Classifications

• • 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)

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• 1996
  • 1996-04-25 WO PCT/DK1996/000185 patent/WO1996036636A1/en not_active Application Discontinuation
  • 1996-04-25 AU AU56845/96A patent/AU721257B2/en not_active Ceased
  • 1996-04-25 CA CA002220963A patent/CA2220963A1/en not_active Abandoned
  • 1996-04-25 HU HU9900318A patent/HUP9900318A3/hu unknown
  • 1996-04-25 BR BR9608471A patent/BR9608471A/pt not_active Application Discontinuation
  • 1996-04-25 JP JP8534464A patent/JPH11505229A/ja active Pending
  • 1996-04-25 CN CN96193942A patent/CN1068597C/zh not_active Expired - Fee Related
  • 1996-04-25 NZ NZ307479A patent/NZ307479A/xx unknown
  • 1996-04-25 EP EP96914861A patent/EP0828735A1/en not_active Ceased
  • 1996-05-16 IL IL11829496A patent/IL118294A0/xx unknown
  • 1996-05-17 ZA ZA963951A patent/ZA963951B/xx unknown

Non-Patent Citations (1)

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