WO2001019805A1 - Composes heterocycliques et procede de preparation de ces derniers - Google Patents

Composes heterocycliques et procede de preparation de ces derniers Download PDF

Info

Publication number
WO2001019805A1
WO2001019805A1 PCT/JP2000/006140 JP0006140W WO0119805A1 WO 2001019805 A1 WO2001019805 A1 WO 2001019805A1 JP 0006140 W JP0006140 W JP 0006140W WO 0119805 A1 WO0119805 A1 WO 0119805A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
atom
compound
derivative
Prior art date
Application number
PCT/JP2000/006140
Other languages
English (en)
Japanese (ja)
Inventor
Taihei Yamane
Original Assignee
Takeda Chemical Industries, Ltd.
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 Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU68758/00A priority Critical patent/AU6875800A/en
Publication of WO2001019805A1 publication Critical patent/WO2001019805A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a heterocyclic compound useful as an intermediate for the synthesis of pharmaceuticals and a method for producing the same.
  • A is an optionally substituted aromatic group
  • X is a chlorine atom or a bromine atom
  • Y is a sulfur atom or an oxygen atom
  • R and R ' are the same or different and are a hydrogen atom or an alkyl group. Or a cycloalkyl group, and R and R 'may combine to form a ring.
  • compounds represented by the formula (I) those in which Y is a sulfur atom (hereinafter referred to as compound (II-1)) are compounds useful as intermediates in the synthesis of pharmaceuticals, and have an anticancer effect in WO97 / 00249.
  • JP-A-62-178590, pp. 15-22 discloses a method for producing compound (II-1) by the following method. That is, (1) Bromine of keto-butyric acid ester is reacted with the derived keto-i3-bromobutyric acid ethyl ester and thiobenzamide, leading to 2-phenylthiazole substituted with an ethoxycarbonyl group at the 4-position and a methyl group at the 5-position. 2 This is subjected to a reduction reaction with lithium aluminum hydride or the like, and 3 A halogenation reaction with thionyl bromide or the like is performed to obtain the compound. is there.
  • the raw material a-ketobutylate ethyl ester in (1) can be obtained from Helvetica Chimica Acta, Vol. 33, p. 725 (1950;) or Journal of American Chemical Society, 76 Volume, p. 5796 (1954).
  • Compound (I) in which Y is an oxygen atom (hereinafter, referred to as compound (II-2)) is also a compound useful as a synthetic intermediate of a drug, and is also useful in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry), Vol. 39, p. 237 (1996), USP5468762, USP5532256, describe a pharmaceutical (eg, a therapeutic agent for diabetes, etc.) using the compound (II-2) and a method for producing the same.
  • a pharmaceutical eg, a therapeutic agent for diabetes, etc.
  • a method of reacting and synthesizing 4-bromomethyl-5-methyl-2-phenyloxazole is described, but several steps are required to synthesize 5-methyl-4-methylene-2-phenyl-4,5 dihydrooxazole.
  • the yield is low (45% from the starting material), and it is not suitable for industrial production because it undergoes an unstable terminal alkyne compound as an intermediate.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, unexpectedly reacting the compound (I) or a salt thereof with an N-cycloamide amide derivative or an N-bromoamide derivative.
  • Compound (II) can be synthesized in as few steps and with high yield, and it is highly safe, and a method for industrially producing compound (II) has been found.
  • the present inventors have found that the novel compound represented by) is useful as a synthetic intermediate for pharmaceuticals such as oxazolidinedione derivatives having hypoglycemic and blood lipid lowering effects, and completed the present invention.
  • Y is a sulfur atom or an oxygen atom
  • A is an optionally substituted aromatic group
  • R and R ′ are the same or different and represent a hydrogen atom, an alkyl group or a cycloalkyl group; ' May combine to form a ring.
  • the compound or a salt thereof is reacted with an N-clo ⁇ amide derivative or an N-bromoamide derivative.
  • ⁇ represents a sulfur atom or an oxygen atom; ⁇ represents an aromatic group which may be substituted; R and R ′ are the same or different and represent a hydrogen atom, an alkyl group or a cycloalkyl group; ' May combine to form a ring. And a salt thereof with an N-cloamide amide derivative or an N-bromoamide derivative to obtain a compound of the formula (II)
  • Za represents a divalent C ⁇ aliphatic hydrocarbon group
  • L and M each represent a hydrogen atom or may be bonded to each other to form a bond.
  • the compound is reacted with a compound represented by the formula:
