WO2011138250A1 - Procédé de préparation de 3-(4-pyridinyl)-propanol et intermédiaires utilisés dans sa synthèse - Google Patents

Procédé de préparation de 3-(4-pyridinyl)-propanol et intermédiaires utilisés dans sa synthèse Download PDF

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Publication number
WO2011138250A1
WO2011138250A1 PCT/EP2011/056885 EP2011056885W WO2011138250A1 WO 2011138250 A1 WO2011138250 A1 WO 2011138250A1 EP 2011056885 W EP2011056885 W EP 2011056885W WO 2011138250 A1 WO2011138250 A1 WO 2011138250A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
pyridinyl
synthesis
Prior art date
Application number
PCT/EP2011/056885
Other languages
English (en)
Inventor
Emanuele Attolino
Alessandro De Marco
Pietro Allegrini
Original Assignee
Dipharma Francis S.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dipharma Francis S.R.L. filed Critical Dipharma Francis S.R.L.
Publication of WO2011138250A1 publication Critical patent/WO2011138250A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters

Definitions

  • the present invention relates to a process for the preparation of 3-(4-pyridinyl)-propanol or a salt thereof, and intermediates useful in its synthesis.
  • An object of the invention is a process for the preparation of a compound of formula (I) or a salt thereof, H
  • R (II) characterized in that a compound of formula (II), or a salt thereof, is obtained by a process comprising:
  • Y is OH, or a leaving group deriving from it, preferably a mesylate, tosylate, nosylate or triflate group; or
  • a C 1 -C4 alkyl group can be straight or branched, preferably methyl, ethyl or isopropyl, in particular isopropyl.
  • a metal hydride is preferably sodium borohydride.
  • the reduction reaction of a compound of formula (II) with a metal hydride can be carried out in a solvent selected for example from an ether, typically tetrahydrofuran or dioxane; a straight or branched C1 -C5 alkanol, preferably a straight or branched C 1 -C4 alkanol, typically methanol, ethanol or isopropanol; or a mixture of two or more, preferably two or three, of said solvents; or in water or an aqueous solution with one or more, preferably two or three, of said solvents.
  • a solvent selected for example from an ether, typically tetrahydrofuran or dioxane; a straight or branched C1 -C5 alkanol, preferably a straight or branched C 1 -C4 alkanol, typically methanol, ethanol or isopropanol; or a mixture of two or more, preferably two or three, of said solvents; or
  • a compound of formula (II), as defined above can be removed to obtain a compound of formula (II), as defined above, for example by conversion to a good leaving group, such as a mesylate, tosylate, nosylate or triflate, followed by treatment with a base, optionally in the presence of a solvent, for example as mentioned above.
  • a compound of formula (III) wherein Y is a hydroxyl can be converted to a compound of formula (III) wherein Y is mesylate, by treatment with mesyl chloride in the presence of a tertiary amine.
  • the resulting mesylate can be treated with a further amount of the same or a different tertiary amine, optionally heating the reaction mixture to the reflux temperature of the mixture to obtain the product of formula (II).
  • a compound of formula (III), wherein Y is hydroxy can be obtained by reaction of a compound of formula (IV) with a compound of formula (V), for example in the presence of a base, and optionally of a solvent, for example as reported above.
  • the same reaction mixture of formation of a compound of formula (III), can yield a compound of formula (II), either spontaneously or by prolonged heating, or by adjusting the pH of the reaction mixture to higher values or subjecting the reaction mixture to prolonged stirring.
  • a compound of formula (III) wherein Y is hydroxy can also be obtained by reduction of a compound of formula (VI)
  • a compound of formula (III), wherein Y is a leaving group derived from a hydroxy group, preferably a mesylate, tosylate, nosylate or triflate, can be prepared starting from the corresponding compound of formula (III) wherein Y is a hydroxy group, according to known procedures, as described above.
  • a compound of formula (VI) can be prepared by Claisen condensation between a compound of formula (VII)
  • CH3COOR (V) wherein is as defined above, according to the known procedures, for example by reacting the compound of formula (VII) with a compound of formula (V) in the presence of a strong, organic or inorganic base, optionally in the presence of a solvent.
  • ester of formula (VII), wherein R is as defined above can be prepared from commercially available isonicotinic acid according to known procedures.
  • 4-Pyridinecarboxaldehyde of formula (IV) is commercially available and acetates CH3COOR of formula (V) are commercially available or obtainable according to known procedures.
  • a further object of the present invention is a process for the preparation of the compound of formula (A), or a salt thereof, which process comprises the conversion of a thus obtained compound of formula (II), for example by reduction, in particular by catalytic hydrogenation as exemplified above.
  • a salt of a compound of formula (A), (I), (II), (III), (IV), (VI) and (VII) can be for example a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt.
  • This can be obtained by known methods.
  • a salt can be obtained dissolving said compound as the free base in ethyl acetate and then reacting it with an organic protic acid, such as acetic, citric, tartaric, fumaric or succinic acid, or with a mineral protic acid, such as hydrochloric, hydrobromic or sulphuric acid.
  • the mineral protic acid is preferably aqueous or gas hydrochloric acid.
  • the conversion of a salt of a compound of formula (I) to the free basic compound can be carried out according to known methods.
  • the catalytic hydrogenation in the processes herein described can be carried out for example with hydrogen and a homogeneous or heterogeneous metal catalyst, for example a palladium, platinum, nickel, rhodium or ruthenium catalyst.
  • a homogeneous or heterogeneous metal catalyst for example a palladium, platinum, nickel, rhodium or ruthenium catalyst.
  • the catalytic hydrogenation can be effected using hydrogen at a pressure which can range from 1 atm to 20 atm approximately.
  • the metal catalyst When the metal catalyst is heterogeneous, it is preferably deposited on an carrier inert, such as carbon, barium hydroxide, alumina, calcium carbonate, preferably carbon.
  • carrier inert such as carbon, barium hydroxide, alumina, calcium carbonate, preferably carbon.
  • concentration of the metal with respect to the carrier can approximately range from 1% to 30%, preferably from 5% to 10%.
  • the reduction reaction is preferably carried out in the presence of a solvent for example selected from a dipolar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, and dimethylsulfoxide; an ether, typically tetrahydrofuran or dioxane; a straight or branched C1 -C5 alkanol, preferably a straight or branched C1 -C4 alkanol, typically methanol, ethanol or isopropanol; a C1 -C5 carboxylic acid, typically acetic acid or propionic acid; or a mixture of two or more, preferably two or three, of said solvents; or in water or an aqueous solution of an organic or mineral protic acid, such as trifluoroacetic, methanesulfonic and hydrochloric acid, or a mixture thereof with one or more, preferably two or three, of said solvents.
  • a solvent for example selected from a dipolar aprotic solvent
  • Ar-CH 141.4 ( 1 C, Ar-C); 120.7 (2C, Ar-CH); 68.6(COOCH); 45.7(COCH 2 COO); 21 .0(2C, CH(CH 3 ) 2 ).
  • Example 2 containing isopropyl 3-(4-pyridinyl)-3-keto-propionate dissolved in 55 ml of AcOEt.
  • three vacuum/H2 cycles are performed, then the mixture is stirred at room temperature under 3 ⁇ 4 atmosphere.
  • the reaction is completed after 6 hours, as monitored by TLC, after which time it is filtered through perlite, washing with 2 x 5 ml of AcOEt.
  • the solvent is evaporated off under reduced pressure to give 8.0 g of a crude (88% yield).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de 3-(4-pyridinyl)-propanol ou d'un sel de celui-ci et des intermédiaires utilisés dans sa synthèse.
PCT/EP2011/056885 2010-05-03 2011-04-29 Procédé de préparation de 3-(4-pyridinyl)-propanol et intermédiaires utilisés dans sa synthèse WO2011138250A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000770A ITMI20100770A1 (it) 2010-05-03 2010-05-03 Procedimento per la preparazione di 3-(4-piridinil)-propanolo e suoi intermedi
ITMI2010A000770 2010-05-03

