EP1904458A1 - Verfahren zur herstellung von chinazolinonderivaten - Google Patents

Verfahren zur herstellung von chinazolinonderivaten

Info

Publication number
EP1904458A1
EP1904458A1 EP06763658A EP06763658A EP1904458A1 EP 1904458 A1 EP1904458 A1 EP 1904458A1 EP 06763658 A EP06763658 A EP 06763658A EP 06763658 A EP06763658 A EP 06763658A EP 1904458 A1 EP1904458 A1 EP 1904458A1
Authority
EP
European Patent Office
Prior art keywords
group
general formula
compound
alkyloxy
benzyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06763658A
Other languages
German (de)
English (en)
French (fr)
Inventor
Albrecht Jacobi
Michael Schul
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP06763658A priority Critical patent/EP1904458A1/de
Publication of EP1904458A1 publication Critical patent/EP1904458A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3

Definitions

  • the invention relates to a process for the preparation of quinazolinone derivatives of the general formula (I)
  • Quinazoline derivatives known in the art WO 2004/108664 describes quinazolinone derivatives for the preparation of quinazoline derivatives, and their use for the treatment of tumor diseases, diseases of the lung and respiratory diseases.
  • the present invention solves the above-mentioned problem by the synthesis process described below, which is in comparison to the process described in WO 2004/108664 and known from the literature represents more suitable and more economical method especially for large-scale production.
  • the invention thus provides a process for the preparation of compounds of the general formula (I),
  • R 1 is a radical selected from the group consisting of benzyl, (R) - (+) - ⁇ ⁇ - phenylmethyl, 4-methoxybenzyl, 4,4'-dimethoxybenzhydryl, 2,4-dimethoxybenzyl, methoxymethyl, benzyloxymethyl , (2-methoxyethyl) oxymethyl, (2-trimethylsilylethyl) oxymethyl and pivaloyloxymethyl, preferably benzyl, (R) - (+) - 1-phenylmethyl, 4-
  • R 2 independently of one another, a radical selected from the group consisting of a hydrogen atom, a hydroxy group, a benzyl group, a Ci -3 alkyloxy group,
  • R 4 is a hydroxy, Ci -3 -alkyloxy-, -yl Cs-e-cycloalkyloxy, di- (Ci 3 alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1, Piperidine-1-yl, homopiperidine-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl, 3-oxa-8-azabicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, 4-Ci - 3- Alkyl-piperazine-1-yl or 4-Ci- 3- alkyl-homopiperazin-1-yl-group, wherein the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and Morpholinyl phenomenon each by one
  • R 5 is a radical selected from the group consisting of C 1 -C 5 -alkyl, benzyl, benzhydryl, p-nitrobenzyl and allyl, preferably methyl or ethyl, particularly preferably methyl, is hydrogenated in the presence of a hydrogenation catalyst with hydrogen, and
  • step (b) the compound of general formula (II) resulting from step (a)
  • Another object of the invention is a process for the preparation of compounds of general formula (I),
  • R to R can have the abovementioned meaning
  • R 2 and R 3 may have the abovementioned meaning, with a compound of the general formula
  • R 1 may be as defined above, and triethyl orthoformate or trimethyl orthoformate, preferably triethyl orthoformate, is reacted.
  • the compound of the formula (III) and the orthoformate may be simultaneously or sequentially added to the reaction mixture be added. Preferably, first the compound of formula and then the orthoformate is added to the reaction mixture.
  • Another object of the invention is a process for the preparation of the general formula (II), wherein R 2 and R 3 may have the meaning given,
  • R 2 and R 3 may have the meaning given, and R 5 is a radical selected from the group consisting of C 1 -C 8 -alkyl, benzyl, benzhydryl, p-nitrobenzyl and allyl, preferably methyl or ethyl, more preferably methyl , means
  • reaction temperature is in a range of from 20 ° C to 60 ° C, preferably from 30 to 55 ° C, particularly preferably from 45 to 50 ° C.
  • the hydrogen pressure is 1 bar to 100 bar, preferably 2 to 50 bar, more preferably 3 to 5 bar.
  • R 2 , R 3 are independently OH or OMe.
  • Another object of the invention are compounds according to the general formula (I),
  • R 1 -R 3 may have the meanings indicated, wherein
  • R 3 can not be OH when R 1 is a radical selected from the group consisting of benzyl, 2,4-dimethoxybenzyl, methoxymethyl, benzyloxymethyl, (2-methoxyethyl) oxymethyl, (2-trimethylsilylethyl) oxymethyl and pivaloyloxymethyl -, means
  • Another object of the invention are compounds according to the general formula (II),
  • Suitable solvents for the reaction are solvents, such as.
  • amides such as dimethylformanide, dimethylacetamide, N-methylpyrrolidinone or sulfoxides such.
  • dimethyl sulfoxide, sulfolane or primary alcohols such.
  • ethanol 1-propanol, 1-butanol, 1-pentanol or secondary alcohols such.
  • 2-propanol, 2-butanol or the isomeric secondary alcohols of pentane or Hexanes or tertiary alcohols such.
  • tert-butanol or nitriles such as acetonitrile or 2-propylnitrile.
  • Particularly preferred is the reaction in water.
  • the workup of the reactions is carried out by customary methods, for example via extractive purification steps or precipitation and crystallization procedures.
  • the compounds of the invention may be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid , or organic acids such as oxah fumaric, diglycolic or methanesulfonic acid.
  • alkyl groups and alkyl groups which are part of other groups are preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, for example: methyl, ethyl, n-propyl and isopropyl.