  • Examples of the aromatic group in the “optionally substituted aromatic group” represented by ⁇ A represented by ⁇ A with respect to the compound represented by or a salt thereof include an aromatic hydrocarbon group and an aromatic heterocyclic group.
  • the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., an aryl group and the like), such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable, and phenyl is particularly preferable.
  • aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4 monooxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl
  • the aromatic group may have 1 to 5, preferably 1 to 3, substitution groups at substitutable positions.
  • substituents include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group, and an aromatic heterocyclic group.
  • aliphatic hydrocarbon group examples include linear or branched aliphatic carbon hydrocarbon radical, for example C i _ 1 5 alkyl group, c 2 _ 1 5 alkenyl group having 1 to 15 carbon atoms, c 2 - 1 5 alkynyl group, C 3 —i 5 alkenyl group and the like.
  • alkyl group examples include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Examples include ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, and decyl.
  • alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl
  • Examples include ethy
  • alkynyl group examples include an alkynyl group having 2 to 2 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
  • alkadienyl group examples include an alkadienyl group having 4 to 10 carbon atoms, such as butadienyl, 1,3-pentenyl, 1,4-pentadienyl, and 1,5-hexadienyl.
  • alkadienyl group having 4 to 10 carbon atoms such as butadienyl, 1,3-pentenyl, 1,4-pentadienyl, and 1,5-hexadienyl.
  • the alicyclic hydrocarbon group includes a saturated or unsaturated alicyclic hydrocarbon having 3 to 12 carbon atoms.
  • Hydrogen group for example c 3 _ 1 2 cycloalkyl group, c 3 - 1 2 cycloalkenyl group, c 5 - i 2 cycloalkadienyl group and the like.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctel, bicyclo [2.2.1] heptyl, bicyclo [ 2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, and the like.
  • cycloalkenyl group examples include a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene- 1 fyl, 3-cyclohexene-1-yl and the like.
  • cycloalkadienyl group examples include cycloalkadienyl groups having 5 to 10 carbon atoms, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexadiene-11-yl. And 2,5-cyclohexadiene-1-yl.
  • aromatic hydrocarbon group examples include those similar to the aromatic hydrocarbon group exemplified as the ⁇ aromatic hydrocarbon group '' in the ⁇ optionally substituted aromatic group '' represented by A. No.
  • an “aromatic hydrocarbon group” as a substituent of the “optionally substituted aromatic group” represented by A preferably a phenyl group, a naphthyl group
  • an aliphatic hydrocarbon group substituted with 1 to 3 identical or different aromatic hydrocarbon groups selected from phenyl groups for example, the “optionally substituted aromatic group represented by A” And the like as the "aliphatic hydrocarbon group” as a substituent of the "group”
  • aromatic monoaliphatic hydrocarbon group examples include an aromatic monoaliphatic hydrocarbon group having 7 to 19 carbon atoms, such as benzyl, phenylethyl, ⁇ Methylbenzyl, trityl Benzhydryl, cinnamyl, styryl, naphthyl propylenyl, anthryl propylenyl, naphthylethenyl, anthryl ethenyl, 4-phenylphenyl, 4-naphthyl butadenyl, 4-anthrylbutenyl, 4-phenylbutynyl, 4-naphthylbutyl Nil, 4 Examples include butyryltin, 3-phenylpropynyl, 3-naphthylpropynyl, 3-anthrylpropynyl, 2-phenylethynyl, 2-naphthynylethynyl, 2-anthrylethyny
  • aromatic heterocyclic group examples include those similar to the aromatic heterocyclic group exemplified as the ⁇ aromatic heterocyclic group '' in the ⁇ optionally substituted aromatic group '' represented by A. No.
  • non-aromatic heterocyclic group examples include those in which all or some of the double bonds of the aromatic monocyclic heterocyclic group represented by A are saturated, and preferable examples thereof include, for example, oxylanil, Azetidinyl, oxetanyl, cesinyl, 1-pyrrolidinyl, tetrahydrofuryl, tetrahydroviranyl, morpholinyl, thiomolphorinyl, 1-piperazinyl, 1-hexamethyleneiminyl, piperidino, morpholino, thiomorpholino, oxazolidin-1-3-yl , Thiazolidine-1 -yl, imidazolidine-1- ⁇ -yl, 2-oxoimidazolidin-1 -yl, 2,4-dioxoimidazolidin-3-yl, 2,4 zio Oxygen atoms and sulfur atoms other than carbon atoms as ring-constituting atoms such as ring
  • halogen atom examples include fluorine, chlorine, bromine and iodine, among which fluorine and chlorine are preferred.
  • Examples of the optionally substituted amino group include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and a cycloalkyl having 3 to 10 carbon atoms.
