WO2001032608A1 - Procédé de préparation de dérivés d'acide oxyminoalcanoïque - Google Patents
Procédé de préparation de dérivés d'acide oxyminoalcanoïque Download PDFInfo
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- WO2001032608A1 WO2001032608A1 PCT/JP2000/007481 JP0007481W WO0132608A1 WO 2001032608 A1 WO2001032608 A1 WO 2001032608A1 JP 0007481 W JP0007481 W JP 0007481W WO 0132608 A1 WO0132608 A1 WO 0132608A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/54—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
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- 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 method for producing an oxyacid derivative having an antidiabetic action.
- a method for producing an oximinoalkanoic acid derivative by arylmethylation of an oxime moiety of an oxime alkanoic acid is disclosed in Japanese Patent Application Laid-Open Nos. Methods for preparing acid derivatives are described. According to the examples in this publication, potassium carbonate, sodium carbonate, and lithium carbonate are used as bases when triphenylmethyl is introduced into an oxime site by the reaction of an oxime alkanoic acid derivative with triphenylmethyl chloride. I have.
- R ' is a hydrocarbon group or heterocyclic group which may be substituted, and' is a bond, one CO—, one CH (OH) — or one N 7 R fi — (R 6 is a hydrogen atom Or an alkyl group which may be substituted.
- R 6 is a hydrogen atom Or an alkyl group which may be substituted.
- Y is an oxygen atom, a sulfur atom, One SO-, -S0 2 - or a N ⁇ - a (R 7 is a hydrogen atom or an optionally substituted alkyl group.)
- Ring A further has 1 to 3 substituents
- R 4 and R 5 are the same or different and each represents a hydrogen atom or And R 4 may be combined with R 2 to form a ring.
- a weak base such as an alkali metal carbonate described in the above-mentioned publication is used in producing the compound represented by the formula (1) or a salt thereof, a by-product is formed and the desired oxyiminoal carboxylic acid derivative is produced. It has been found that the yield of the product may be reduced, and that it may be mixed as a related substance into the final product. Further, for this removal, further purification by silica gel column chromatography is required, which complicates the operation and may adversely affect the environment such as the treatment of a large amount of waste silica gel. It became clear.
- R s and R 9 are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group. R s and R 9 may combine to form a ring. Other symbols are as defined above.
- a low-polar solvent such as 1,2-dimethoxyethane described in the above-mentioned article
- the oxime alkane is contained in the reaction mixture. It has been found that the acid amide precipitates as a metal salt, which significantly inhibits the progress of the reaction, lowers the reaction yield, and leaves raw materials. In order to remove these remaining raw materials, further purification by silica gel chromatography is required, which makes the operation complicated and may have an adverse effect on the environment such as the treatment of large amounts of waste silica gel. It became clear.
- the present inventors have conducted intensive studies on an industrially advantageous method for producing an oxyiminoalkanoic acid derivative in order to solve the above-mentioned problems.
- the compound represented by the above general formula (III) or a salt thereof by arylmethylation of an oxime moiety of an acid by using a metal alkoxide which is a strong base, it is possible to suppress generation of by-products. I found it.
- the oximinoalkanoic acid amide derivative represented by the above general formula (V) by arylmethylation of the oxime alkanoic acid amide at the oxime position, by using an amide which is a polar solvent as the reaction solvent, the reaction rate can be increased. And it was found that it was possible to suppress the remaining of raw materials.
- the present inventors have further studied and found that an oxyiminoalkanoic acid derivative is industrially advantageous and high-yield and high-quality without silica gel column chromatography purification.
- the present invention has been completed as an environmentally friendly manufacturing method. That is, the present invention
- R 1 represents a hydrocarbon group or a heterocyclic group which may be substituted;
- X represents a bond, one CO—, one CH (0H) _ or one NR fi — (R 6 represents a hydrogen atom or N represents an integer of 1 to 3;
- Y represents an oxygen atom, a sulfur atom, one SO—, one SO 2 — or one NR 7 — (R 7 is a hydrogen atom)
- ring A is a benzene ring which may further have 1 to 3 substituents;
- p is an integer of 1 to 8; and
- Z is a halogen atom. or 0S0 2 R IC (R iG is.
- R 2 is a hydrogen atom or a hydrocarbon group or a heterocyclic group which may be substituted each; q is an integer of 0 to 6; 111 is 0 or 1; R 4 and R 5 are The same or different, each represents a hydrogen atom or a hydrocarbon group which may be substituted, and R 4 may combine with R ′ 2 to form a ring.
- the compound represented by the general formula (III) is represented by the following formula: (E) -4- [4-1 (5-methyl-2-phenyl-2-oxazolylmethoxy) benzyloxyimino] —4—
- the production method according to the above (1) which is phenylbutyric acid or a salt thereof,
- R s and R 9 are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acetyl group; R s and R 9 may combine to form a ring. Other symbols are as defined above.
