WO2022269643A1 - Procédé amélioré pour la préparation d'un intermédiaire pour la paroxétine - Google Patents

Procédé amélioré pour la préparation d'un intermédiaire pour la paroxétine Download PDF

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Publication number
WO2022269643A1
WO2022269643A1 PCT/IN2022/050586 IN2022050586W WO2022269643A1 WO 2022269643 A1 WO2022269643 A1 WO 2022269643A1 IN 2022050586 W IN2022050586 W IN 2022050586W WO 2022269643 A1 WO2022269643 A1 WO 2022269643A1
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formula
methanol
fluorophenyl
methylpiperidin
preparation
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PCT/IN2022/050586
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English (en)
Inventor
Mafatlal Maganlal PATEL
Vital Mafatlal Patel
Dr. RAMESH CHANDRA SINGH
Dr. SACHIN ASHOK PATIL
Dr. Sharad Raghunath BOBE
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Vihita Chem Private Limited
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Publication of WO2022269643A1 publication Critical patent/WO2022269643A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to an improved process for preparation of intermediate for paroxetine and pharmaceutically acceptable salts thereof which are suitable for large scale commercial operation.
  • the present invention further relates to a process for the preparation of ((35',45')-4-(4-fluorophenyl)-l- methy lpiperi din-3 -yl)me than ol of formula I.
  • paroxetine is useful as an antidepressant and anti- Parkinson.
  • the process for preparation of paroxetine are described in US3912743A and US4007196A.
  • An especially important intermediated compound among those disclosed is ((35',45')-4-(4-fluorophenyl)-l- methylpiperi din-3 -yl)methanol.
  • (+)-2 '-nitrotartranilic acid is used, and in another Example the resolving agent is (-)-di-p-toluoyltartaric acid.
  • the (-) trans carbinol is subsequently liberated from the chiral acid salt and may then be coupled with sesamol, then deprotected, to give paroxetine.
  • An object of the present invention is to provide a compound useful as an intermediate for preparing paroxetine and a process for simply and industrially preparing the compound.
  • the present invention provides an efficient and industrially advantageous process for the preparation of highly pure ((35',45')-4-(4-fluorophenyl)-l- methy lpiperi din-3 -yl)me than ol of formula I in high yields.
  • the preparation method of the present invention has the advantages of moderate reaction condition, strong exclusivity for generating byproduct, high yield, low cost of raw materials, etc.
  • the present invention is a new method for large-scale industrial production.
  • present invention provides an improved process for the preparation of ((35',45')-4-(4-fluorophenyl)-l- methylpiperidin-3- yl)methanol of formula I
  • a) Prepare a mixture of Ethyl acetate and Sodium tert-butoxide 1 to 1.5 mole equivalent by addition of Sodium tert-butoxide in 2 to 4 lots at -5°C to 30°C temperature; b) addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes; c) addition of Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in in presence of Sodium methoxide with mole ratio 1 to 2 mole further acidified the reaction mass with acetic acid at 0 to -5°C and followed by addition of process water at same temperature to obtain ethyl 4-(4-fluorophenyl)- 1 -methyl-2, 6-di ox opi
  • present invention provides an improved process for the preparation of ((35',45')-4-(4-fluorophenyl)-l- methylpiperidin-3- yl)methanol of formula I
  • an object of the present invention is to provide a method of producing ((33,43)-4-(4-fluorophenyl)- 1 -methylpiperidin-3-yl)methanol compound of formula I with high efficiency.
  • the present invention provides an improved process for the preparation of ((3k,4S>4-(4-fluorophenyl)-l - methylpiperidin-3- yl)methanol of formula I
  • the present invention provides an improved process for the preparation of ((35',45')-4-(4-fluorophenyl)-l- methylpiperidin-3- yl)methanol of formula I
  • Fromula II Fromula III Fromula IV b) Reduction of ethyl 4-(4-fluorophenyl)-l -methyl-2, 6-di ox opiperidine-3- carboxylate compound of formula IV with Sodium borohydride/ BF 3 .0Et 2 in presence of solvent to obtain (4-(4-fluorophenyl)-l- methy lpiperi din-3 -yl)me than ol compound of formula V;
  • a process for the preparation of ethyl 4-(4-fluorophenyl)-l -methyl-2,6- dioxopiperidine-3-carboxylate compound of formula IV by reacting 4- fluorobenzaldehyde of compound of formula II with Ethyl acetate in presences of Sodium tert-butoxide and further reacted with Ethyl 3-(methylamino)-3- oxopropanoate of compound of formula III in presences of Sodium methoxide to obtain ethyl 4-(4-fluorophenyl)-l -methyl-2, 6-dioxopiperidine-3-carboxylate compound of formula IV.
  • the reaction is preferably conducted in presence of mixture of bases such as Sodium hydride, Sodium tert-butoxide, Potassium tert-butoxide, Sodium methoxide etc.
