WO2010020628A1 - Nouveau procédé de production de l-pipéridin-4-yl-1,3-dihydro-imidazo-[4,5-b]-pyridin-2-one et de son mono- et dichlorhydrate - Google Patents

Nouveau procédé de production de l-pipéridin-4-yl-1,3-dihydro-imidazo-[4,5-b]-pyridin-2-one et de son mono- et dichlorhydrate Download PDF

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Publication number
WO2010020628A1
WO2010020628A1 PCT/EP2009/060654 EP2009060654W WO2010020628A1 WO 2010020628 A1 WO2010020628 A1 WO 2010020628A1 EP 2009060654 W EP2009060654 W EP 2009060654W WO 2010020628 A1 WO2010020628 A1 WO 2010020628A1
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Prior art keywords
group
formula
compounds
compound
general formula
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PCT/EP2009/060654
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German (de)
English (en)
Inventor
Guenther Huchler
Werner Rall
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Boehringer Ingelheim International Gmbh
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Publication of WO2010020628A1 publication Critical patent/WO2010020628A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is a process for the preparation of compounds of general formula I.
  • the present application is a process for the preparation of the compound 1-piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one of the formula I.
  • the inventive method results in a few Steps to good yields of the desired
  • Step A The use of the UV-active Z-protecting group allows a fast and efficient reaction control and a good detection of the starting material 4-oxo-piperidine-1-carboxylic acid benzyl ester in the product by HPLC measurement with UV detection.
  • Step C By using tert-amyl alcohol as a solvent, a significantly simplified reaction is possible. By distillation, water residues can be effectively azeotropically removed from the reaction mixture, so that the analytical
  • Step D The possibility of hydrogenolytic cleavage of the protecting group allows for complete and virtually byproduct-free reaction. In this case, isolation of the product either as a base or by direct precipitation in the form of a dihydrochloride from the reaction solution is possible. Both compounds are crystalline.
  • the ring-open urea V is formed by reaction of IV with chlorosulfonyl isocyanate, which is reacted under Pd catalysis to give the corresponding imidazolone VI.
  • the catalytic hydrogenation of VI leads to elimination of the Z-protecting group to I
  • a first subject of the present invention relates to a process for the preparation of compounds of general formula I. - A -
  • n one of the numbers O, 1 or 2, comprising the steps of:
  • LG represents a leaving group, for example a fluorine, chlorine, bromine or iodine atom or the triflate (-OSO 2 CF 3 ), preferably a chlorine atom, with a compound of general formula III
  • Ar represents an unsubstituted or substituted phenyl group which is selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6- Trimethylphenyl and 4-nitrophenyl, in a solvent and in the presence of an acid and a reducing agent;
  • LG represents a leaving group as described above, and Ar represents a phenyl group as described above from a solvent;
  • Ar is a phenyl group as described above, from a solvent; (D) reacting a compound of general formula VI obtained under (C) or (CC) by adding a reducing agent in a polar organic solvent; and
  • step (A) 1.0 equivalents of a compound of general formula II can be reacted with 1.0 to 2.0, preferably 1.1 to 1.3 equivalents, of a compound of general formula III.
  • a solvent ethyl acetate, isopropyl acetate or THF may be used.
  • the solvent in an amount of 1.5 to 3.5, preferably in an amount of 2.4 to 2.6 L / mol of the compound of formula II, are added.
  • the acid used in step (A) may be selected from the group consisting of trifluoroacetic acid or acetic acid; preferably trifluoroacetic acid is used.
  • the acid may be added in an amount of from 1 to 3, preferably from 1.5 to 2.5, equivalents, in each case based on the amount of compound of general formula II used.
  • the reducing agent used in step (A) may be selected from the group consisting of Sodium triacetoxyborohydride or sodium cyanoborohydride, preferably sodium triacetoxyborohydride is used.
  • the reducing agent may be added in an amount of 1 to 3, preferably from 1.0 to 1.5, equivalents, in each case based on the amount of compound of the general formula II used.
  • the reaction temperature is preferably between 0 and 30 ° C., more preferably between 10 and 20 0 C, in particular between 14 and 16 ° C.
  • step (B) 1.0 equivalents of a compound of general formula IV with 1.0 to 2.0, preferably 1.3 to 1.7 equivalents, of a compound selected from the group consisting of chlorosulfonyl isocyanate, NaOCN, phosgene / NH 3 , triphosgene / NH 3 , CDI / NH 3 or CDT / NH 3 , preferably chlorosulfonyl isocyanate and NaOCN; particularly preferably, chlorosulfonyl isocyanate can be reacted.
  • a compound selected from the group consisting of chlorosulfonyl isocyanate, NaOCN, phosgene / NH 3 , triphosgene / NH 3 , CDI / NH 3 or CDT / NH 3 preferably chlorosulfonyl isocyanate and NaOCN; particularly preferably, chlorosulfonyl isocyanate can be reacted.