- R 1 represents an optionally substituted hydrocarbon group or a heterocyclic group
- X represents a bond, one CO—, —CH (OH) — or one NR
- R f ′ represents a hydrogen atom or be substituted represents an alkyl group
- n is 1 to 3 of an integer
- Y is oxygen atom, a sulfur atom, -SO-, _S0 2 - or a NR 7 - (R 7 is a hydrogen atom or Ring A is a benzene ring which may further have 1 to 3 substituents
- p is an integer of 1 to 8
- Z is a halogen atom or
- R 1Q is. Represents an alkyl group, Ariru group of carbon number! ⁇ Carbon atoms which may be substituted with an alkyl group having 4 6-10 having 1 to 4 carbon atoms). Or a salt thereof and a compound represented by the general formula (IV)
- R 2 represents a hydrogen atom or each Ku If an optionally substituted hydrocarbon group of the heterocyclic group; q is 0 to an integer of 6; m is 0 or 1; R 8 and are identical or Differently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, and R s and R 9 are bonded to form a ring R 4 and R 5 may be the same or different and represent a hydrogen atom or a hydrocarbon group which may be substituted, and R 4 may be bonded to R 2 to form a ring Good.
- the compound represented by the general formula (V) is reacted with an amide in the presence of a metal carbonate.
- Amides are NT , N-dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 1-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone
- the compound represented by the general formula (V) is (E) -4-1 [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -14-phenyl
- the present invention relates to the production method according to the above (11), which is butylamide or a salt thereof.
- hydrocarbon group in the ⁇ optionally substituted hydrocarbon group '' represented by R 1 an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, An araliphatic hydrocarbon group and an aromatic hydrocarbon group are exemplified.
- the number of carbon atoms in these hydrocarbon groups is preferably from 1 to 14.
- an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable.
- the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, ⁇ -butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, and octyl.
- Saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, alkyl group); for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- Methyl-1-propenyl, 1-1pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1_hexenyl, 3-hexenyl, 2,4-hexenyl, 5- Hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pen 2 carbons such as nyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,
- Unsaturated aliphatic hydrocarbon group having up to 8 carbon atoms eg, alkenyl group having 2 to 8 carbon atoms, alkadienyl group having 4 to 8 carbon atoms, alkenylalkynyl group having 2 to 8 carbon atoms, alkadiynyl having 4 to 8 carbon atoms
- alkenyl group having 2 to 8 carbon atoms alkadienyl group having 4 to 8 carbon atoms
- alkenylalkynyl group having 2 to 8 carbon atoms alkadiynyl having 4 to 8 carbon atoms
- an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable.
- the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl (eg, cycloalkyl group); For example, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptenyl And unsaturated alicyclic hydrocarbon groups having 5 to 7 carbon atoms (eg, cycloalkenyl group, cycloalkadienyl group, etc.).
- Examples of the alicyclic monoaliphatic hydrocarbon group include those in which the alicyclic hydrocarbon group and the aliphatic hydrocarbon group are bonded (eg, a cycloalkyl monoalkyl group, a cycloalkenyl alkyl group, and the like). Of these, an alicyclic monoaliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable. Examples of the alicyclic monoaliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, and 2-cyclopentylmethyl.
- Examples include cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.
- a araliphatic hydrocarbon group having 7 to 13 carbon atoms eg, an aralkyl group having 7 to 13 carbon atoms, an aralkyl alkenyl group having 8 to 13 carbon atoms, etc. is preferable.
- Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; , Naphthylethyl, 3-naphthylmethyl, 3-naphthylethyl, etc., naphthylalkyl having 11 to 13 carbons; phenylalkenyl having 8 to 10 carbons, such as styryl; 2- (2_naphthylvinyl) And naphthylalkenyl having 12 to 13 carbon atoms.
- phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; , Naphthylethyl,
- an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group) is preferable.
- the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
- a compound in the “optionally substituted heterocyclic group” represented by R 1 As the ring group, a 5- to 7-membered monocyclic heterocyclic group or a fused heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring constituent atoms And a ring group.
- the condensed heterocyclic ring include, for example, a condensed ring of a 5- to 7-membered monocyclic heterocyclic ring and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom. Is mentioned.
- heterocyclic group examples include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5_pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2- Virazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2_imidazolyl, 4-imidazolyl, 5- ⁇ — midazolyl, 1-birazolyl, 3-birazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4_oxaziazolyl 5-yl, 1,3,4-oxaziazolyl_ 2-yl, 1, 3, 4—thiadiazol—2—yl, 1,2,4
- a hydrocarbon group and heterocyclic group represented by R 1 is optionally substituted ability positions respectively And preferably 1 to 3 substituents.
- substituents include an aliphatic hydrocarbon group which may be substituted, an alicyclic hydrocarbon group which may be substituted, an aromatic hydrocarbon group which may be substituted, and a substituted Aromatic heterocyclic group, optionally substituted non-aromatic heterocyclic group, halogen atom, nitro group, optionally substituted amino group, optionally substituted acyl group, optionally substituted Examples include a good hydroxy group, a substituted or unsubstituted thiol group, and a carboxyl group which may be esterified or amidated.
- optionally substituted aliphatic hydrocarbon group “optionally substituted aliphatic hydrocarbon group”, “optionally substituted alicyclic hydrocarbon group”, “optionally substituted aromatic hydrocarbon group”, “substituted an aromatic heterocyclic group “and also relates to” optionally substituted non-aromatic heterocyclic group ", the substituent, ( ⁇ - 6 alkyl group, C i _ 6 alkoxy group, a halogen atom (e.g. , Fluorine, chlorine, bromine, iodine, etc.), nitro group, haloalkyl group, haloalkoxy group, etc.
- the number of substituents is, for example, 1-3.
- aliphatic hydrocarbon group examples include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group.
- alkyl group examples include an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, s-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, s-butyl, pentyl, isopentyl, neopentyl
- Examples include ethyl
- alkenyl group examples include alkenyl groups having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-11-propenyl.