  • bases such as Sodium hydride, Sodium tert-butoxide, Potassium tert-butoxide, Sodium methoxide etc.
  • the reaction is preferably conducted in solvent or a mixture of solvents selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n- hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.
  • solvent or a mixture of solvents selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n- hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.
  • the reaction is preferably conducted in presence of complexing agent selected from the Sodium borohydride/ BF 3 .0Et 2 .
  • complexing agent selected from the Sodium borohydride/ BF 3 .0Et 2 .
  • the reaction is preferably conducted in presence Sodium borohydride/ BF 3 .OEt2is used in an amount of 2 to 8 moles, preferably 3 to 6 moles, of ethyl 4-(4-fluorophenyl)- 1 -methyl-2, 6-dioxopiperidine-3-carboxylate.
  • the complexing agent selected from Raney nickel or nickel nanoparticles on zeolite, palladium-on-carbon, platinum(IV) oxide, or Umshibara nickel, Sodium hydrosulfite, Sodium sulfide (or hydrogen sulfide and base), Tin(II) chloride, Titanium(III) chloride, Zinc, Samarium, Raney nickel, platinum-on-carbon, or zinc dust and formic acid or ammonium formate, Decaborane in presence of palladium-on-carbon and acetic acid, Hydroiodic acid.
  • reaction is by addition of ethyl 4-(4-fluorophenyl)-l -methyl-2, 6- dioxopiperidine-3-carboxylate compound of formula IV in 2 to 15 lots at 5°C to -15 °C temperature in complexing agent in presence of solvent to obtain (4- (4-fluorophenyl)-l- methylpiperidin-3-yl)methanol compound of formula V.
  • the reaction is preferably conducted in solvent or a mixture of solvents selected from the group consisting dimethylsulfoxide (DMSO), sulfolane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene, xylene, Methanol, Ethanol, Isopropyl alcohol or mixtures thereof.
  • solvent or a mixture of solvents selected from the group consisting dimethylsulfoxide (DMSO), sulfolane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene, xylene, Methanol, Ethanol, Isopropyl alcohol or mixtures thereof.
  • the reaction temperature is not particularly limited. However, a temperature not higher than 0°C to 100°C. Specifically, reaction temperature of 0°C to 10°C or lower is appropriate because the rate of reaction is excessively low, whereas when the temperature is 70°C or higher, the amount of required heat increases due to boiling the solvent, leading to a disadvantage with respect to energy consumption.
  • the reaction time which varies depending on reaction conditions and the type and amount of the catalyst employed, is typically 2-30 hours.
  • the (4-(4-fluorophenyl)-l- methylpiperidin-3-yl) methanol compound of formula V is reacted with D-(-) Tartaric acid, a solvent can be used.
  • the solvent includes, for instance, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol; ketones, such as acetone and methyl ethyl ketone, and the like. Those solvents can be used alone or in an admixture thereof.
  • solvents are methanol or ethanol or mixture thereof in obtaining ((35, 4S)-4-(4-fluorophenyl)-l-methylpiperidin-3-yl) methanol (25, 3S)-2, 3- dihydroxysuccinic acid compound of formula VI having high optical purity.
  • the solvent comprising methanol or ethanol or mixture thereof refers to a solvent containing at least 50% by volume of methanol or ethanol.
  • methanol or a mixed solvent of methanol and at least one compound of isopropyl alcohol and acetone is desirable from the viewpoint of obtaining ((35,45)-4-(4-fluorophenyl) -1- methylpiperidin-3-yl) methanol(25,35)-2,3-dihydroxysuccinic acid compound of formula VI having higher optical purity.
  • the mixed solvent of methanol and at least one compound of ethanol and l%Toluene: Ethanol or isopropyl alcohol and acetone is also desirable from the viewpoint of obtaining ethanol in high yields.
  • the ratio of methanol to at least one compound of ethanol is such that the amount of at least one compound of ethanol is at least 10 parts by volume, preferably at least 20 parts by volume, more preferably at least 30 parts by volume, and l%Toluene:Ethanol, based on 100 parts by volume of methanol; from the viewpoint of obtaining the ((35,45)-4-(4- fluorophenyl)- 1 -methylpiperidin-3-yl) methanol(25,35)-2,3-dihydroxysuccinic acid compound of formula VI in high yields.
  • the ratio of methanol to at least one compound of ethanol cannot be absolutely determined, because the optical purity of the resulting ((3S,4S)-4-(4-fluorophenyl)-l- methylpiperidin-3-yl) methanol (25, 35)-2,3-dihydroxysuccinic acid compound of formula VI may differ depending upon several factors such as amount of the solvent, temperatures during the formation of a salt, and period of time required for the formation of a salt as well as the ratio of methanol to at least one compound of isopropyl alcohol and acetone. Generally, in accordance with the increase of the ratio of methanol to at least one compound of isopropyl alcohol and acetone, its optical purity tends to be lowered.