  • Solvents can be used tetrahydrofuran, isopropyl acetate or a mixture of both solvents.
  • the solvent may be added in an amount of 2 to 5, preferably in an amount of 3 to 3.5 L / mol of the compound of general formula IV used.
  • the reaction temperature is preferably between -30 and -7 ° C, more preferably between -20 and -7 ° C, in particular between -10 and -7 ° C.
  • step (BB) can be carried out from a polar organic solvent, e.g. Ethyl acetate, n-butyl acetate, isopropyl acetate or mixtures of the two solvents.
  • the solvent may be added in an amount of 0.5 to 3, preferably in an amount of 1.5 to 2.5 L / mol of the compound of general formula V used.
  • step (C) is 1 equivalent of the compound of general formula V with 1.5 to 4.5, preferably 2.0 to 4.0, particularly preferably 2.5 to 3.5
  • a weak base preferably sodium bicarbonate or potassium bicarbonate
  • sodium hydrogen carbonate in a volume of 3.0 to 7.0, preferably 4.0 to 6.0, particularly preferably 4.5 to 5.5 L / mol of compound of the general formula V used, of a solvent selected from the group consisting of n-propanol, n-butanol, isobutanol , n-amyl alcohol, iso-amyl alcohol, tert-amyl alcohol or tert-butanol, preferably tert-amyl alcohol; heated and then distilled off a volume of 10-30%, preferably 15-25, particularly preferably 18-22% of the liquid portion.
  • the remaining liquid volume 0.01-0.2%, preferably 0.1% water is added.
  • 0.01 to 0.03, preferably 0.015 to 0.025, particularly preferably 0.02 equivalents of catalyst and 0.02 to 0.06, preferably 0.03 to 0.05, particularly preferably 0.04 equivalents of a ligand are added and the reaction mixture is heated under reflux.
  • the catalyst used may be selected from the group consisting of palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), bis (dibenzylideneacetone) palladium (Pd (dba) 2 ), 1 !
  • the ligand used can be selected from 1,4-bis (diphenylphosphino) butane (DPPB), 9,9-dimethylsilane-4,4-bis (diphenylphosphino) xanthene (xantphos) and 2-dicyclohexylphosphino-2 ', 4''6'-triisopropylbiphenyl(X-Phos);
  • DPPB 1,4-bis (diphenylphosphino) butane
  • DPPB 1,4-bis (diphenylphosphino) butane
  • the reaction is preferably conducted overnight, which corresponds to a reaction time of 6 to 18, preferably 9 to 15, particularly preferably 11 to 13 hours. Thereafter, the reaction mixture is preferably treated with water and worked up.
  • step (CC) can be carried out from a polar, organic solvent.
  • a polar organic solvent ethyl acetate, isopropyl acetate, or butyl acetate, preferably isopropyl acetate (IPAC) can be used.
  • IPAC isopropyl acetate
  • 1.0 equivalents of a compound of general formula VI may be reacted by means of hydrogen as known in the art using a hydrogenation catalyst.
  • a hydrogenation catalyst As the organic solvent, methanol, ethanol, THF or ethyl acetate, preferably methanol or ethanol, more preferably methanol can be used.
  • the solvent may be added in an amount of 1.0 to 5.0, preferably in an amount of 2.0 to 3.0 L / mol.
  • the hydrogenation catalyst used in step (D) may be selected from the group consisting of palladium / carbon or rhodium / carbon; preferably
  • the hydrogenation catalyst may be added in an amount of 0.5 to 20% by weight, preferably 3 to 10% by weight.
  • the product can be isolated by precipitation by means of methylcyclohexane (MCH) or the crystallization described in step (DD) can be carried out by means of hydrochloric acid-containing alcohols directly from the reaction medium.
  • the product isolated by means of methylcyclohexane (MCH) can be crystallized out in hydrochloric acid-containing alcohols and thus converted into the monohydrochloride or dihydrochloride. In this case, the methods known in the prior art for solidification and recrystallization applied.
  • the hydrochloric acid-containing alcohol used may be selected from the group consisting of methanol, ethanol, isopropanol, propanol, preferably methanol, ethanol, isopropanol; particularly preferably ethanol.
  • the concentration of hydrochloric acid in the alcohol can be in the range from 5 to 15, preferably 7 to 13, particularly preferably 9 to 1 1 mol / L.
  • Another object of the present invention are the compounds of general formula III
  • Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl.
  • Another object of the present invention relates to the use of the above-mentioned compounds of general formula III as intermediates for the preparation of compounds of general formula I by a method described above.
  • Another object of the present invention are the compounds of general formula IV
  • Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the A group consisting of a fluorine, chlorine, bromine or iodine atom or the triflate group (-OSO 2 CF 3 ).
  • Another object of the present invention relates to the use of the above-mentioned compounds of general formula IV as intermediates for the preparation of compounds of general formula I by a method described above.
  • Another object of the present invention are the compounds of general formula V
  • Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the group consisting of a fluorine, chlorine, bromine or iodine atom or the triflate group (-OSO 2 CF 3 ).
  • Another object of the present invention relates to the use of the above-mentioned compounds of general formula V as intermediates for the preparation of compounds of general formula I by a method described above.
  • Another object of the present invention are the compounds of general formula VI
  • Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl.
  • Another object of the present invention relates to the use of the above compounds of general formula VI as intermediates for the preparation of compounds of general formula I by a method described above.
  • the term "optionally substituted” is understood to mean the abovementioned group which is optionally substituted by a lower-molecular radical.
  • Low-molecular radicals are understood to be chemically meaningful groups consisting of 1-200 atoms. Preferably, such groups have no negative effect on the pharmacological activity of the compounds.
  • the groups may include: straight or branched carbon chains, possibly interrupted by
  • Heteroatoms optionally substituted with rings, heteroatoms or other common functional groups.
  • Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.
  • a plurality of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may be substituted by one or more carbon chains, optionally interrupted by heteroatoms substituted with heteroatoms or other common functional groups can be linked.
  • Protecting groups in the meaning of the present invention are to be understood as a collective term for such organic radicals with which certain functional groups of a molecule containing several active sites can be temporarily protected against the attack of reagents so that reactions take place only at the desired (unprotected) sites occur.
  • the protecting groups should be selectively introduced under mild conditions. They must be stable for the duration of the protection under all conditions of the reactions and cleaning operations to be performed; Racemizations and epimerizations must be suppressed. Protective groups should again be cleavable under mild conditions selectively and ideally with high yield.
  • a solvent is understood to mean an organic, low-molecular substance which can bring other organic substances to solution by physical means.
  • a solvent is understood to mean an organic, low-molecular substance which can bring other organic substances to solution by physical means.
  • Prerequisite for the suitability as a solvent is that during the dissolution process neither the solvent nor the solute chemically change, so that the components of the solution can be recovered by physical separation processes such as distillation, crystallization, sublimation, evaporation, adsorption in its original form.
  • physical separation processes such as distillation, crystallization, sublimation, evaporation, adsorption in its original form.
  • Alcohols preferably methanol, ethanol, propanol, butanol, octanol, cyclohexanol;
  • Glycols preferably ethylene glycol, diethylene glycol
  • Ether / glycol ethers preferably diethyl ether, tert-butyl methyl ether, dibutyl ether, anisole, dioxane, tetrahydrofuran, mono-, di-, tri-, polyethylene glycol ethers;
  • Ketones preferably acetone, butanone, cyclohexanone
  • Esters preferably acetic acid esters, glycol esters;
  • Amides inter alia, nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone, acetonitrile; Sulfur compounds, preferably carbon disulfide, dimethylsulfoxide, sulfolane;
  • Nitro compounds preferably nitrobenzene
  • Halogenated hydrocarbons preferably dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, tetrachloroethene, 1,2-dichloroethane, chlorofluorocarbons; Aliphatic or alicyclic hydrocarbons, preferably benzines, petroleum ethers, cyclohexane, methylcyclohexane, decalin, terpene-L; or
  • Aromatic hydrocarbons preferably benzene, toluene, o-xylene, m-xylene, p-xylene; or corresponding mixtures thereof.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
  • Reaction mixture was cooled to 35 ° C (see above) and treated with 11 ml of water. Subsequently, 13 g (0.058 mol, 0.02 eq) of palladium acetate and 49 g (0.115 mol, 0.04 eq) of DPPB were added and heated to reflux temperature. The mixture was stirred at 100 0 C until the reaction was complete, cooled to RT and 7.5 L of water was added. The organic phase was separated, washed with 5 L of water and then concentrated. The oily residue was mixed twice with 3 L IPAC and distilled off. The residue was then dissolved hot in 7 L IPAC and cooled slowly to room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de production de composés de formule (I) dans laquelle n est défini comme suit, et que l'on trouve comme élément constitutif dans les antagonistes du CGRP.
PCT/EP2009/060654 2008-08-20 2009-08-18 Nouveau procédé de production de l-pipéridin-4-yl-1,3-dihydro-imidazo-[4,5-b]-pyridin-2-one et de son mono- et dichlorhydrate WO2010020628A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08162692.1 2008-08-20
EP08162692 2008-08-20