- alkynyl group examples include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1_propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3 —Pentynyl, 4-pentinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
- alicyclic hydrocarbon group examples include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkenyl group.
- cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, Bicyclo [2.2.2] Octel, 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.
- cycloalkenyl group examples include cycloalkenyl groups having 3 to 10 carbon atoms, such as 2-cyclopentene-11-yl, 3-cyclopentene-1-yl, and 2-cyclohexene-11-yl. , 3-cyclohexene_1-yl and the like.
- cycloalkadienyl group examples include a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexadienyl, 2,5-cyclohexadiene-1-yl and the like.
- the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., an aryl group), such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, phenyl, 1.1-naphthyl, 2-naphthyl and the like are preferable.
- Preferred examples of the aromatic heterocyclic group include, for example, furyl, phenyl, pyrrolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3 oxaziazolyl, 1,2,4-oxaziazolyl, 1,3,4 oxaziazolyl, furzanil, 1,2,3 thiaziazolyl, 1,2, Oxygen atoms other than carbon atoms as ring constituent atoms such as 4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl 5- to 7-membered aromatic monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from sulfur atom and nitrogen atom; for example, be
- non-aromatic heterocyclic group examples include those having 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
- hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
- examples thereof include oxilanil, azetidinyl, oxedinyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino, and thiomorpholino.
- halogen atoms include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being 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 cycloalkenyl group having 3 to 10 carbon atoms.
- Mono- or di-substituted with an alkoxy group having 1 to 13 carbon atoms eg, an alkanol group having 2 to 10 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms
- an aryl group having 6 to 12 carbon atoms e.g, an amino group which may be used.
- the acyl group here has the same meaning as the acyl group in the "optionally substituted acyl group" described later.
- substituted amino group examples include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, dibutylamino, diarylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methylaminophenyl, and the like.
- acyl group in the optionally substituted acyl group examples include an acyl group having 1 to 13 carbon atoms, specifically, formyl, for example, an alkyl group having 1 to 10 carbon atoms, and a cyclo group having 3 to 10 carbon atoms.
- acetyl group examples include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanylcarbonyl, cycloheptanylcarbonyl Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinol, 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, for example, an alkyl group having 1 to 3 carbon atoms.
- alkoxy group e.g, a halogen (eg, fluorine, chlorine, iodine, etc.), nitro, hydroxy, amino and the like.
- acyl group is represented by the following general formula.
- R 11 , R 14 , R 15 , R 16 and R 17 are the same or different A hydrocarbon group which may be ]
- Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 11 , R 14 , R 15 , R 16 and R 17 include an alkyl group having 1 to 10 carbon atoms and a carbon number Examples thereof include a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and an aryl group having 6 to 12 carbon atoms.
- examples of the substituted hydroxy group include an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acryloxy group and an aryloxy group each of which may be substituted.
- alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyl Oxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- alkenyloxy group examples include an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cycloalkyl. Hexenylmethoxy and the like.
- aralkyloxy group examples include an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl C14 alkyloxy (eg, benzyloxy, phenethyloxy and the like).
- acyloxy group examples include an acyloxy group having 2 to 13 carbon atoms, more preferably an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy, etc.) and the like.
- aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
- alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have one or two substituents at substitutable positions.
- substituents include halogen (eg, fluorine, chlorine, bromine, etc.), and an alkoxy group having 1 to 3 carbon atoms.
- the substituted aryloxy group includes, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like.
- examples of the substituted thiol group include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, heteroarylthio and the like.
- alkylthio group examples include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, butylthio, pentylthio, isopentylthio, and the like. Neopentylthio, hexylthio, heptylthio, nonylthio and the like.
- cycloalkylthio group examples include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
- aralkylthio group examples include an aralkylthio group having 7 to 10 carbon atoms, such as phenyl C14 alkylthio (eg, benzylthio, phenylethylthio, etc.).
- acylthio group examples include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
- alkanoylthio group having 2 to 4 carbon atoms
- arylthio groups include arylthio groups having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
- heteroarylthio group examples include 2-pyridylthio, 3-pyridylthio and the like, 2-imidazolylthio, 1,2,4-triazo-l-5-ylthio and the like.
- Examples of the carboxyl group include an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), an aralkyloxycarbonyl group having 8 to 10 carbon atoms (eg, Benzyloxycarbonyl) or 1 to 2 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms? To 15 aryloxycarbonyl groups (eg, phenoxycarbonyl, p-tolyloxycarbonyl, etc.).
- an alkoxycarbonyl group having 2 to 5 carbon atoms eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.
- an aralkyloxycarbonyl group having 8 to 10 carbon atoms eg, Benzyloxycarbonyl
- 1 to 2 carbon atoms which may be substituted by an al
- R 12 and R 13 are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
- the hydrocarbon group in the ⁇ optionally substituted hydrocarbon group '' and the heterocyclic group in the ⁇ optionally substituted heterocyclic group '' represented by R 12 and R 13 are respectively the same as those described above.
- Aliphatic exemplified as "the hydrocarbon group in the" optionally substituted hydrocarbon group "represented by the scale 1 " and "the heterocyclic group in the” optionally substituted heterocyclic group "represented by R” Examples include a hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a heterocyclic group.
- the hydrocarbon group and the heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include halogen (eg, fluorine, chlorine, bromine). , Iodine, etc.), an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and the like.
