10 | 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 |
| WO2002006275A1 (en) * | 2000-07-17 | 2002-01-24 | Smithkline Beecham P.L.C. | Novel processes for the preparation of 4-phenylpiperidine derivatives |
| GB0021147D0 (en) * | 2000-08-30 | 2000-10-11 | Knoll Ag | Chemical process |
| GB0021145D0 (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 |
| IL156768A0 (en) * | 2001-01-04 | 2004-02-08 | Ferrer Int | 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 |
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 EP EP96914861A patent/EP0828735A1/en not_active Ceased
- 1996-04-25 BR BR9608471A patent/BR9608471A/en not_active Application Discontinuation
- 1996-04-25 HU HU9900318A patent/HUP9900318A3/en unknown
- 1996-04-25 CA CA002220963A patent/CA2220963A1/en not_active Abandoned
- 1996-04-25 NZ NZ307479A patent/NZ307479A/en unknown
- 1996-04-25 CN CN96193942A patent/CN1068597C/en not_active Expired - Fee Related
- 1996-04-25 WO PCT/DK1996/000185 patent/WO1996036636A1/en not_active Application Discontinuation
- 1996-04-25 JP JP8534464A patent/JPH11505229A/en active Pending
- 1996-04-25 AU AU56845/96A patent/AU721257B2/en not_active Ceased
- 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 |
|---|---|
| WO1996036636A1 (en) | 1996-11-21 |
| ZA963951B (en) | 1997-01-21 |
| BR9608471A (en) | 1998-12-29 |
| AU721257B2 (en) | 2000-06-29 |
| NZ307479A (en) | 1999-08-30 |
| JPH11505229A (en) | 1999-05-18 |
| AU5684596A (en) | 1996-11-29 |
| CN1184476A (en) | 1998-06-10 |
| CN1068597C (en) | 2001-07-18 |
| HUP9900318A2 (en) | 1999-09-28 |
| EP0828735A1 (en) | 1998-03-18 |
| IL118294A0 (en) | 1996-09-12 |
| HUP9900318A3 (en) | 2001-09-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20040426 |