Publications (1)

Publication Number Publication Date
WO2011138250A1 true WO2011138250A1 (fr) 2011-11-10

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IT (1) ITMI20100770A1 (fr)
WO (1) WO2011138250A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177179A1 (fr) * 2014-05-21 2015-11-26 Intervet International B.V. Procédé amélioré de préparation d'acides crotoniques substitués
RU2779258C1 (ru) * 2021-10-12 2022-09-05 Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" Способ получения метиловых эфиров пиридинкарбоновых кислот

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081205A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr de type pipéridine
WO2008081204A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes du gpcr de pipéridine
WO2009034388A1 (fr) 2007-09-10 2009-03-19 Prosidion Limited Composés pour le traitement de troubles métaboliques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081205A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr de type pipéridine
WO2008081204A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes du gpcr de pipéridine
WO2009034388A1 (fr) 2007-09-10 2009-03-19 Prosidion Limited Composés pour le traitement de troubles métaboliques

Non-Patent Citations (6)

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Title
ADGER, BRIAN M. ET AL: "Synthesis of 2-substituted 4-pyridylpropionates. Part 1. Claisen condensation approach", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1972-1999) , (10), 2785-9 CODEN: JCPRB4; ISSN: 0300-922X, 1988, XP008137079 *
BUNTING J.W., KANTER J.P.: "Acidity and tautomerism of beta-ketoesters and amides in aqueous solutio", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 115, 1 January 1993 (1993-01-01), pages 11705 - 11715, XP002638931 *
J. ORG. CHEM., vol. 47, 1982, pages 3008 - 3011
KITBUNNADAJ R ET AL: "Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 46, no. 25, 4 December 2003 (2003-12-04), pages 5445 - 5457, XP002280992, ISSN: 0022-2623, DOI: DOI:10.1021/JM030905Y *
MELANCTHON S. BROWN, HENRY RAPOPORT: "The Reduction of Esters with Sodium Borohydride1", JOURNAL OF ORGANIC CHEMISTRY, vol. 28, no. 11, 1 January 1963 (1963-01-01), pages 3261 - 3263, XP002638930, DOI: 10.1021/jo01046a538 *
TETRAHEDRON, vol. 57, 2001, pages 3125 - 3130

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177179A1 (fr) * 2014-05-21 2015-11-26 Intervet International B.V. Procédé amélioré de préparation d'acides crotoniques substitués
US10562834B2 (en) 2014-05-21 2020-02-18 Intervet Inc. Process for preparing substituted crotonic acids
RU2779258C1 (ru) * 2021-10-12 2022-09-05 Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" Способ получения метиловых эфиров пиридинкарбоновых кислот

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