- the substituent in the hydrocarbon group and the heterocyclic group represented by R 1 is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, or an aryl group having 6 to 14 carbon atoms. And more preferably alkyl having 1 to 3 carbon atoms, furyl, phenyl, phenyl, phenyl and naphthyl.
- Substituents on the hydrocarbon group and the heterocyclic group represented by R 1 are, when they are an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, Each substituent may have one or more, preferably 1 to 3 suitable substituents, such as an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, Cycloalkyl having 3 to 10 carbon atoms , An aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), an aromatic heterocyclic group (eg, phenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), a non-aromatic heterocyclic group (eg, Tetrahydrofuryl, morpholino, thiomololino, piperidino, pyrrolidinyl, piperazinyl, etc.), an
- R 1 is preferably an optionally substituted heterocyclic group, and more preferably an optionally substituted pyridyl, oxazolyl, thiazolyl or triazolyl.
- R 1 particularly preferably has 1 or 2 substituents selected from alkyl having 1 to 3 carbons, cycloalkyl having 3 to 7 carbons, furyl, phenyl, phenyl, phenyl and naphthyl. Good pyridyl, oxazolyl, thiazolyl or triazolyl.
- furyl, phenyl, phenyl, and naphthyl are alkyls having 1 to 3 carbons, alkoxys having 1 to 3 carbons, halogens (eg, fluorine, chlorine, bromine, iodine, etc.) or 1 to 3 carbons. It may have 1 or 2 haloalkyls as substituents.
- R 1 include an optionally substituted heterocyclic group represented by the following formula: Or a cyclic hydrocarbon group which may be substituted.
- These groups may have one or two substituents selected from phenyl, furyl, phenyl and alkyl having 1 to 4 carbon atoms.
- the phenyl, furyl and phenyl are alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 1 to 6 carbons, It may have one or two substituents selected from haloalkoxy having 1 to 6 carbon atoms.
- the alkyl having 1 to 4 carbons is alkoxy having 1 to 6 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 1 to 6 carbons, 1 to 6 carbons. It may have one or two substituents selected from haloalkoxy.
- halogen eg, fluorine, chlorine, bromine, iodine, etc.
- nitro haloalkyl having 1 to 6 carbons, 1 to 6 carbons. It may have one or two substituents selected from haloalkoxy.
- R 1 is more preferably a group represented by the following formula.
- Ph represents an optionally substituted phenyl group
- R represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms.
- Examples of the substituent in the phenyl group represented by Ph and the alkyl group having 1 to 6 carbon atoms represented by R “include alkoxy having 1 to 6 carbon atoms, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), Examples thereof include nitro, haloalkyl having 1 to 6 carbon atoms, and haloalkoxy having 1 to 6 carbon atoms
- the number of substituents is, for example, 1 to 3.
- X represents a bond, —CO—, CH (OH) — or NR e — (R 6 represents a hydrogen atom or an optionally substituted alkyl group) As shown, a bond, —CH (OH) 1 or 1 NR 6 — is preferable, and a bond or 1 NR 6 — is more preferable.
- the alkyl group in the “optionally substituted alkyl group” represented by R 6 includes an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. .-Butyl, t-butyl and the like.
- the alkyl group may have 1 to 3 substituents at substitutable positions.
- substituents examples include halogen (eg, fluorine, chlorine, bromine, iodine) and carbon atoms of 1 ⁇ 4 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, shi-butoxy, etc.), hydroxy group, nitro group, C1-4 acyl group ( Examples are C 1 -C 4 alkynyl groups such as formyl, acetyl and propionyl.
- halogen eg, fluorine, chlorine, bromine, iodine
- carbon atoms of 1 ⁇ 4 alkoxy groups eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, shi-butoxy, etc.
- hydroxy group e.g, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se-butoxy, shi-but
- n represents an integer of 1 to 3, and is preferably 1 or 2.
- Y represents one O—, —S—, —SO—, —SO 2— or —NR 7 — (R 7 represents a hydrogen atom or an optionally substituted alkyl group), but _o One, one S— or one NR 7 — is preferred.
- R 7 represents a hydrogen atom or an optionally substituted alkyl group
- examples of the “optionally substituted alkyl group” represented by R 7 include the same as the above-mentioned “optionally substituted alkyl group” represented by R 6 .
- ring A represents a benzene ring, and the benzene ring may further have 1 to 3 substituents at substitutable positions.
- substituents include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, a nitro group, and an optionally substituted amino group.
- those exemplified as the substituents in the hydrocarbon group and the heterocyclic group represented by R 1 are used.
- the substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom.
- p represents an integer of 1 to 8, and is preferably an integer of 1 to 3.
- R 2 is preferably an optionally substituted hydrocarbon group.
- R 2 is more preferably an optionally substituted aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an araliphatic hydrocarbon group or an aromatic hydrocarbon group, and particularly preferably An alkyl group having 1 to 4 carbon atoms, a phenylalkenyl group having 8 to 10 carbon atoms, and an aryl group having 6 to 14 carbon atoms.
- the substituents which these hydrocarbon groups may have are preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms, and an aromatic heterocyclic group (eg, furyl, chenyl) ).
- the number of substituents is, for example, 1 to 3.
- Q represents an integer of 0 to 6, and is preferably 0 to 4.
- m is 0 or 1.
- R 8 and R 9 are the same or different and each represent a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R 8 and R 9 may combine to form a ring.
- Examples of the ⁇ optionally substituted acyl group '' represented by R 8 and R 9 include those exemplified as the substituents which the ⁇ optionally substituted hydrocarbon group '' represented by R 1 may have The same as the "optionally substituted acyl group" can be mentioned.
- R 8 and R 9 may combine to form a 5- to 7-membered cyclic amino group.
- Specific cyclic amino groups include 1-pyrrolidinyl, 1-piberidinyl, 1-hexamethyleneiminyl, 4 —Morpholino and 4-thiomorpholino.
- R 4 and R 5 are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R 4 may combine with R 2 to form a ring.
- Examples of the ⁇ optionally substituted hydrocarbon group '' represented by R 4 and R 5 include the same as the aforementioned ⁇ optionally substituted hydrocarbon group '' for R 1 , preferably And the same as the “optionally substituted alkyl group” for R 6 .
- R 4 may combine with R 2 to form a ring.
- R 4 and The ring R 2 and is formed by combining, for example, carbon number 5-1 1 cycloalkane and Shikuroarugen C 5 -C 1 1 can be mentioned, specifically, cyclopentane, consequent Mouth pentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, cyclononane, cyclononene, cyclodecane, cyclodecene, cycloundecane and cycloundecen And so on.
- Z represents a halogen atom or OSO ⁇
- R'G represents an alkyl group having 1 to 4 carbon atoms, or an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms.
- halogen atom examples include fluorine, chlorine, and bromine, and among them, chlorine is preferable.
- alkyl group having 1 to 4 carbon atoms and the “aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms”
- the “alkyl group having 1 to 4 carbon atoms” examples thereof include those exemplified as the aforementioned R 6 .
- Examples of the aryl group having 6 to 10 carbon atoms in the "aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms” include phenyl, naphthyl, and the like. Is preferred.
- Preferred examples of ⁇ include chlorine, methanesulfonyl, toluenesulfonyl and the like. Of these, chlorine is preferred.
- the compounds represented by the general formulas ( ⁇ ) and (III) have ( ⁇ ) -form and ( ⁇ ) -form with respect to imino bond.
- the compound includes the ( ⁇ ) -form and the ( ⁇ ) -form alone and in a mixture thereof.
- Preferred specific examples of the compounds represented by the general formulas (III) and (V) produced by the production method of the present invention include the following compounds.
- 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 and ammonium salt.
- Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Salts.
- salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, P— Examples thereof include salts with toluenesulfonic acid and the like.
- Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
- Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, dalminic acid, etc. And salts thereof.
- reaction A The reaction between the compound (I) and the compound (II) (hereinafter may be abbreviated as reaction A) is performed in an amide in the presence of a metal alkoxide.
- examples of the metal alkoxide include an alkali metal alkoxide. Specific examples include sodium, potassium, and lithium tert-butoxide, methoxide, and ethoxide.
- Metal Al Kokisaido is preferably an alkali metal C doctor 6 alkoxide, sodium t er t-butoxide is rather more preferable.
- the amount of metal alkoxide used depends on the amide used and the reaction temperature.
- the amount is usually 0.5 to 20 equivalents, preferably 2 to 20 equivalents, and more preferably 2 to 5 equivalents, relative to compound (II). That is, the metal alkoxide is used in an amount of 50 to 200 mol%, preferably 200 to 200 mol%, more preferably 200 to 500 mol%, based on the compound (II).
- the amide examples include ⁇ , ⁇ -dimethylformamide, acetoamide, ⁇ , ⁇ -dimethylacetoamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and the like.
- the amides are preferably ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, particularly preferably ⁇ , ⁇ -dimethylacetamide. Amides. These amides may be used alone or as a mixture of two or more at an appropriate ratio.
- the equivalent ratio of the compound (I) to the compound (II) is about 5: 1 to about 1: 5.
- it is about 1 to 1 to 2. That is, the compound ( ⁇ ) is used in an amount of about 20 to about 500 mol%, preferably about 100 to about 200 mol%, based on the compound (I).
- reaction II The reaction between compound (I) and compound (IV) (hereinafter sometimes abbreviated as reaction II) is performed in an amide in the presence of a metal carbonate.
- examples of the metal carbonate include sodium, potassium, lithium, calcium, cesium, rubidium and the like.
- the metal carbonate is preferably an alkali metal carbonate, more preferably potassium carbonate.
- the metal carbonate is generally used in an amount of 20 to 500 mol%, preferably 50 to 200 mol%, based on compound (IV).
- amides examples include the amides exemplified in the above-mentioned Reaction II. Among them, IV, N-dimethylformamide and the like are preferable.
- the equivalent ratio of compound (I) to compound (IV) is from about 5: 1 to about 1: 5. Preferably it is about 1 to 1 to 2. That is, the compound (IV) is used in an amount of about 20 to about 500 mol%, preferably about 100 to about 200 mol%, based on the compound (I).
- the order of charging reaction A and reaction B is not particularly limited as long as the reaction is not affected.
- a mixture of compound (I) and compound (II) or compound (IV) Metal alkoxide or metal carbonate may be added respectively, or
- Compound (I) and compound (II) or compound (II) may be added to the metal alkoxide or metal carbonate previously dissolved or suspended in amides, respectively.
- the compound (I) dissolved or suspended in the amides may be added to the solution or suspension thus prepared.
- the reaction temperatures of the reaction A and the reaction B differ depending on the type of the metal alkoxide or the metal carbonate and the amide used, but may be in the range of from ⁇ 178 ° C. to the boiling point of the amide, preferably ⁇ 51: To the boiling point of amides (eg, 200 V).