  • these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
  • the substituents are fluorine and chlorine. Most preferably, the substituent is chlorine.
  • all hydrogen atoms of the alkyl group may also be replaced.
  • saturated or unsaturated cycloalkyl radicals having 3 to 7 carbon atoms are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptyl, preferably
  • the substituent R 1 may be a radical selected from the group consisting of benzyl, (R) - (+) - 1-phenylmethyl, 4-methoxybenzyl, 4,4'-dimethoxybenzhydryl, 2,4-dimethoxybenzyl, methoxymethyl , Benzyloxymethyl, (2-methoxyethyl) oxymethyl, (2-trimethylsilylethyl) oxymethyl and pivaloyloxymethyl, preferably benzyl, (R) - (+) - 1-phenylmethyl-,
  • the substituent F? may represent a group selected from the group consisting of a hydrogen atom, a hydroxy group, a Ci -3 alkyloxy group, a C 2 -4-alkyloxy group which is substituted by a radical R 4, wherein
  • R 4 is a hydroxy, Ci -3 -alkyloxy-, 0 3 - 6 cycloalkyloxy, di- (Ci 3 alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1 -yl , Piperidine-1-yl, homopiperidine-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-Oxa-8-azabicyclo [3.2.1] oct-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, 4-Ci- 3- alkyl piperazin-1 -yl or 4-Ci-3 alkyl, homopiperazin-1-yl group is, while the above mentioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups in each case by one or two Ci -3
  • the substituent R 3 may represent a group selected from the group consisting of a hydrogen atom, a hydroxy group, a Ci -3 alkyloxy group, a
  • Alkyl groups may be substituted, a C 3 -7-Cycloalkyloxy- or C 3 - 7 -cycloalkyl-C 3 -alkyloxy distr, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy distr, and a tetrahydrofuranyl-Ci -3 alkyloxy or tetrahydropyranyl-Ci -3 alkyloxy group, particularly preferably a hydroxy group or a Ci -3 alkyloxy group, particularly preferably a hydroxy group or a methoxy group, most preferably a hydroxy group.
  • the compound of formula (IV) is commercially available and may, for. B. be obtained from Sigma-Aldrich. It can be prepared by methods known from the literature (P. Carpenter et al., J. Chem. Soc. Perkin Trans. 1 (1979), 103).
  • a compound of formula (IV) is hydrogenated to the compound of formula (II) (step 1).
  • step 1 2 to 5 equivalents, preferably 3.5 equivalents of a base, preferably potassium hydroxide, sodium hydroxide, are particularly preferred
  • Potassium hydroxide in a diluent for example water, ethanol, preferably stirred water.
  • a diluent for example water, ethanol, preferably stirred water.
  • compound (IV) 1 equivalent of compound (IV)
  • the reaction mixture is stirred under distillative removal of methanol for a further 3 to 5 hours, preferably 4 hours at reflux.
  • a pH of 8.5 to 10, preferably pH 9 is set with acetic acid.
  • the resulting mixture is in the presence of a hydrogenation catalyst, for example Pd / C, Raney nickel, preferably Pd / C in an amount of 0.1 to 10% by weight based on the use of the compound (IV), preferably 1 to 5 % By weight, particularly preferably 2-3% by weight, at a temperature of 20 ° C to 60 ° C, preferably 45 ° C to 55 ° C, particularly preferably 50 ° C and a hydrogen pressure of 1 bar to 100 bar, preferably 2 to 50 bar, particularly preferably 3 to 5 bar hydrogenated with hydrogen until the recording stop.
  • the resulting hydrogenation solution is treated under protective gas with acetic acid until a pH of 4 to 7, preferably pH 6 is reached.
  • compound (II) fails. It is isolated and then dried for 6 to 18 hours, preferably 12 hours at 30 ° C to 70 ° C, preferably 50 ° C in vacuo.
  • the compound (II) can be used without prior purification in step 2.
  • step 2 1 equivalent of compound (II) is suspended under protective gas in an organic solvent, for example ethanol, isopropanol, toluene, dioxane, acetonitrile, N-methyl-2-pyrrolidinone, triethyl orthoformate, trimethyl orthoformate, preferably ethanol, and heated to reflux with stirring , at
  • Reflux is 1 to 1.5 equivalents, preferably 1.05 equivalents of an amine, for example benzylamine, (/ : -) - (+) - 1-phenylmethylamine, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 4,4'-dimethoxybenzhydrylamine , preferably benzylamine added.
  • 2 to 10 equivalents, preferably 2.4 to 3 equivalents of a trialkyl orthoformate for example triethyl orthoformate, trimethyl orthoformate, preferably triethyl orthoformate are added at reflux.
  • the resulting reaction mixture is stirred for a further 2 to 10 hours, preferably 4 hours at reflux.
  • reaction mixture is heated to 10 ° C to 40 ° C, preferably 20 ° C and stirred for a further 10 to 120 minutes, preferably 30 minutes at this temperature.
  • the suspension is isolated and the compound (I) thus obtained is dried for 6 to 18 hours, preferably 12 hours at 30 ° C to 70 ° C, preferably 50 ° C in vacuo.
  • the compound 1 is commercially available and can, for. From Sigma-Aldrich (CAS No. 26791 -93-5). Level A:
  • the hydrogenation solution is filtered off and adjusted under inert gas with 31, 82 g (0.525 mol) of glacial acetic acid to pH 5.1.
  • the light green suspension is stirred for 30 min at RT, then cooled to 5 ° C and stirred for 30 min.
  • the compound 1 is commercially available and can, for. From Sigma-Aldrich (CAS No. 26791 -93-5).
  • the compound 1 is commercially available and can, for. From Sigma-Aldrich (CAS No. 26791 -93-5).
  • Stage A was carried out analogously to stage A in example 1.
  • Level B is a