  • substituted amino group examples include, for example, methylamino, dimethylamino, ethylamino, acetylamino, propylamino, dipropylamino, butylamino, dibutylamino, diarylamino, cyclohexylamino, and aceamino.
  • Examples of the optionally substituted acyl group include an acyl group having 1 to 13 carbon atoms, specifically, a formyl group, an alkyl group having 1 to 10 carbon atoms, and a carbon atom having 3 to 10 carbon atoms. Cycloalkyl group, alkenyl group having 2 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbon atoms, alkynyl group having 2 to 10 carbon atoms, carbon number? To 19 aralkyl groups, 6 to 12 carbon atoms, or an aryl group or an aromatic heterocyclic group (eg, the same as the aromatic heterocyclic group represented by A, preferably chenyl, furyl, pyridyl) And a carbonyl group.
  • aralkyl groups 6 to 12 carbon atoms, or an aryl group or an aromatic heterocyclic group (eg, the same as the aromatic heterocyclic group represented by A, preferably chenyl, furyl, pyridyl
  • Preferred examples of the acryl group include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, hepnoyl, octanoyl, cyclobutane carbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptane carbonyl Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.
  • the acyl group may have 1 to 3 substituents at substitutable positions.
  • substituents include an alkyl group having 1 to 3 carbon atoms and an alkyl group having 1 to 3 carbon atoms.
  • examples include an alkoxy group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a hydroxy group, an amino group, and the like.
  • the substituted hydroxy group includes, for example, an optionally substituted alkoxy group, a cycloalkyloxy group, an alkenyloxy group, a cycloalkenyloxy group, an aralkyloxy group, Examples include an acyloxy group, an aryloxy group and a heteroaryloxy group.
  • alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and neopentyloxy. , Hexyloxy, heptyloxy, octyloxy, nonyloxy and the like.
  • cycloalkyloxy group include a cycloalkyloxy group having 3 to 10 carbon atoms, for example, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • alkenyloxy group examples include an alkenyloxy group having 2 to 10 carbon atoms, such as aryloxy, crotyloxy, 2-pentenyloxy, and 3-hexenyloxy.
  • cycloalkenyloxy group examples include a cycloalkenyloxy group having 3 to 10 carbon atoms, for example, 2-cyclo-pentene-11-yloxy, 3-cyclopentene-1-yloxy, 2-cyclohexene-11. Yloxy, 3-cyclohexene-1-yloxy and the like.
  • aralkyloxy group examples include an aralkyloxy group having 7 to 19 carbon atoms, such as benzyloxy, phenylethyloxy, ⁇ -methylbenzyloxy, triteroxy, benzhydryloxy, and the like, preferably phenyl-C. And 4- alkyloxy.
  • acyloxy group examples include an alkoxy group having 1 to 13 carbon atoms, and more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy, etc.) and the like.
  • alkanoyloxy group having 2 to 4 carbon atoms
  • aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
  • heteroaryl of the heteroaryloxy group examples include those similar to the aromatic heterocyclic group represented by the above ⁇ .
  • Preferred examples of the heteroaryloxy group include 2-pyridyloxy and 3-pyridyloxy. Besides, 2-imidazolyloxy, 1,2,4-triazole-5-yloxy and the like can be mentioned.
  • the alkoxy group, cycloalkyloxy group, alkenyloxy group, cycloalkenyloxy group, aralkyloxy group, acyloxy group, aryloxy group and heteroaryloxy group each have 1 to 2 substituents at substitutable positions.
  • a substituent may be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a linear or branched hydrocarbon group having 1 to 4 carbon atoms.
  • examples of the substituted thiol group include an optionally substituted alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, aralkylthio, acrylsil, arylthio, and heteroaryl. Thio and the like.
  • alkylthio group examples include an alkylthio group having 1 to 10 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, Isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, octylthio, nonylthio and the like.
  • alkylthio group having 1 to 10 carbon atoms for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, Isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexy
  • cycloalkylthio group examples include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • alkenylthio group examples include an alkenylthio group having 2 to 10 carbon atoms, such as arylthio, crotylthio, 2-pentenylthio, and 3-hexenylthio.
  • cycloalkenylthio group examples include a cycloalkenylthio group having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-ylthio, 3-cyclopentene-11-ylthio, 2-cyclohexene- Examples include 1-ylthio and 3-cyclohexene-1 ⁇ -fluoro.