  • the amount of at least one compound of ethanol is usually at most 500 parts by volume, preferably at most 200 parts by volume, more preferably at most 100 parts by volume, further preferably at most 60 parts by volume, particularly preferably at most 40 parts by volume, based on 100 parts by volume of methanol, from the viewpoint of improvement in optical purity.
  • the amount of the solvent is at least 200 parts by weight, preferably at least 500 parts by weight, based on 100 parts by weight of the ((35, 45)-4-(4-fluorophenyl)-l-methylpiperidin-3-yl (methanol (25, 35)-2, 3- dihydroxysuccinic acid compound of formula VI with high optical purity, and that the amount of the solvent is at most 2000 parts by weight, preferably at most 700 parts by weight, based on 100 parts by weight of the ((35,45)-4-(4- fluorophenyl)-l-methylpiperidin-3-yl) methanol (25,35)-2,3- dihydroxysuccinic acid compound of formula VI, from the viewpoint of improvement in yields.
  • any of ((35',45')-4-(4-fluorophenyl)-l-methylpiperidin-3-yl)methanol(25',35') -2,3- dihydroxysuccinic acid compound of formula VI can be firstly dissolved in the solvent.
  • the amount of D-(-) Tartaric acid is at least 1.0 mol, preferably at least 1.01 mol, per one mol of the (4-(4-fluorophenyl)-l- methylpiperidin-3- yl)methanol compound of formula V compound, giving a compound with high optical purity, and that the amount of D-(-) Tartaric acid is at most 2 mol, preferably at most 1.0 mol, per one mol of the (4-(4-fluorophenyl)-l- methy lpiperi din-3 -yl)me than ol compound of formula V compound of suppression of the residual D-(-) Tartaric acid and economic advantages.
  • the temperature during the formation of a salt is at least 0° C., preferably at least 10° C., more preferably at least 20° C., from the viewpoint of acceleration of the formation of a salt, and that the temperature is at most a boiling point of the solvent used, preferably at most 40° C.
  • the temperature during the formation of a salt is 20° to 35° C., and obtain ((35',45')-4-(4-fluorophenyl)- 1 -methylpiperidin-3-yl)methanol(25',35')- 2,3 -dihydroxy succinic acid compound of formula VI having high optical purity in high yields.
  • the atmosphere the formation of a salt is not limited to specified ones, and it may be air, or an inert gas such as nitrogen gas.
  • the time period required for the formation of a salt cannot be absolutely determined, because it may differ depending upon the conditions for the formation of a salt. Usually, the time period for the reaction is 1 to 24 hours or so.
  • the time period for the reaction is longer, the optical purity of the resulting ((35',45')-4-(4-fluorophenyl)-l-methylpiperidin-3- yl)methanol(25',35')-2,3-dihydroxysuccinic acid compound of formula VI tends to be lowered, it is desired that the time period is as short as possible, for instance, at most 5 hours, preferably at most 3 hours.
  • the ((35',45')-4-(4-fluorophenyl)-l-methylpiperidin-3-yl) methanol (25',35')-2, 3 -dihydroxy succinic acid compound of formula VI can be precipitated as crystals by reacting the (4-(4-fluorophenyl)-l- methylpiperidin- 3-yl)methanol compound of formula V with D-(-) Tartaric acid to form a salt.
  • ((35',45')-4-(4-fluorophenyl)-l-methylpiperidin-3- yl)methanol(25',35')-2,3-dihydroxysuccinic acid compound of formula VI is neutralized first, preferably with a base.
  • the base is preferably selected so that the base forms a water soluble.
  • inexpensive and readily available bases containing alkali metals are preferred, and particularly preferred are sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate and the like.
  • Sodium hydroxide is extremely particularly preferable because it is available with high purity.
  • Example 1 Process for preparation of ethyl 4-(4-fluorophenyl)-l-methyl- 2,6-dioxopiperidine-3-carboxylate compound of formula IV.
  • Example 2 Process for preparation of (4-(4-fluorophenyl)-l- methylpiperidin-3-yl)methanol compound of formula V
  • reaction mass 0 to 5 °C, adjust pH of reaction mass to 12 to 13 using caustic lye charged Toluene (300 ml). Raised reaction mass temperature 60 to 70 °C, stirred and separated organic layer. Aqueous layer further extracted with Toluene (150 ml X 2), combined organic layer washed with water (200 ml). Distilled out reaction mass under vacuum, Charged Toluene (40 ml) and n-Heptane (160 ml) at 40 to 45 °C and cool reaction mass 0 to 10 °C. Stirred reaction mass for 30 minutes, filter reaction mass and washed w/c with n-Heptane (50 ml X 2). Dry w/c for 8 hours at 50 to 60 °C to obtain (4-(4-fluorophenyl)-l- methy lpiperi din-3 -yl)methanol compound of formula V.