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP06763658A 2005-07-04 2006-06-13 Verfahren zur herstellung von chinazolinonderivaten Withdrawn EP1904458A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06763658A EP1904458A1 (de) 2005-07-04 2006-06-13 Verfahren zur herstellung von chinazolinonderivaten

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05106036 2005-07-04
EP06763658A EP1904458A1 (de) 2005-07-04 2006-06-13 Verfahren zur herstellung von chinazolinonderivaten
PCT/EP2006/063127 WO2007003486A1 (de) 2005-07-04 2006-06-13 Verfahren zur herstellung von chinazolinonderivaten

Publications (1)

Publication Number Publication Date
EP1904458A1 true EP1904458A1 (de) 2008-04-02

Family

ID=35241213

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06763658A Withdrawn EP1904458A1 (de) 2005-07-04 2006-06-13 Verfahren zur herstellung von chinazolinonderivaten

Country Status (5)

Country Link
US (1) US20080319194A1 (ja)
EP (1) EP1904458A1 (ja)
JP (1) JP2009500306A (ja)
CA (1) CA2627590A1 (ja)
WO (1) WO2007003486A1 (ja)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143049A1 (en) * 2008-05-19 2009-11-26 Schering Corporation Bicyclic heterocycle derivatives and use thereof as gpr119 modulators
CN103524431B (zh) * 2013-09-24 2016-01-13 西安交通大学 3-苄基-4-喹唑啉酮类化合物及其合成方法和应用
EP4069252A4 (en) * 2019-12-02 2024-01-10 Academia Sinica PDI-A4 INHIBITORS AND THEIR USE TO INHIBIT BETA CELL PATHOGENESIS AND TREAT DIABETES

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9707800D0 (en) * 1996-05-06 1997-06-04 Zeneca Ltd Chemical compounds
DE69838172T2 (de) * 1997-08-22 2008-04-10 Astrazeneca Ab Oxindolylchinazolinderivate als angiogenesehemmer
US6734201B1 (en) * 2003-06-02 2004-05-11 Allergan, Inc. 8-Azaprostaglandin carbonate and thiocarbonate analogs as therapeutic agents
DE10326186A1 (de) * 2003-06-06 2004-12-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US20070032508A1 (en) * 2003-09-16 2007-02-08 Bradbury Robert H Quinazoline derivatives as tyrosine kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007003486A1 *

Also Published As

Publication number Publication date
US20080319194A1 (en) 2008-12-25
CA2627590A1 (en) 2007-01-11
JP2009500306A (ja) 2009-01-08
WO2007003486A1 (de) 2007-01-11

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