  • Ararukiruchio group Ararukiruchio group having a carbon number of 7 to 9, for example base Njiruchio, phenylene Ruechiruchio, shed one methylbenzylthio, Torichi Lucio, benzhydryl Lucio etc., preferably, phenyl - 4 alkylthio or the like No.
  • acylthio group examples include an acylthio group having 1 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
  • arylthio group examples include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
  • the heteroaryl of the heteroarylthio group includes the same as the aromatic heterocyclic group represented by A, and preferable examples of the heteroarylthio group include 2-pyridylthio, 3-pyridylthio and the like. 2-imidazolylthio, 1,2,4-triazo-1-yl 5-ylthio and the like.
  • the alkylthio group, the cycloalkylthio group, the alkenylthio group, the cycloalkenylthio group, the aralkylthio group, the acylthio group, the arylthio group and the heteroarylthio group have one or two substituents at substitutable positions.
  • substituents include the aforementioned alkoxy group, cycloalkyloxy group, alkenyloxy group, cycloalkenyloxy group, aralkyloxy group, acyloxy group, aryloxy group and heteroaryloxy group. And the same substituents as mentioned above.
  • the esterified hydroxyl group may be a group represented by the formula: —COOR 3 (where R 3 is an optionally substituted hydrocarbon group or a substituted And an alkoxycarbonyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxylproponyl, butoxycarbonyl, etc.), and a carbon number of 2 to 5 carbon atoms. 8 to: 10 aralkyloxycarbonyl groups (eg, benzyloxycarbonyl, etc.), 1 to 2 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms. And a luponyl group (eg, phenoxycarbonyl, p-tolyloxycarbonyl, etc.).
  • R 3 is an optionally substituted hydrocarbon group or a substituted
  • an alkoxycarbonyl group having 2 to 5 carbon atoms e.g., methoxycarbonyl, eth
  • the amidated carboxyl group is represented by the formula: —CO NiR ⁇ iR 2 ) (wherein R 1 and R 2 are the same or different, and represent a hydrogen atom, And R 1 and R 2 may be bonded to each other to form a ring together with an adjacent nitrogen atom.) Groups.
  • the hydrocarbon group in the optionally substituted hydrocarbon group represented by R 1 R 2 and R 3 is an aliphatic hydrocarbon group exemplified as a substituent in the aromatic group represented by A.
  • alicyclic hydrocarbon groups, aromatic hydrocarbon groups and aromatic monoaliphatic hydrocarbon groups may have 1 to 3 substituents at substitutable positions. Examples of such substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms.
  • the ring formed by R 1 and R 2 together with the adjacent nitrogen atom by bonding to each other among the non-aromatic heterocyclic groups exemplified as the substituent for the aromatic group represented by A, at least one nitrogen atom Including those that may contain oxygen atoms (eg, piperazino, piperidino, morpholino, thiomoriforno, etc.) No.
  • the heterocyclic group in the optionally substituted heterocyclic group represented by R 1 R 2 and R 3 includes an aromatic heterocyclic group exemplified as an aromatic group represented by A, and a 'non-aromatic heterocyclic group'. And the like.
  • the heterocyclic group may have 1 to 3 substituents at substitutable positions, such as a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), Examples thereof include an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. '
  • the substituent of the aromatic group represented by A is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic monoaliphatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group.
  • substituents include, for example, an alkyl group having 1 to 6 carbon atoms, An alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.), an aromatic heterocyclic group (e.g., phenyl, furyl, pyridyl, oxazolyl) , Thiazolyl, etc.), non-aromatic heterocyclic groups (e.g., tetrahydrofuryl, morpholino, thiomorpholino, piberidino, pyrrolidinyl, piperazinyl, etc.), aralkyl groups having 7 to 19 carbon atoms, amino groups, having 1 to 4 carbon atoms Amino groups, amidino groups, for example, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group
  • A is preferably an optionally substituted aromatic hydrocarbon group, and more preferably phenyl, 1-naphthyl and 2-naphthyl. A is particularly preferably phenyl.
  • R and R ' are the same or different and each represent a hydrogen atom, an alkyl group or a cycloalkyl group, or R and R' combine to form a ring with an adjacent carbon atom. May be.
  • alkyl group and the cycloalkyl group include those similar to the alkyl group and the cycloalkyl group exemplified as the ⁇ aliphatic hydrocarbon group '' in the substituent of the aromatic group represented by A.