  • Example 3 Process for preparation of ((3S,4S)-4-(4-fluorophenyl)-l- methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI
  • Example 4 Process for preparation of ((3S,4S)-4-(4-fluorophenyl)-l- methylpiperidin-3-yl)methanol compound of formula I.
  • Weight of wet cake 60 to 55 g
  • Example 5 Process for preparation of of ((3S,4S)-4-(4-fluorophenyl)-l- methylpiperidin-3-yl)methanol compound of formula I
  • Stage-01 1. Providing a mixture comprising of formula II with Ethyl acetate in presence of Sodium tert-butoxide 1 to 1.5 mole equivalent having respectively.
  • step-I reaction carried out between temperature ranges at -5°C to 30°C.
  • step-I of formula IV further reaction with Ethyl 3-(methylamino)-3- oxopropanoate in presence of Sodium methoxide with mole ratio 1 to 2 mole equivalent respectively.
  • Formula IV is prepared by using mixture of Sodium tertiary butoxide: sodium methoxide with mole ratio 0.66.
  • Solvent includes, for instance, such as THF, Isopropanol; ketones, such as acetone, 1,4-dioxane and ethereal solvents.
  • Formula V is prepared firstly by formation of complex of Sodium borohydride with BF 3 .OEt2 in THF solvent then lot wise addition of Formula IV. Complex formation in initial stage is preferred.
  • Solvent includes, for instance, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol; ketones, such as acetone and methyl ethyl ketone.
  • Stage-04 1. The improved process for the preparation of ((3S,4S)-4-(4- fluorophenyl)-l- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, base selected from sodium hydroxide, potassium hydroxide and dibasic metal carbonates.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation d'un intermédiaire pour la paroxétine et de sels pharmaceutiquement acceptables de celui-ci qui sont appropriés pour un usage commercial à grande échelle. La présente invention concerne en outre un procédé de préparation de ((3S,4S)-4-(4-fluorophényl)-1- méthylpipéridin-3-yl)méthanol de formule I.
PCT/IN2022/050586 2021-06-25 2022-06-27 Procédé amélioré pour la préparation d'un intermédiaire pour la paroxétine WO2022269643A1 (fr)

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IN202121028666 2021-06-25

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223334B1 (fr) * 1985-08-10 1991-07-10 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
US6316628B1 (en) * 1998-06-29 2001-11-13 Sumika Fine Chemicals Co., Ltd. L-tartrate of trans-(-)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine compound and process for preparing the same
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
US20030004352A1 (en) * 1999-12-23 2003-01-02 Brook Christopher S. Novel process
EP1384711A1 (fr) * 1996-06-13 2004-01-28 SUMIKA FINE CHEMICALS Co., Ltd. Résolution optique d'un dérivé pipéridine
CN104402800A (zh) * 2014-12-02 2015-03-11 千辉药业（安徽）有限责任公司 一种反式-4-(4-氟苯基)-3-羟甲基-1-甲基哌啶的制备方法
WO2017037662A1 (fr) * 2015-09-03 2017-03-09 Piramal Enterprises Limited Procédé amélioré de préparation de paroxétine et de son intermédiaire

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223334B1 (fr) * 1985-08-10 1991-07-10 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
EP1384711A1 (fr) * 1996-06-13 2004-01-28 SUMIKA FINE CHEMICALS Co., Ltd. Résolution optique d'un dérivé pipéridine
US6316628B1 (en) * 1998-06-29 2001-11-13 Sumika Fine Chemicals Co., Ltd. L-tartrate of trans-(-)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine compound and process for preparing the same
US20030004352A1 (en) * 1999-12-23 2003-01-02 Brook Christopher S. Novel process
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
CN104402800A (zh) * 2014-12-02 2015-03-11 千辉药业（安徽）有限责任公司 一种反式-4-(4-氟苯基)-3-羟甲基-1-甲基哌啶的制备方法
WO2017037662A1 (fr) * 2015-09-03 2017-03-09 Piramal Enterprises Limited Procédé amélioré de préparation de paroxétine et de son intermédiaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GANGULA SRINIVAS, KOLLA NAVEEN KUMAR, ELATI CHANDRASEKAR, DONGAMANTI ASHOK, BANDICHHOR RAKESHWAR: "Improved Process for Paroxetine Hydrochloride Substantially Free from Potential Impurities", SYNTHETIC COMMUNICATIONS, TAYLOR & FRANCIS INC., US, vol. 42, no. 22, 15 November 2012 (2012-11-15), US , pages 3344 - 3360, XP093020207, ISSN: 0039-7911, DOI: 10.1080/00397911.2011.582216 *

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