- the reaction temperature is more preferably 15 ° C to 80 ° C.
- the reaction time of the reaction A and the reaction B is, for example, 0.5 to 20 hours.
- reaction A and reaction B a quaternary ammonium salt such as tetrabutylammonium bromide; an alkali or alkali metal salt such as potassium iodide, sodium iodide, potassium bromide or sodium bromide to promote the reaction;
- the reaction may be carried out in the presence of brown ether or the like.
- compound (V) can also be produced by amidating compound (III) obtained in reaction A as follows.
- a salt thereof such salts include those exemplified as salts of compound (I), etc.
- a condensing agent eg, dicyclohexylcarbodiimide, etc.
- Direct condensation The method is or how to appropriately react reactive derivative and the compound (VI) of the compound (III) or Organic Functional Group Pre Roh,, 0 Reishiyonzu (Organic Fund ional Group Preparat ions, Second Edi ⁇ ion), 3 ] It is performed using the method described on pages 6 to 355, ACADEMIC PRESS IN.
- the reactive derivative of the compound (1) for example, acid anhydride, acid halide (acid chloride, acid promide), imidazolide, or mixed acid anhydride (for example, anhydride with methyl carbonate, ethyl carbonate, isobutyl carbonate) Object).
- acid halide acid chloride, acid promide
- imidazolide or mixed acid anhydride (for example, anhydride with methyl carbonate, ethyl carbonate, isobutyl carbonate) Object).
- acid anhydride for example, acid anhydride, acid halide (acid chloride, acid promide), imidazolide, or mixed acid anhydride (for example, anhydride with methyl carbonate, ethyl carbonate, isobutyl carbonate) Object.
- the reaction is carried out in the presence of a base in a solvent that does not affect the reaction.
- the base include triethylamine, N-methylmorpholine, N, N-dimethyl
- Solvents that do not affect the reaction include, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; and ethyl acetate. , Water and the like. These solvents may be used in a mixture at an appropriate ratio.
- the amount of compound (VI) to be used is 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (II).
- the reaction temperature is usually 30 ° (: to 100 :, the reaction time is 0.5 to 20 hours.
- the compound (III) and a carbonic acid ester eg, Methyl carbonate, ethyl ethyl carbonate, isobutyl carbonate, etc.
- bases eg, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium bicarbonate, sodium carbonate, lithium carbonate, etc.
- the reaction is carried out in the presence of the compound (VI), and the compound (VI) is used in an amount of 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to the compound (II).
- the reaction time is usually 30 ° (: ⁇ 100 ° (:, reaction time is 0.5 to 20 hours.
- the compound (II) or compound (V) thus obtained is separated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, activated carbon treatment and the like. be able to. That is, the treatment after the reaction may be performed by a method known per se, for example, an extraction operation using a mixed solvent system of an organic solvent insoluble or hardly soluble in water and water. Any organic solvent that is insoluble or hardly soluble in water may be used as long as it can dissolve the target compound, and is preferably an aromatic hydrocarbon such as toluene. Hydrogens; esters such as ethyl acetate; ethers such as diisopropyl ether, monobutyl methyl ether, and tetrahydrofuran are used.
- a known separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, activated carbon treatment and the like. be able
- the reaction mixture after completion of the reaction is kept basic, the target compound is dissolved in water in the form of a salt, and the resulting solution is washed with an insoluble or hardly soluble organic solvent in water and then made acidic.
- the target compound may be purified by a method known per se, for example, recrystallization.
- the recrystallization is carried out in a solvent in which the target compound is insoluble or hardly soluble at a certain temperature (eg, diisopropyl ether, t.-butyl methyl ether, n-hexane, etc.) using the difference in solubility under heating conditions.
- a solvent in which the target compound is soluble or easily soluble eg, tetrahydrofuran, acetone, etc.
- a solvent in which the target compound is insoluble or hardly soluble (eg, diisopropyl ether, t. Butyl methyl ether, n-hexane, water, etc.) may be used to take advantage of the difference in solubility of the mixed solvent system.
- the starting compounds used in each of the above-mentioned reactions can be synthesized, for example, by the following methods.
- Compound (I) can be prepared by the method described in (1) Chemical and Pharmaceutical Bulletin, Vol. 9, page 2050 (1970), ie, butanedioxime and benzaldehyde are reacted in the presence of an acid.
- a chloromethyl compound synthesized by a method that leads to N-oxide and reacts it with oxalyl chloride, phosphorus oxychloride, etc. was obtained from (2) Journal of Chemical Society, Chemical Communications. 9, p. 582 (1988), by reacting with p-hydroxybenzyl alcohol in the presence of a base, or in the Journal of Organic Chemistry, 57, 589. Reaction with p-hydroxybenzaldehyde in the presence of a base as described on page 1992.
- Compound (U) and compound UV) are described in Pharmazie, Vol. 38, p. 313 (1983) or in Acta Crystallographica, C50, p. 78 (1994).
- the compound can be synthesized by the method described, that is, a method of reacting ketone and hydroxyamine in the presence of a base, or a method analogous thereto.
- the compound (I), compound ( ⁇ ) and compound (IV) thus obtained may be separated and purified by known means, respectively, and then used in the production method of the present invention, or as a reaction mixture. It may be used in the production method of the invention.