  • an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms are preferable.
  • R and R ′ are bonded to each other to form a ring with adjacent carbon atoms, for example, a cycloalkane having 3 to 8 carbon atoms (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexane, Heptane, cyclooctane, etc.).
  • a cycloalkane having 3 to 8 carbon atoms eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexane, Heptane, cyclooctane, etc.
  • R and R ' are preferably
  • R or R ' is a hydrogen atom
  • R and R ' may be the same or different and each is a hydrogen atom or an alkyl group, and R and R, may combine to form a ring;
  • R and R ' are the same or different and are a hydrogen atom, an alkyl group or a cycloalkyl group;
  • Compound (I) in which Y is a sulfur atom can be obtained by a method known per se, for example, BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE , Vol. 12, p. 4523 (1967), or a similar method thereof.
  • Compound (I) wherein Y is an oxygen atom (hereinafter referred to as compound (1-2))
  • compound (1-2) is an oxygen atom
  • compound (II) or a salt thereof can be obtained by reacting compound (I) or a salt thereof with an N-chloroamide derivative or an N-bromoamide derivative.
  • the equivalent ratio of the compound (I) [compound (1-1), compound (1-2)] and the N-chloroamide derivative or N-bromoamide derivative used in the reaction is usually 2: 1 to 1: 2.
  • Compound (I) [Compound (1-1), compound (1-3 ⁇ 4) or compound (II) may be a suitable salt with an inorganic acid or an organic acid. When the compound has an acidic group, it may be a suitable salt with an inorganic base or an organic base.
  • Suitable examples of salts with inorganic or organic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, Examples include salts with malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • salts of organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine. And the like.
  • the N-clomouth amide derivative or N is directly introduced into the reaction system without neutralization.
  • Promomide derivative may be added, or N-chloro Mouth amide derivatives or N-bromoamide derivatives may be added.
  • the base used for neutralization is not particularly limited, but hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide, and calcium hydroxide; potassium hydride, sodium hydride, hydrogenation Metal hydrides such as lithium and calcium hydride; metal amides such as lithium amide, sodium amide and potassium amide; metal alkoxides such as sodium, potassium and lithium methoxide, ethoxide and tert-butoxide; triethylamine, trimethylamine, pyridine
  • Organic bases such as n-butyllithium, methyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, and alkylmetals such as lithium diisopropylamide; preferably triethylamine, trimethylamine, Organic base such as pyridine
  • the amount of these bases varies depending on the type of the base, the solvent used, and the reaction temperature.
  • the amount is usually 0.5 to 2 equivalents (50 to 200 mol%) with respect to the compound (I), and is preferable. Is from 1 to 1.3 equivalents (100 to 130 mol%).
  • extraction and washing may be performed about 1 to 5 times with, for example, water / organic solvent (eg, ethyl acetate, toluene, methylene chloride, etc.), or in one step without such treatment. You may go.
  • the amount of these acids to be used varies depending on the kind of the acid, the solvent used and the reaction temperature, but is usually 0.5 to 2 equivalents (50 to 200 mol%), preferably 1 to 2 based on compound (I). : 1.3 equivalents (100 to 130 mol%).
  • extraction and washing may be performed about 1 to 5 times with, for example, water / organic solvent (eg, ethyl acetate, toluene, methylene chloride, etc.). It may be performed in stages.
  • the N-cycloamide derivative or the N-bromoamide derivative is substituted with one or two optionally substituted acyl groups and a chlorine atom or a bromine atom. It means a derivative having a structure containing a substituted amino group, and the optionally substituted acyl group is defined by the following definitions. Further, the acyl groups may be bonded to each other to form a cyclic amide derivative or imide derivative together with an adjacent nitrogen atom.
  • N-chloroamide derivative or N-bromoamide derivative for example, N-chloroamide derivative or N-bromoamide derivative
  • N-chloroamide derivative or N-bromoamide derivative also include a compound obtained by condensing two identical or different compounds (VI).
  • acyl group in the optionally substituted acyl group examples include formyl and optionally substituted hydrocarbon groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl).