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WO2010020628A1 true WO2010020628A1 (fr) 2010-02-25

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742052A (en) * 1981-07-15 1988-05-03 Sumitomo Pharmaceuticals Company, Limited Antibacterial β-lactam compounds
WO2007120590A2 (fr) * 2006-04-10 2007-10-25 Merck & Co., Inc. Procédé de préparation d'un intermédiaire antagoniste du peptide cgrp d'hétérocycle de pyridine
WO2009050232A1 (fr) * 2007-10-18 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes du cgrp
WO2009050235A1 (fr) * 2007-10-18 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes du cgrp
WO2009065919A2 (fr) * 2007-11-22 2009-05-28 Boehringer Ingelheim International Gmbh Nouveaux composés
WO2009065921A2 (fr) * 2007-11-22 2009-05-28 Boehringer Ingelheim International Gmbh Nouveaux composés

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742052A (en) * 1981-07-15 1988-05-03 Sumitomo Pharmaceuticals Company, Limited Antibacterial β-lactam compounds
WO2007120590A2 (fr) * 2006-04-10 2007-10-25 Merck & Co., Inc. Procédé de préparation d'un intermédiaire antagoniste du peptide cgrp d'hétérocycle de pyridine
WO2009050232A1 (fr) * 2007-10-18 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes du cgrp
WO2009050235A1 (fr) * 2007-10-18 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes du cgrp
WO2009065919A2 (fr) * 2007-11-22 2009-05-28 Boehringer Ingelheim International Gmbh Nouveaux composés
WO2009065921A2 (fr) * 2007-11-22 2009-05-28 Boehringer Ingelheim International Gmbh Nouveaux composés

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MCLAUGHLIN M ET AL: "Efficient Access to Cyclic Ureas via Pd-Catalyzed Cyclization", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 8, no. 15, 20 July 2006 (2006-07-20), pages 3311 - 3314, XP002452928, ISSN: 1523-7060 *
PETER G. M. WUTS, THEODORA W. GREENE: "Greene's Protective Groups in Organic Synthesis (Fourth Edition)", 2006, JOHN WILEY & SONS, INC, XP002550751 *
TAKEMURA, SHOJI; MIKI, YASUYOSHI; KURODA, MASAYUKI; OZAKI, TOSHIYUKI; SUZUKI, ARITOMO;: "Synthesis and Selective Activity of Cholinergic Agents with Rigid Skeletons", CHEMICAL PHARMACEUTICAL BULLETIN, vol. 30, no. 3, 1982, pages 1084 - 1087, XP002550640 *

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