- Benzoylpropionic acid 100 g was suspended in methanol (300 ml) at room temperature, and then hydramine xyamine hydrochloride (46.8 g) and sodium acetate (138 g) were added. After stirring at room temperature at 22-27 ° C for 4.5 hours, pure water (500 ml) was added at 24-26 ° C under cooling. After adding seed crystals at 25 ° C, the mixture was stirred at room temperature for about 1 hour, cooled to 10 ° C over about 30 minutes, and stirred at 5-10 ° C for about 2 hours.
- the precipitated solid was collected by filtration, washed with pure water (100 ml ⁇ 2), and dried under reduced pressure (40 ° C.) to give a white solid of 4- (hydroxyimino) -14-phenylbutyric acid (94.4 g) in a yield of 87.1 g. %.
- Benzaldehyde (342 g) and acetic acid (800 ml) were added to 2,3-butanedioxime (300 g), dissolved under stirring at room temperature, and cooled. Blowing of hydrochloric acid gas was started at 5 C, and blowing of hydrochloric acid gas was continued at 10 to 25 ° C for 5 hours. Diisopropyl ether (1200 ml) was added at 10-15 ° C over about 1 hour, and after aging at 5-10 ° C for 1 hour, the precipitated solid was collected by filtration and twice with diisopropyl ether (400m). After washing, a pale yellow-white solid (undried, 527 g) was obtained.
- step3 4 ⁇ [4- (Chloromethyl) phenoxy] methyl ⁇ 1-Methyl-2-phenyl-1,3-oxazole
- activated carbon (15 g ) was added to the organic layer, and the mixture was stirred for about 1 hour and filtered off. (300 ml). After concentrating the organic layer to about 805 g, the temperature was raised to about 60 ° C to dissolve the crystals, and then allowed to cool. After cooling to about 25 ° C in 30 minutes, n-hexane (1800 ml) was added dropwise in about 30 minutes. After cooling to around 5 ° C. and aging for 1 hour, the crystals were collected by filtration and washed with cooled toluene-n-hexane (1: 3) (600 ml).
- the yellow oil was dissolved in 12.5 ml of methanol-denatured ethanol, and 12.5 ml of a 4N sodium hydroxide solution was refluxed for 1 hour at room temperature. After cooling to room temperature (25 ° C.) or lower, 1.08 g of hydroxyamine hydrochloride was added, and the mixture was refluxed for 9 hours. After cooling to room temperature (25 ° C or lower), 9 ml of 3N 'hydrochloric acid was added dropwise to crystallize. After aging for 1 hour under ice cooling, the crystals were collected by filtration and washed with 10 ml of water. The crystals were vacuum dried at 40 ° C for 3 hours to obtain pale yellow crystals.
- the obtained crystals were suspended in 12.5 ml of acetone and 12.5 ml of distilled water and dissolved under reflux. The mixture was allowed to cool to room temperature, crystallized, and then aged for 1 hour under ice cooling. The obtained crystals were filtered, washed with 12.5 ml of distilled water, and dried under vacuum at 40 ° C. for 4 hours to obtain 1.96 g of the desired product as pale yellow crystals (yield: 60.4).
- the precipitated solid was collected by filtration, washed with 50 ml of pure water, and dried under reduced pressure (40 ° C) to obtain 34.5 g of 4- (hydroxyimino) 14-phenylbutyramide as a pale purple white solid in a yield of 53.0 %.
- the weight of the content was adjusted to 59.4 g, and 2N-HC1 was added dropwise to the aqueous layer at around 25 ° C to adjust the pH to 7.0, seed crystals were added, and the mixture was stirred for 1 hour to precipitate crystals. Then, 2N-HC1 was added dropwise to the mixture to adjust the pH to 4.0, and the mixture was stirred for 1 hour to age the crystals. The crystals were collected by filtration, washed with water, dried at 40 ° C. under reduced pressure, and dried as white crystals.
- 2N-HC1 was added dropwise to the aqueous layer while keeping the temperature at around 25 ° C to adjust the pH to 7.0, seed crystals were added, and the mixture was stirred for 1 hour to precipitate crystals.
- 2N-HC1 was added dropwise to the mixture to adjust the pH to 4.0, and the mixture was stirred for 1 hour to mature the crystals. The crystals were collected by filtration, washed with water, and dried at 50 ° C. under reduced pressure to give the target compound as yellowish white crystals (6.11 g). ; Yield 77%).
- a 10 saline solution (25 ml) was added dropwise to the reaction solution at 20 to 30 ° C, and the mixture was allowed to stand, and the organic layer was separated. After adding 10% saline (25 ml) to the organic layer, the mixture was allowed to stand, and the aqueous layer was separated. ⁇ , ⁇ -dimethylacetamide (20 ml) was added to the organic layer, and 20 to 30 ml of the solvent was distilled off under reduced pressure at an external temperature of 50 to 55 ° C. Toluene (13 ml) was added to the residue, and 8 to 18 ml of the solvent was distilled off under reduced pressure at an external temperature of 50 to 55 ° C.
- the concentrate obtained in the above (1) was added dropwise to the resulting solution at 20 to 30 ° C, and the mixture was stirred at the same temperature for 2 hours.
- sodium terl-butoxide (0.33 g) was added at 20 to 30 ° C, and the mixture was stirred at the same temperature for 2 hours.
- water 25 ml was added dropwise, and then a 1N aqueous sodium hydroxide solution (l ml) was added, followed by stirring at 20 to 30 ° C. for 1 hour.
- Toluene (20 ml) was added to the mixture, and the mixture was stirred and allowed to stand, and the aqueous layer was separated.
- Toluene (10 ml) was added to the aqueous layer, and the mixture was stirred, allowed to stand, and the aqueous layer was separated. After the aqueous layer was concentrated under reduced pressure, 2N hydrochloric acid was added dropwise at 20 to 30 ° C to adjust the pH to 7.0. The resulting mixture was stirred at 20 to 30 ° C for 1 hour, and 2N hydrochloric acid was added dropwise to adjust the pH to 4. After the resulting mixture was stirred at 20 to 30 ° C. for 1 hour, the precipitated crystals were collected by filtration. The obtained crystals were washed with water (20 ml) and dried in vacuo to give the desired product (6.19 g, yield 77.73 ⁇ 4) as pale yellow crystals.
- the oximininoal carboxylic acid derivatives (in) and (V) which have an anti-diabetic effect can be obtained in high yield and high quality. Absent. Further, the production method of the present invention is excellent in operability. Therefore, the production method of the present invention is effective as an industrial production method.
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US10/111,480 US6518435B1 (en) | 1999-10-29 | 2000-10-26 | Process for the preparation of oxyiminoalkanoic acid derivatives |
CA002389208A CA2389208A1 (en) | 1999-10-29 | 2000-10-26 | Process for the preparation of oxyiminoalkanoic acid derivatives |
KR1020027005498A KR20020051925A (ko) | 1999-10-29 | 2000-10-26 | 옥시이미노알카노산 유도체의 제조 방법 |
AU79580/00A AU7958000A (en) | 1999-10-29 | 2000-10-26 | Process for the preparation of oxyiminoalkanoic acid derivatives |
EP00970080A EP1227081A4 (en) | 1999-10-29 | 2000-10-26 | PROCESS FOR THE PREPARATION OF OXYMINOALKANOIC ACID DERIVATIVES |
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AR031078A1 (es) * | 1999-10-29 | 2003-09-10 | Takeda Pharmaceutical | Compuesto acido (e)-4-[4-(5-metil-2-fenil-4-oxalilmetoxi)benziloxiimino]-4-fenilbutirico cristalino, composicion farmaceutica que lo comprende y su uso para fabricar esta ultima. |
PL356745A1 (en) * | 1999-11-10 | 2004-06-28 | Takeda Chemical Industries, Ltd | Body weight gain inhibitors |
WO2010011302A1 (en) * | 2008-07-22 | 2010-01-28 | Chdi, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
EA027451B1 (ru) | 2011-08-30 | 2017-07-31 | Схди Фаундейшн, Инк. | Ингибиторы кинуренин-3-монооксигеназы, фармацевтические композиции и их применение |
AU2012300246A1 (en) | 2011-08-30 | 2014-03-06 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
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WO1996002507A1 (en) * | 1994-07-18 | 1996-02-01 | Abbott Laboratories | Iminoxycarboxylates and derivatives as inhibitors of leukotriene biosynthesis |
WO1999058510A1 (en) * | 1998-05-11 | 1999-11-18 | Takeda Chemical Industries, Ltd. | Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity |
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JP3518819B2 (ja) | 1994-12-19 | 2004-04-12 | 株式会社トクヤマ | チアゾール誘導体結晶 |
JP3248852B2 (ja) | 1996-12-05 | 2002-01-21 | 株式会社トクヤマ | 2−アミノチアゾール酢酸塩誘導体及びその製造方法 |
-
2000
- 2000-10-26 CA CA002389208A patent/CA2389208A1/en not_active Abandoned
- 2000-10-26 US US10/111,480 patent/US6518435B1/en not_active Expired - Fee Related
- 2000-10-26 AU AU79580/00A patent/AU7958000A/en not_active Abandoned
- 2000-10-26 EP EP00970080A patent/EP1227081A4/en not_active Withdrawn
- 2000-10-26 KR KR1020027005498A patent/KR20020051925A/ko not_active Application Discontinuation
- 2000-10-26 WO PCT/JP2000/007481 patent/WO2001032608A1/ja not_active Application Discontinuation
- 2000-10-26 CN CN00816737A patent/CN1407969A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996002507A1 (en) * | 1994-07-18 | 1996-02-01 | Abbott Laboratories | Iminoxycarboxylates and derivatives as inhibitors of leukotriene biosynthesis |
WO1999058510A1 (en) * | 1998-05-11 | 1999-11-18 | Takeda Chemical Industries, Ltd. | Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity |
Non-Patent Citations (1)
Title |
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See also references of EP1227081A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1229026A1 (en) * | 1999-11-10 | 2002-08-07 | Takeda Chemical Industries, Ltd. | Alkoxyiminoalkanoic acid derivatives |
EP1229026A4 (en) * | 1999-11-10 | 2003-09-24 | Takeda Chemical Industries Ltd | ALKOXYIMINOALKANSÄURE DERIVATIVES |
Also Published As
Publication number | Publication date |
---|---|
CA2389208A1 (en) | 2001-05-10 |
KR20020051925A (ko) | 2002-06-29 |
US6518435B1 (en) | 2003-02-11 |
AU7958000A (en) | 2001-05-14 |
EP1227081A4 (en) | 2004-08-11 |
CN1407969A (zh) | 2003-04-02 |
EP1227081A1 (en) | 2002-07-31 |
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