  • cycloalkenyl group ethynyl, 1-propynyl, 2_propynyl, 1-butynyl, 2-butenyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- Alkynyl groups having 2 to 10 carbon atoms, such as hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, and 1-octynyl; carbons such as benzyl, phenylethyl, naphthylmethyl, and naphthylethyl An aralkyl group having the number of 7 to 19; an aryl group having a carbon number of 6 to 12 such as phenyl and naphthyl, or an aromatic heterocyclic group (eg, the same as the aromatic complex
  • acyl group those having 1 to 13 carbon atoms are preferable, and preferable examples thereof include, for example, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, vivaloyl, hexanoyl, heptanyl, octanoyl, and cyclobutane-potionyl. Cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptane-potassium, crotonyl, 2-cyclohexene-potassium, benzoyl, nicotinoyl, isonicotinoyl and the like.
  • the Ashiru group may have 1 to 3 substituents at substitutable positions, substituents such as this, for example, C ⁇ - 6 alkyl group, an alkoxy group, a halo gen atom (e.g. , Fluorine, chlorine, bromine, iodine, etc.), nitro group, C- 6 haloalkyl group, 6 haloalkoxy group, hydroxy group, amino group and the like.
  • substituents such as this, for example, C ⁇ - 6 alkyl group, an alkoxy group, a halo gen atom (e.g. , Fluorine, chlorine, bromine, iodine, etc.), nitro group, C- 6 haloalkyl group, 6 haloalkoxy group, hydroxy group, amino group and the like.
  • a halo gen atom e.g. , Fluorine, chlorine, bromine, iodine, etc.
  • nitro group e.g
  • examples of the divalent hydrocarbon group represented by tau zeta 2 and zeta 3 for example, "aromatic group” possess the "optionally substituted aromatic group” represented by ⁇ described above
  • aromatic group possess the "optionally substituted aromatic group” represented by ⁇ described above
  • aliphatic hydrocarbon group”, “alicyclic hydrocarbon group”, “aromatic hydrocarbon group” and “aromatic monoaliphatic hydrocarbon group” exemplified as the substituents which may be substituted Examples include a group formed by removing one hydrogen atom. Among them, a linear or branched alkylene having 2 to 4 carbon atoms (eg, —CH 2 —CH 2 —,
  • Cycloalkenylene having 3 to 6 carbon atoms eg, 1,2-cyclohexylene
  • phenylene eg, o-phenylene
  • N-chloro amide derivative examples include N-chlorosuccinimide, 1,3-dichloro-1,5,5-dimethylhydantoin, N-chloroacetamide, N-chlorofuramide, N-chloromaleimide and the like. More preferred is N-chlorosuccinimide.
  • N-bromoamide derivative examples include N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide, N-bromophthalimide, N-bromomaleimide and the like. More preferred is N-bromosuccinimide.
  • This reaction may be performed in the presence of a radical initiator.
  • Radical initiators include heat, benzoyl peroxide, azobis compounds (eg, 2,2'-azobis (2,4-valeronitrile), 2,2'-azobis (2-methylbutyronitrile), azobisiso Valeronitrile, 2,2'-azobisisobutyronitrile and the like.
  • Peracid Benzoyl and azobis compounds are used in an amount of 0.1 to 100 ° / N-cloamide or N-bromoamide derivative. (w / w), preferably 0.1 to 10% (w / w).
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • alcohols such as methyl alcohol, ethyl alcohol, and denatured alcohol
  • ketones such as acetone and methyl ethyl ketone
  • sulfoxides such as dimethyl sulfoxide
  • Ethers such as mono-ter, diisopropyl ether, tert-butyl methyl ether, anisol, tetrahydrofuran, and dioxane
  • nitriles such as propionitryl and acetonitrile
  • aromatic hydrocarbons such as benzene; dichloromethane
  • Halogenated hydrocarbons such as 1,2-dichloroethane and benzene
  • esters such as ethyl acetate
  • N N-dimethylformamide, acetoamide, ⁇ , ⁇ -dimethylacetoamide, 1-methyl-2-amine Pyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • Solvents are preferably solvents other than halogenated hydrocarbons such as carbon tetrachloride, for example, ketones such as acetone and methylethyl ketone; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; Esters: Amides such as ⁇ , ⁇ -dimethylformamide.
  • the solvent is more preferably a ketone such as acetone or methyl ethyl ketone; an ether such as tetrahydrofuran or dioxane; a nitrile such as acetonitrile; or an ester such as ethyl acetate.
  • nitriles are preferred, and acetonitrile is most preferred.
  • These solvents may be used alone or in combination of two or more at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to 100-fold (vZw), preferably 1- to 20-fold (vZw), relative to compound (I).
  • the reaction temperature varies depending on the type of the base and the solvent used, but may be in the range of 1 to 78 ° C to the boiling point of the solvent (for example, ⁇ 78 ° C to 100 ° C), preferably 0 ° C to the boiling point of the solvent. Range (eg, 0 to 100 ° C).
  • the reaction time is generally 0.5 hour to 24 hours, preferably 1 hour to 8 hours.
  • the compound ( ⁇ ⁇ ) can be isolated from the reaction mixture by, for example, mixing with the reaction solvent used and a solvent having low solubility of the compound ( ⁇ ). It may be crystallized by adding it to the compound and then isolated.
  • the reaction solvent is a solvent that does not mix with water
  • the reaction mixture may contain water / organic solvent (eg, ethyl acetate, toluene, methylene chloride, etc.) After extraction and washing about 1 to 5 times, the solvent may be removed, for example, by concentration under reduced pressure.
  • the compound (II) may be used for the next reaction after isolation, or may be used for the next reaction as a reaction mixture without isolation. Further, the solution obtained by extracting and washing the reaction mixture may be used for the next reaction as it is or after being appropriately concentrated under reduced pressure.
  • the compound (II) can be purified by a method known per se, such as recrystallization and purification using silica gel column chromatography.
  • Za represents a divalent Ci- 7 aliphatic hydrocarbon group
  • L and M each represent a hydrogen atom or may be bonded to each other to form a bond.
  • A is preferably _ 4 alkylene, more preferably - (CH 2) 2 _.
  • L and M may each represent a hydrogen atom or combine with each other to form a bond.
  • L and M are preferably a hydrogen atom.
  • compound (IV) As the salt of the compound represented by the formula (IV) (hereinafter referred to as compound (IV)) and the compound represented by the formula (V) (hereinafter referred to as compound (V)), a salt of the compound (I) And the salts with the inorganic acids, organic acids, inorganic bases and organic bases exemplified above.
  • the reaction of compound (II) or a salt thereof with compound (IV) or a salt thereof is carried out in a suitable solvent in the presence of a base.
  • Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium hydrogen carbonate; amines such as pyridine, triethylamine, ⁇ , ⁇ -dimethylaniline; potassium hydride, sodium hydride, and the like.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; ketones such as acetone and 2-butanone; amides such as ⁇ , ⁇ -dimethylformamide. And sulfoxides such as dimethyl sulfoxide; and halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. These solvents may be used alone or as a mixture of two or more at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • ketones such as acetone and 2-butanone
  • amides such as ⁇ , ⁇ -dimethylformamide.
  • the reaction temperature is usually from 150 ° C. to 150 ° C., preferably from ⁇ 10 t: to 100.
  • the reaction time is usually 0.5 hour to 30 hours.
  • Compound (V) or a salt thereof obtained by this reaction can be purified by a method known per se, such as recrystallization or purification using silica gel column chromatography.
  • the compound (V) or a salt thereof thus obtained has an excellent pharmaceutical effect (eg, a blood glucose and blood lipid lowering effect).
  • a blood glucose and blood lipid lowering effect e.g, a blood glucose and blood lipid lowering effect.
  • the method described in EP-A-612, 743, etc. was used. Can be used.
  • room temperature means about 20 to about 30.
  • solvent ratio As used herein, room temperature means about 20 to about 30.
  • the mixture was dried under vacuum at 40 for 2 hours to obtain 2.45 g (yield: 82.7%) of a target substance as a yellowish white solid.
  • the crystals were heated in 17.2 ml of acetonitrile while hot (40-5 ( ⁇ dissolved and allowed to cool). 17.2 ml of water was added dropwise, and the mixture was aged for 1 hour under ice-cooling. After drying under vacuum at 40 ° C for 2 hours, 2.31 g (yield: 78.0%) of the desired product was obtained as yellow crystals.
  • the present invention relates to intermediates of pharmaceuticals such as oxazolidinedione derivatives (for example, compounds represented by the formula (V)) having a blood glucose and blood lipid lowering action disclosed in EP-A-612, 743 and the like.
  • oxazolidinedione derivatives for example, compounds represented by the formula (V)
  • This is an industrially advantageous production method in which a heterocyclic compound useful as a compound can be obtained in a small number of steps in a high yield as compared with a known production method.
  • the compounds represented by the formula (III) are novel novel compounds useful as synthetic intermediates of pharmaceuticals such as oxazolidinedione derivatives having blood glucose and blood lipid lowering effects. Compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

On décrit un procédé de préparation, avantageux sur le plan industriel, de composés de formule (II) ou de sels de ces derniers, qui se caractérise par le fait qu'on fait réagir un composé de formule (I) ou un sel d'un tel composé avec un dérivé N-chloroamide ou un dérivé N-bromoamide. Dans la formule (I) Y représente soufre ou oxygène; A représente un groupe aromatique facultativement substitué; et R et R' représentent chacun indépendamment hydrogène, alkyle ou cycloalkyle ou bien R et R' peuvent être réunis pour former un anneau); dans la formule (II) X représente chloro ou bromo et les autres symboles sont chacun tels que définis ci-dessus.
PCT/JP2000/006140 1999-09-10 2000-09-08 Composes heterocycliques et procede de preparation de ces derniers WO2001019805A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68758/00A AU6875800A (en) 1999-09-10 2000-09-08 Heterocyclic compounds and process for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/257540 1999-09-10
JP25754099 1999-09-10

Publications (1)

Publication Number Publication Date
WO2001019805A1 true WO2001019805A1 (fr) 2001-03-22

Family

ID=17307711

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/006140 WO2001019805A1 (fr) 1999-09-10 2000-09-08 Composes heterocycliques et procede de preparation de ces derniers

Country Status (2)

Country Link
AU (1) AU6875800A (fr)
WO (1) WO2001019805A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US7122555B2 (en) 2003-06-20 2006-10-17 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives
US7718666B2 (en) 2003-06-20 2010-05-18 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62178590A (ja) * 1986-01-30 1987-08-05 Toyama Chem Co Ltd 新規なチアゾール化合物またはその塩
US5468762A (en) * 1994-05-18 1995-11-21 American Home Products Corporation Azolidinediones as antihyperglycemic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62178590A (ja) * 1986-01-30 1987-08-05 Toyama Chem Co Ltd 新規なチアゾール化合物またはその塩
US5468762A (en) * 1994-05-18 1995-11-21 American Home Products Corporation Azolidinediones as antihyperglycemic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HING-KWOK HUNG ET AL.: "The total synthesis of 4-deoxy-D,L-daunosamine", CAN. J. CHEM., vol. 56, 1978, pages 638 - 644, XP002934384 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US7314884B2 (en) 2001-10-26 2008-01-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US7803819B2 (en) 2001-10-26 2010-09-28 Hoffmann-La Roche Inc. DPP IV inhibitors
US7122555B2 (en) 2003-06-20 2006-10-17 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives
US7718666B2 (en) 2003-06-20 2010-05-18 Hoffmann-La Roche Inc. Pyrido [2,1-a] isoquinoline derivatives

Also Published As

Publication number Publication date
AU6875800A (en) 2001-04-17

Similar Documents

Publication Publication Date Title
JP3328720B2 (ja) ２，４−オキサゾリジンジオン誘導体、その製造法およびそれを含んでなる医薬組成物
ES2248107T3 (es) Benciliden-tiazolidindionas y analogos y su utilizacion en el tratamiento de la diabetes.
KR920002131B1 (ko) 타아졸리딘디온 유도체의 제조방법
CN102702082B (zh) 2-取代的-5-((1-烷硫基)烷基)吡啶的制备方法
US20060148858A1 (en) 1, 2-Azole derivatives with hypoglycemic and hypolipidemic activity
KR100292363B1 (ko) 티아졸리딘디온유도체,그의제조방법및용도
WO2009081970A1 (fr) Procédé pour la fabrication d'un dérivé de pyridine substitué par un hétérocycle
EP0643050A1 (fr) Dérivés d'oxazolidinedione et leur utilisation comme agents hypoglycémiques
KR20050056908A (ko) 3-히드록시-엔,1,6-트리알킬-4-옥소-1,4-디히드로피리딘-2-카르복스아미드의 제조방법
WO2001019805A1 (fr) Composes heterocycliques et procede de preparation de ces derniers
JP5167242B2 (ja) 複素環式誘導体の製造方法
JP2012514630A5 (fr)
JPH044312B2 (fr)
JP2005035933A (ja) 含窒素縮合複素環化合物の製造方法
JP2001151763A (ja) 複素環化合物およびその製法
WO2001032608A1 (fr) Procédé de préparation de dérivés d'acide oxyminoalcanoïque
CN106279144B (zh) 一锅法制备吡格列酮杂质c的方法
JP3466273B2 (ja) テトラゾール誘導体、その製造法およびそれを含んでなる医薬
JPS6257635B2 (fr)
JP3300869B2 (ja) ２，４−オキサゾリジンジオン誘導体、その製造法およびそれを含んでなる医薬組成物
JP3722855B2 (ja) ２，４−オキサゾリジンジオン誘導体およびそれを含んでなる医薬
JP2000212174A (ja) ２，４−オキサゾリジンジオン誘導体、その製造法およびそれを含んでなる医薬組成物
JP3880108B2 (ja) ２，４−オキサゾリジンジオン誘導体、その製造法およびそれを含んでなる医薬組成物
JP3869531B2 (ja) ビフェニル誘導体の製造法
KR20030021263A (ko) 이미다조-（1,2-ｃ）（2,3）-벤조디아제핀의 제조 방법 및그 제조에서의 중간체 생성물

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AU AZ BA BB BG BR BY BZ CA CN CR CU CZ DM DZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MA MD MG MK MN MX MZ NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase