WO1999009002A1 - Derives de phenol - Google Patents

Derives de phenol Download PDF

Info

Publication number
WO1999009002A1
WO1999009002A1 PCT/JP1998/003647 JP9803647W WO9909002A1 WO 1999009002 A1 WO1999009002 A1 WO 1999009002A1 JP 9803647 W JP9803647 W JP 9803647W WO 9909002 A1 WO9909002 A1 WO 9909002A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
butyl
reaction
solvent
Prior art date
Application number
PCT/JP1998/003647
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Kogen
Akihiro Tamura
Ichiro Hayakawa
Teiichiro Koga
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU86498/98A priority Critical patent/AU8649898A/en
Publication of WO1999009002A1 publication Critical patent/WO1999009002A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • 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
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a phenol derivative having an excellent low-density lipoprotein (hereinafter abbreviated as LDL) oxidation inhibitory action and an inhibitory action against acylcoenzyme.cholesterol.acyltransferase (hereinafter abbreviated as ACAT). Or a pharmacologically acceptable salt thereof, a composition containing them for the treatment or prevention of arteriosclerotic diseases, their use for producing a medicament for the treatment or prevention of atherosclerotic diseases,
  • the present invention relates to a method for treating or preventing arteriosclerotic disease, which comprises administering a pharmacologically effective amount to a warm-blooded animal, or a method for producing the same.
  • Atherosclerosis is the most important cause of ischemic heart disease such as angina and myocardial infarction.
  • a major cause of atherosclerosis is that foam cells under vascular endothelial cells accumulate cholesterol esters.
  • LDL is a type of serum lipoprotein that acts to carry cholesterol to various tissues in the body.
  • the LDL that has leached into the intima through the cell layer undergoes oxidative modification, promotes monocyte migration, and causes monocyte-derived macrophages to stagnate in the intima. Macrophages that have been taken up by The involvement of oxidative modification of LDL in the mechanism of atherosclerosis, which eventually forms foam cells and accumulates in vascular walls to form plaques, has been described.
  • a drug having an LDL oxidation inhibitory action suppresses LDL oxidation, thereby preventing macrophages from foaming and inhibiting the formation and development of atheromatous lesions.
  • a compound having an LDL oxidation inhibitory action for example, probucol and the like are known.
  • Atherosclerosis is correlated with hypercholesterolemia.
  • Cholesterol in food is absorbed by the intestinal mucosal cells as free cholesterol, where it is esterified by ACAT and transferred to the blood as cholesterol esters. Therefore, ACAT inhibitors are expected to inhibit cholesterol esterification in foam cells, reduce cholesterol accumulation, and suppress the formation and development of atheromatous lesions.
  • ACAT and LDL oxidation are two important routes, and compounds that inhibit both routes at the same time are better than conventional drugs for treating atherosclerosis or It was thought that it could be a prophylactic.
  • the present inventors have aimed at developing compounds having both excellent LDL oxidation inhibitory activity and ACAT inhibitory activity, and have studied the synthesis of various phenol derivatives and their pharmacological activities for many years.
  • the fuynol derivative having a unique structure has both excellent LDL oxidation inhibitory activity and ACAT inhibitory activity, shows excellent oral absorption, and has therapeutic effects on atherosclerotic diseases or
  • the present inventors have found that they have a preventive effect (especially a therapeutic effect) and completed the present invention.
  • the present invention relates to a phenol derivative or a phenol derivative having an excellent low-density lipoprotein (hereinafter abbreviated as LDL) oxidation inhibitory activity and an inhibitor of acylcoenzyme.cholesterol.acyltransferase (hereinafter abbreviated as ACAT).
  • LDL low-density lipoprotein
  • ACAT inhibitor of acylcoenzyme.cholesterol.acyltransferase
  • the phenol derivative of the present invention has the general formula (I).
  • R 1a represents a hydroxyl group
  • R lb and R lc are the same or different and each represent a hydrogen atom or a C i -C 4 alkyl group (provided that one of R 1b and R 1c represents a C l -C 4 alkyl group) ,
  • R 2 represents a C 4 -C 6 alkyl group
  • R 3 is a 5- or 6-membered cyclic saturated heterocyclyl group containing one or two hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; selected from the group consisting of nitrogen, oxygen and sulfur atoms 5- or 6-membered cyclic heteroaryl group containing 1 or 2 hetero atoms; 5-membered containing 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms To 6-membered cyclic heteroamino group; cyano group; hydroxyl group; hydroxyiminomethyl group; carboxy group; carbamoyl group; mono (C ⁇ -C 6 alkyl) carbamoyl group; di (j-C 6 alkyl) A carbamoyl group; or -C 6 alkanoylamino group;
  • A represents a single bond or a C - shows the C 4 alkylene group.
  • the active ingredient of the anti-atherosclerotic agent of the present invention is a phenol derivative having the general formula (I). In the definition of R 1 b and R 1 c in the above general formula (I) "-.
  • C 4 alkyl group for example, a methyl group, Echiru group, a propyl group, an isopropyl group, heptyl group, isobutanol butyl group, s- It may be a linear or branched alkyl group having 1 to 4 carbon atoms such as a butyl group or a t-butyl group, preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
  • C 4 -C 6 alkyl group in the definition of R 2 is, for example, a butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a 2-methylbutyl group , Neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethyl
  • a straight chain having 4 to 6 carbon atoms such as a butyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylinobutyl group or a 2-ethylbutyl group.
  • J-C 4 alkylene group in the definition of A includes, for example, a methylene group, a methylmethylene group, a dimethylmethylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, A linear or branched alkyl having 1 to 4 carbon atoms such as a 1-methyltrimethylene group, a 2-methyltrimethylene group or a 3-methyltrimethylene group; It may be a kylene group, preferably a methylene group, an ethylene group or a trimethylene group, more preferably a methylene group or an ethylene group, particularly preferably a methylene group.
  • the term "5- or 6-membered cyclic saturated heterocyclyl group containing one or two hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms" in the definition of R 3 is, for example, a pyrrolidinyl group , A piperidyl group, a piperazinyl group, a morpholinyl group, a thiomonole folinyl group, an imidazolidinyl group or a birazolidyl group, preferably a piperazinyl group, a morpholinyl group or a thiomorpholinyl group, and particularly preferably a 4-morpholinyl group. is there.
  • a 5- or 6-membered cyclic heteroaryl group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms is, for example, a furyl group, a chenyl group Group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrazul group, pyrimidinyl group or pyridazinyl group, preferably imidazolyl group, thiazolyl group or oxazolyl group And particularly preferably a 2-oxazolyl group.
  • the “5- or 6-membered cyclic heteroarylamino group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms” in the definition of R 3 is, for example, furylamino Group, chenylamino group, pyrrolylamino group, imidazolylamino group, virazolylamino group, thiazolylamino group, isothiazolylamino group, oxazolylamino group, isoxazolylamino group, pyridylamino group, pyrazinylamino group, pyrimidinylamino group or pyridinyl group It may be a dinylamino group, preferably an imidazolylamino group, a thiazolylamino group or an oxazolylamino group, particularly preferably a 2-thiazolylamino group.
  • the “mono (C i -C 6 alkyl) -powered rubamoyl group” in the definition of R 3 is, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylpowered rubamoyl group, an isopropylpowered rubamoyl group, a butyl carbamoyl group Nore group, isobutyl canolebamoy Or a s-butylcarbamoyl group, a t-butylcarbamoyl group, a pentylcarbamoyl group or a hexylcarbamoyl group, preferably a mono (C i -C 4 ) alkyl group.
  • the “di-C 6 alkyl) caproluvyl group” in the definition of R 3 is, for example, N, N-dimethylcanolebamoyl group, N-ethyl-N-methynolecanoreno moyl group, N-methyl-1-N —Isopropynolecanolebamoyl group, N, N-Jetinolecanolenomoyl group, N, N-dipropyl rubamoyl group, N, N-diisopropyl rubamoyl group, N, N-dibutylcarbamoyl group, N, N —Diisobutylcarbamoyl, N, N-di-s-butylcarbamoyl, N, N, N
  • the “C i -C 6 alkanoylamino group” in the definition of R 3 represents a linear or branched alkanoylamino group having 1 to 6 carbon atoms, for example, formino amino Group, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, bivaloylamino or hexanoylamino, preferably C2-C5 alkanoylamino.
  • R la , R lb , Rlc, R 2, R 3 and A have the same meanings as described above.
  • the compound represented by the general formula (la) It has the formula (Ic), and particularly preferably has the general formula (Ic).
  • R 3 is a heteroarylamino group in the compound (I) of the present invention
  • the corresponding pharmacologically acceptable salt can be obtained by treating the compound with an acid according to a conventional method.
  • compound (I) is treated with a corresponding acid in a solvent (eg, ethers, particularly dioxane) for 5 to 30 minutes at room temperature, and the precipitated crystals are collected by filtration or the solvent is distilled off under reduced pressure. Can be obtained.
  • a solvent eg, ethers, particularly dioxane
  • Such salts include mineral salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonate, trifluoromethanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate or p-toluenesulfonate; carboxylate salts such as fumarate, succinate, citrate, tartrate, oxalate or maleate; Or amino acid salts such as glutamate or aspartate.
  • mineral salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate
  • methanesulfonate trifluoromethanesulfonate
  • Sulfonates such as ethanesulfonate, benzenesulfonate or p-toluenesulfon
  • the compound (I) or a salt thereof of the present invention may absorb moisture, become adsorbed water, or form a hydrate when left in the air or recrystallized. Such water-containing compound salts are also included in the present invention.
  • the compound (I) of the present invention or a salt thereof has an asymmetric carbon atom in the molecule, and there are stereoisomers each having an R configuration or an S configuration. Any mixture in any proportion is encompassed by the present invention.
  • preferred compounds include
  • R 1 b and R 1 c are the same or different, a hydrogen atom, the compound is a methyl group or Echiru group,
  • R 1 b and R 1 c are the same or different and are hydrogen or methyl.
  • R 2 compounds such as butyl, isobutyl, pentyl or hexyl
  • R 3 force piperazinyl group, morpholinyl group, thiomorpholinyl group, imidazolyl group, thiazolyl group, oxazolyl group, imidazolylamino group, thiazolylamino group, oxazolylamino group, cyano group, hydroxyl group, hydroxy Compounds which are a siminomethyl group, a carboxy group, a carbamoyl group, a mono (di-C 4) alkyl carbamoyl group, a di (C! -C 4 alkyl) carbamoyl group, a butyrylamino group or a vivaloylamino group, 8/03647
  • R3 force 4-morpholinyl group, imidazolyl group, thiazolyl group, oxazolyl group, 2-thiazolylamino group, cyano group, carbamoyl group, methylcarbamoinole group, ethylcarbamoyl group, N, N-dimethyl
  • R3 compounds which are S, 2-oxazolyl, cyano, rubamoyl, methylcarbamoyl or N, N-dimethylcarbamoyl;
  • the preferred rank goes up from (1) to (3), and for R 2 , the preferred rank goes up from (4) to (5).
  • R 3 the preferred rank rises from (6) to (8), and for A, the preferred rank rises from (9) to (10).
  • the compound having the general formula (I) may be selected from the group consisting of (1)-(3), (4)-(5), (6)-(8) and (9)-(10). 4 to 4 and any combination of them can be mentioned. Preferred examples of the combination include, for example,
  • R 1 b and R 1 c are the same or different, a hydrogen atom, a methyl group or Echiru group,
  • R 2 butyl group, isobutyl group, pentyl group or hexyl group
  • R 3 piperazinyl group, morpholinyl group, thiomorpholinyl group, imidazolinole group, thiazolyl group, oxazolyl group, imidazolylamino group, thiazolylamino group, oxazolylamino group, cyano group, hydroxyl group, hydroxyiminomethyl group, Carboxy Group, carbamoyl group, mono (C i -C 4) alkyl carbamoyl group, di (C i -C ⁇ ⁇ ⁇ alkyl) carbamoyl group, butyrylamino group or bivaloylamino group, and A is a single bond, methylene group, ethylene group Or a compound that is a trimethylene group,
  • R 1 b and R 1 c are the same or different, a hydrogen atom or a methyl group, R 2 is pentyl group,
  • R 3 4-morpholinyl group, imidazolyl group, thiazolyl group, oxazolyl group, 2-thiazolylamino group, cyano group, carbamoyl group, methylcarbamoyl group, ethylcasazolevamoinole group, N, N-dimethinole valvamoyl group , N-ethyl-N-methynole group, N, N-getylcarbamoyl group or Vivaloylamino group,
  • R 1b and R 1c are methyl groups
  • R 2 is a pentyl group
  • R 3 is 2-oxazolyl group, cyano group, rubamoyl group, methylcarbamoyl group or N, N-dimethylcarbamoyl group;
  • Representative compounds of the present invention include, for example, the compounds described in the following table, but the present invention is not limited to these compounds.
  • the abbreviations in the table are as follows.
  • H0N H32 H32 HD Ing H-£ no-z OS I ng H-£ HO-Z 6
  • HON HD u d mz ⁇ - ⁇ 90
  • H0N H3 i "8 m- ⁇ m- £ HO-ja 199
  • HON HD 2 H3 "d -s-£ HO- OIL
  • HON H3 «d m-s ⁇ HO-60
  • HON HD z HD ud ms ia- ⁇ HO- 89
  • H0N H3 ud ia- ⁇ ⁇ -se L9L
  • CU P 0-.a, CU.. A.
  • H0N H3 Z HD mt HO-ja 9ZS
  • HON HD X H m- ⁇ m- £ HO ZZ6
  • suitable compounds in the phenol derivative having the general formula (I) of the present invention include, but are not limited to, exemplified compound numbers 60, 61, 64, 69, 72, 73, 74, 75, 83, 92, 93, 97, 105 , 108, 1 1 1, 1 1 5, 1 23, 1 52, 3 1 1, 31 7, 327, 33 1, 332, 333, 334, 336, 34 1, 342, 346, 356, 36
  • Particularly preferred compounds include
  • Illustrative Compound No. 61 3- (2-hydroxy-3-methylphenyl) octanoic acid (2_t-butyl-5-morpholine-4-ylmethylphenyl) amide
  • Illustrative Compound No. 72 3- (2- Hydroxy-1-methylphenyl) octanoic acid (2-t-butyl-5-oxazole-12-ylphenyl) amide
  • Illustrative Compound No. 11 3- (2-Hydroxy-13-methylfuunyl) octanoic acid [5- (acetylaminomethyl) -12-t-butylphenyl] amide, Illustrative Compound No. 11: 3- (2-hydroxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2,2-dimethylpropionylaminomethyl) phenyl] amide,
  • Exemplified Compound No. 714 3- (4-hydroxy-1,3,5-dimethylphenyl) octanoic acid (2-tbutyl-5-canolebamoylmethylpheninole) amide
  • Exemplified Compound No. 715 4- t-Butyl-3- [3- (4-hydroxy-1,3,5-dimethinolepheninole) mino] —N-methylbenzamide
  • Exemplified Compound No. 71 9 4-t-butyl-13- [ 3- (4-Hydroxy-1,3,5-dimethynolepheninole) octamino] -N, N-dimethylbenzamide.
  • the method for producing the compound of the present invention is shown below.
  • R la , R lb , R lc , R 2 , R 3 and A have the same meanings as described above
  • R 4 represents a hydroxyl-protecting group
  • R 5 represents C i represents an i-C 6 alkyl group
  • B ut represents a tert-butyl group.
  • the “protecting group for hydroxyl group” of R 4 can be generally used without particular limitation as long as it is a group used as a protecting group for hydroxyl group.
  • Me methoxymethyl group
  • MEM methoxymethyl group
  • MEM 2-methoxyethoxymethyl group
  • BOM benzyloxymethyl group
  • Bn benzyl group
  • it may be an acetyl group (Ac), particularly preferably a methyl group.
  • the “ ⁇ ⁇ -C 6 alkyl group” of R 5 represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2- Methylpentyl group, 1-methylpentinole group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group , A 2,3-dimethylbutyl group or a 2-ethylbutyl group, preferably
  • Method A is a method for producing compound (I). Step A 1 (deprotection)
  • This step is a step of producing the compound (I) by removing the hydroxyl-protecting group (R 4 ) of the compound having the general formula (II).
  • Compound (I) can be produced.
  • the solvent used in the Al (1) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hexane, heptane, rigoin, and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as toluene, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; nitriles such as acetonitrile; formamide, dimethylformamide, dimethylacetamide, hexane Methylphosphoramide (HMPA) or hexame Le phosphoramidite Austria Mi de (H MPT) Ami de, such as; give a or dimethyl sulfoxide or sulfoxide, such as sulfolane, preferably a halogenated hydrocarbon (particularly dichloromethane).
  • the reaction temperature of the Al (1) step varies
  • the reaction time of the Al (1) step varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 3 hours.
  • the target compound of the Al (1) step is collected from the reaction mixture according to a conventional method.
  • alcohol or the like preferably methanol
  • the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (for example, benzene, Ether, ethyl acetate, etc.), and the mixture is extracted.
  • the organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the solvent used in Step A1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.For example, it is the same as that in Step Al (1). And preferably halogenated hydrocarbons (especially black form).
  • the reaction temperature of the step A1 (2) varies depending on the starting compounds, reagents and the like, but is usually from 18 to 50 ° C, preferably from 0 to 30 ° C.
  • the reaction time of the step A1 (2) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 2 hours.
  • the target compound of Step A1 (2) is collected from the reaction mixture by a conventional method.
  • a small amount of water is added to the reaction solution to decompose excess reagents, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (for example, benzene, ether) , Ethyl acetate, etc.), and the mixture is extracted.
  • the organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Method B is a method for separately producing a compound having the general formula (IIa), a compound having the general formula (Ic), and a compound having the general formula (Id), which are the starting compounds of the method A.
  • This step is a step of producing a compound (IIa) by reacting a compound having the general formula (III) with a reducing agent in an inert solvent.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene
  • Ethers such as pyrether, tetrahydrofuran, dioxane, dimethoxetane or methylenglycol dimethyl ether, preferably aromatic hydrocarbons (particularly toluene).
  • the reducing agent used is, for example, an aluminum borohydride such as lithium borohydride.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 100 to 50 ° C, preferably from 178 to 30 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • an alcohol or the like preferably methanol
  • the reaction solution is added to a saturated saline solution or a solvent immiscible with water (for example, benzene, ether, or the like).
  • a saturated saline solution or a solvent immiscible with water for example, benzene, ether, or the like.
  • an ethyl acetate and a drying agent such as anhydrous magnesium sulfate
  • the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing a compound having the general formula (IV) by reacting the compound (IIa) with an oxidizing agent in an inert solvent.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and has a certain amount of starting materials.
  • aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, chloroform and dichloroethane.
  • Halogenated hydrocarbons esters such as ethyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxetane; ketones such as acetone or methyl ethyl ketone; or acetonitrile Or nitriles such as isobutyronitrile, preferably halogenated hydrocarbons (especially dichloromethane or chloroform).
  • the oxidizing agent used examples include manganese oxides such as manganese dioxide; chromic acid compounds such as chromic anhydride-pyridine complex; reagents usable for DMSO oxidation (dimethyl sulfoxide and dicyclohexylcarbodi- dium). Imide, oxalyl chloride, anhydrous Acetic acid or complex with pentoxide or pyridine-sulfuric anhydride complex); 4-methylmorpholine-4 using as a catalyst peroxide oxide such as Des' Martin reagent or tetrapropylammonium perruthenate —Oxides, preferably manganese oxides, especially manganese dioxide.
  • manganese oxides such as manganese dioxide
  • chromic acid compounds such as chromic anhydride-pyridine complex
  • reagents usable for DMSO oxidation dimethyl sulfoxide and dicyclohexylcarbodi- dium.
  • the reaction temperature varies depending on the solvent, raw materials, reagents and the like, but is usually from 150 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the solvent, the raw material, the reagent, the reaction temperature and the like, but is usually from 1 hour to 24 hours, preferably from 2 hours to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a catalyst when used, the catalyst is appropriately filtered off, the solvent is distilled off, water is added to the reaction solution, and a water-immiscible solvent (such as benzene, ether or ethyl acetate) is added.
  • a water-immiscible solvent such as benzene, ether or ethyl acetate
  • the organic layer containing the target compound is washed with water, dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing a compound having the general formula (V) by removing the hydroxyl-protecting group (R 4) of the compound (IV), and is carried out under the same conditions as in the step A1. be able to.
  • Step B 4 (Oximization)
  • a compound (Ic) is produced by reacting compound (V) with hydroxylamine or hydroxylamine hydrochloride in an inert solvent in the presence or absence (preferably in the presence) of a base. It is.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • examples thereof include aliphatic hydrocarbons such as hexane, heptane, rigoin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dibenzene Halogenated hydrocarbons such as benzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; esters such as ethyl acetate or propyl acetate; Nitriles; ketones such as acetone or methyl ethyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkaline metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium acetate; Alkali metal hydrides such as lithium hydride, sodium hydride or hydrogen hydride; alkaline metal hydrides such as sodium hydroxide, potassium hydroxide or lithium hydroxide Alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium t-butoxide or lithium methoxide; mercaptan alkali metals such as methyl mercaptan sodium or ethyl mercaptan sodium; Triethylamine, Tributylamine, Isopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo
  • Organics such as nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] pentadec-7-ene (DBU) Amines; alkyl lithiums such as methyl lithium, ethyl lithium or butyl lithium; lithium alkyl amides such as lithium diisopropyl amide or lithium dicyclohexyl amide; preferably, alkali metal Acetates (especially sodium acetate) or organic amines (especially triethylamine).
  • the reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from 150 ° C to 100 ° C. More preferably, the temperature is from 20 ° C. to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, water is added to the obtained residue, and a solvent that is immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed.
  • the organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • This step is a step of reacting the compound (Ic) with a dehydrating agent in an inert solvent to produce the compound (Id).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene
  • getyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl alcohol
  • alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isoptanol
  • formamide, dimethylformamide Amides such as methylacetamide, hexamethylphosphoramide (HMPA) or hex
  • the dehydrating agent to be used is not particularly limited as long as it is usually used for a dehydration reaction.
  • phosphorus compounds such as phosphorus pentachloride, and carboerdiimidazole (CDI) Such as imidazoles or dicyclohexylcarbodiimide (DCC)
  • CDI carboerdiimidazole
  • DCC dicyclohexylcarbodiimide
  • carboxyalkyl carbodiimides preferably carbodimidazole.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 5 days, preferably 12 hours to 3 days.
  • the target compound of this step is collected from the reaction mixture according to a conventional method as in Step B4.
  • a conventional method as in Step B4.
  • the starting compounds (VI), (IX), (XI 1), (XV), (XVI 11), (XIX), (XXI), (XXII) and (XXIII) known Alternatively, it is easily manufactured according to a known method or a method similar thereto.
  • the starting compounds (II) and (III) are known or are easily produced according to known methods or methods analogous thereto. [For example, JP-A-9-1143137 (EP0763524) and the like].
  • the starting compounds (II) and (III) can also be produced by the following method.
  • R 3 a Is a 5- or 6-membered cyclic saturated heterocyclyl group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms
  • R 3 b is nitrogen, an oxygen and a heteroaryl group the hetero atom to one or two containing 5 In ⁇ optimum 6-membered ring is selected from the group consisting of sulfur atom, R4 a represents a methyl group, R6 also hydrogen atoms C; indicates L -C 6 alkyl group, R 7 represents a C i -C 6 Arukanoiru group, a a is -CA alkyl Shows the emission group, X represents a halogen atom.
  • nitrogen heteroaryl group oxygen and to be selected from the group consisting of sulfur atom TeroHara terminal 1 or to 2 containing 5-membered or 6-membered ring includes, for example, furyl group, Ji Phenyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyragel group, pyrimidinyl group or pyridazinyl group, preferably imidazolyl group, thiazolyl group Or an oxazolyl group, particularly preferably a 2-oxazolyl group.
  • R 3a “5- or 6-membered cyclic heteroarylamino group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms” is, for example, a furylamino group, a chenylamino group , Pyrrolylamino, imidazolylamino, virazolylamino, thiazolylamino, isothiazolylamino, oxazolylamino, isoxazolylamino, pyridylamino, pyrazuramino, pyrimidinylamino or pyridazinylamino It is possible, preferably, imidazolylamino, thiazolylamino or oxazolylamino, particularly preferably 2-thiazolylamino.
  • C i - C 6 alkyl group refers to 1 to 6 straight or branched chain aralkyl Kill group carbon atoms, such as methyl group, Echiru group, a propyl group, an isopropyl group, butyl group, isobutyl Group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl Group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3 —Dimethylbutyl or 2-ethylbutyl, preferably c-C ⁇ alkyl, More
  • C l -C 6 Arukanoiru group represents an alk noisy Rua amino group of straight or branched chain having 1 to 6 carbon atoms, e.g., formyl group, Asechiru group, a propionyl group, a butyryl group, It may be an isobutyryl group, a valeryl group, an isovaleryl group, a bivaloyl group or a hexanoyl group, preferably a C 2 -C 5 alkanoyl group, more preferably a butyryl group or a vivaloyl group, and particularly preferably It is a vivaloyl group.
  • the “C i -C 4 alkylene group” of A a is, for example, a methylene group, a methylmethylene group, a dimethylmethylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, a 1-methyltrimethylene group, or 2-methyl It may be a linear or branched alkylene group having 1 to 4 carbon atoms such as a trimethylene group or a 3-methyltrimethylene group, preferably a methylene group, an ethylene group or a trimethylene group. Is a methylene group or an ethylene group, particularly preferably a methylene group.
  • halogen atom of X can be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a chlorine atom or a bromine atom.
  • the method C is a method for producing a compound (III) which is a raw material compound of the method B, a compound having the general formula (lib), and a compound having the general formula (lie) which are raw material compounds of the method A.
  • This step is a step for producing a compound having the general formula (VII) by protecting the hydroxyl group of the compound (VI).
  • Step C1 (1) The solvent used in Step C1 (1) is not particularly limited as long as it does not inhibit the reaction and does not dissolve the starting material to some extent, but may be, for example, the same as in Step B5.
  • Preferred are amides (particularly dimethylformamide).
  • the base used in Step C1 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate.
  • Metal alkoxides such as sodium methoxide, sodium methoxide, potassium t-butoxide or lithium methoxide; metal alkoxides such as methyl mercaptan sodium or ethyl mercaptan sodium
  • alkyllithiums such as methyllithium, ethyllithium or butyllithium Lithium alkylamides such as lithium diisopropyl pyramide or lithium dicyclohexylamide, preferably alkali metal hydrides (particularly sodium hydroxide).
  • the reaction time of the step C1 (1) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 12 hours, preferably 10 minutes to 3 hours.
  • Step C 1 (2) is collected from the reaction mixture according to a conventional method, similarly to Step B4.
  • Ethers such as dimethyl ether or alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, preferably ethers (especially getyl ether). It is.
  • the reaction temperature of the step C 1 (2) varies depending on the starting compounds, reagents, etc., but is usually from 20 ° C. to 50 ° C. C, preferably 0 ° C to 30 ° C.
  • the reaction time of the step C1 (2) varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 5 hours, preferably from 30 minutes to 2 hours.
  • Step C1 (2) After completion of the reaction, the target compound of Step C1 (2) is collected from the reaction mixture according to a conventional method in the same manner as in Step B4.
  • Step C2 (formylation)
  • This step is a step of producing a compound having the general formula (VIII) by reacting the compound (VII) with 11-formylpiperidine in an inert solvent in the presence of a base.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be the same as that in Step B5, and preferably the ethers ( In particular, tetrahydrofuran).
  • the base used can be, for example, the same as in step C1 (1), preferably alkyllithiums (particularly butyllithium).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 1100 ° C to 50 ° C, preferably from 178 ° C to 0 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 1 hour.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the excess reagent is decomposed by using a saturated aqueous solution of ammonium chloride or the like, then the solvent is distilled off, water is added to the obtained residue, and a solvent immiscible with water (for example, benzene, ether, (Ethyl acetate, etc.) to extract the target compound, then wash the extracted organic layer with water, dry over anhydrous magnesium sulfate, etc., and distill off the solvent to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of protecting the hydroxyl group of the compound having the general formula (IX), and can be performed under the same conditions as in Step C1.
  • Step C4 (formylation)
  • This step is a step of reacting compound (X) with 1-formylpiperidine in an inert solvent in the presence of a base to separately produce compound (VIII), under the same conditions as in step C2.
  • Step C5 KinnoeVenage1 reaction
  • This step is a step of producing a compound having the general formula (XI) by reacting the compound (VIII) with getyl malonate in an inert solvent in the presence of a base and an acid catalyst.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.For example, it may be an aromatic hydrocarbon such as benzene, toluene or xylene. Is benzene.
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction, and may be, for example, secondary amines, preferably pyrrolidine or piperidine.
  • the acid used is not particularly limited as long as it is used as an acid in a usual reaction.
  • it can be a carboxylic acid, and is preferably benzoic acid or acetic acid.
  • the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like, but is usually from 20 ° C to 150 ° C, and preferably from 70 ° C to 120 ° C.
  • the reaction time varies depending on the solvent, the raw material, the reagent, the reaction temperature and the like, but is usually from 1 hour to 48 hours, preferably from 5 hours to 30 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent eg, ethyl acetate
  • the mixture is washed with water (if necessary, using dilute hydrochloric acid or a saturated aqueous sodium hydrogen carbonate solution). Dry using anhydrous magnesium sulfate etc. and evaporate the solvent Thereby, the target compound is obtained.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound (XI) is reacted with a compound (Grignard reagent) having the general formula (XII) in an inert solvent to produce a compound having the general formula (XIII).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • it may be the same as that in Step B5, and preferably includes ethers ( Tetrahydrofuran).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 30 minutes to 1 hour.
  • Step C7 (hydrolysis, decarboxylation)
  • alkali metal hydroxide preferably sodium hydroxide, potassium hydroxide or lithium hydroxide
  • Step C7 (1) A step of producing a compound having the general formula (XIV) by heating in an inert solvent.
  • the solvent used in Step C7 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Examples include getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and the like.
  • Ethers such as dimethoxetane or diethylene glycol dimethyl ether; methanol, ethanol, prono; Alcohols such as ethanol, isopropanol, butanol or isobutanol; water or It may be a mixed solvent of the organic solvent and water, preferably an alcohol or a mixed solvent of alcohol and water, particularly preferably a mixed solvent of ethanol and water.
  • the reaction temperature of Step C7 (1) varies depending on the starting compounds, reagents and the like, but is usually from 10 to 100 ° C, preferably from 30 to 80 ° C.
  • the reaction time of the step C7 (1) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours.
  • the target compound of Step C7 (1) is collected from the reaction mixture by a conventional method.
  • a aqueous solution of sodium hydroxide is added to the reaction solution, and the aqueous layer is washed with a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.), and then concentrated hydrochloric acid is used.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the pH of the solution is made acidic, the target compound is extracted using a solvent that is immiscible with water (for example, benzene, ether, ethyl acetate, etc.), the extract is washed with water, and then anhydrous magnesium sulfate, After drying and distilling off the solvent, the target compound is obtained.
  • the resulting target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or close chromatography.
  • the compound obtained in this step can be used in the next step without purification. Does the solvent used in Step C7 (2) not hinder the reaction, and does the starting material have a certain degree of solubility?
  • aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene.
  • Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol.
  • aromatic hydrocarbons especially xylene).
  • the reaction temperature of Step C7 (2) varies depending on the starting compounds, reagents and the like, but is usually 30 ° C to 200 ° C, preferably 70 ° C to 150 ° C.
  • the reaction time of Step C7 (2) varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours.
  • the target compound of Step C7 (2) is collected from the reaction mixture by a conventional method. It is.
  • the target compound can be obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of reacting the compound (XIV) with a compound having the general formula (XV) in an inert solvent to produce a compound (III), which is a conventional method in peptide synthesis, for example, an active ester method. It is carried out according to the mixed acid anhydride method or the condensation method (preferably the active ester method).
  • the active ester method is carried out by reacting a compound (XIV) with an active esterifying agent in an inert solvent to produce an active ester, and then reacting the compound with the compound (XV) in an inert solvent.
  • the solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • examples include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and chloroform.
  • Halogenated hydrocarbons such as benzene or dichlorobenzene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether; acetonitrile or isobutyronitrile Or tolyls; or formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide
  • HM PA hexamethylphosphorous triamide
  • HM PT hexamethylphosphorous triamide
  • ethers especially tetrahydrofuran
  • nitriles especially acetonitrinole
  • amides especially dimethylformamide
  • the active esterifying agent used may be, for example, N-hydroxysuccinimide, N-hydroxybenzotriazole or N-hydroxy-15-norbornene-1,2,3-dicalpoxyimide.
  • a hydroxy compound or a disulfide compound such as dipyridyl disulfide, and the active esterification reaction is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbodildimidazole or triphenylphosphine.
  • the reaction temperature varies depending on the starting compounds, reagents, and the like, but is usually 120 for an active esterification reaction.
  • C preferably 0 ° C to 50 ° C
  • ⁇ 20 ° C to 100 ° C preferably 0 ° C to 50 ° C
  • the time required for the reaction varies depending on the starting compounds, the reagents and the reaction temperature, but is usually 30 minutes to 24 hours (preferably 1 hour to 12 hours) for both reactions.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer is washed with water, it is dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound (XIV) is reacted with a mixed acid anhydride in an inert solvent in the presence or absence (preferably in the presence of a base) of the mixed acid anhydride to produce a mixed acid anhydride.
  • the reaction is performed by reacting the mixed acid anhydride with the compound (XV) in an inert solvent.
  • the solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Examples include dichloromethane, chloroform, and carbon tetrachloride.
  • Halogenated hydrocarbons such as dichloroethane, cyclobenzene, dichlorobenzene or dichlorobenzene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; or It may be an amide such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphoratriamide (HMPT), preferably a halogenated compound. They are hydrocarbons (dichloromethane).
  • Mixed acid anhydride agent for example, halides such as chloride Okizariru Okizariru, carbonate such as click Lol carbonate Echiru or chloroformate isobutyl C i - C 4 Arukiruharai de, C as Pibaroirukurori de! -C 5 -C 4 alkyl or di-C such as alkanoyl halide or getylcyanolinic acid or diphenylcyanophosphoric acid It can be 6-C ⁇ 4 arylcyanophosphoric acid, preferably oxalyl halide (especially oxalyl chloride).
  • halides such as chloride Okizariru Okizariru
  • carbonate such as click Lol carbonate Echiru or chloroformate isobutyl C i - C 4 Arukiruharai de, C as Pibaroirukurori de! -C 5 -C 4 alkyl or di-C
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamido).
  • the reaction temperature in the reaction for producing the mixed acid anhydride is fluctuating depending on the starting compounds, reagents, etc., usually from 150 ° C to 100 ° C (preferably from 110 ° C to 50 ° C). is there.
  • the reaction time in the reaction for producing the mixed acid anhydride varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours).
  • the solvent used in the reaction between the mixed acid anhydride and the compound (XV) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • getyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether or formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethyl It may be an amide such as phosphorous triamide (HMPT), preferably an amide (particularly, dimethylformamide).
  • the reaction temperature in the reaction between the mixed acid anhydride and the compound (XV) varies depending on the starting compounds, reagents, etc., but is usually from 30 ° C to 100 ° C (preferably from 0 ° C to 80 ° C). It is.
  • the reaction time of the reaction between the mixed acid anhydride and the compound (XV) varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 12 hours). .
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and mixed with water.
  • the target compound is extracted by adding a solvent that does not soak (for example, benzene, ether, ethyl acetate, etc.), and the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off.
  • a compound is obtained.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the condensation method is carried out by reacting compound (lib) with compound (XV) in an inert solvent in the presence of a condensing agent.
  • the condensing agent used can be, for example, dicyclohexylcarbodiimide, carboediimidazole or 1-methyl-12-chloro-pyridemodioxide-triethylamine, preferably carberdiimide It is an imidazole.
  • This reaction can be carried out under the same conditions as in the above-mentioned reaction for producing an active ester.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer is washed with water, it is dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of reacting compound (III) with an alkali metal hydroxide (preferably sodium hydroxide, potassium hydroxide or lithium hydroxide) in an inert solvent to produce compound (IIb). Yes, it can be performed under the same conditions as in Step C7 (1).
  • Step C 10 (condensation)
  • compound (IIb) is reacted with hydrazine, ammonium, mono (C i -C 6 alkyl) amine or di (C -C 6 alkyl) amine in an inert solvent, if desired, to give compound (II lie) by a conventional method in peptide synthesis, for example, azide method, active ester method, mixed acid anhydride method or condensation method (preferably condensation method).
  • the azide method comprises the step of reacting a compound (lib) and hydrazine in an inert solvent [for example, formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphoamide].
  • Amides such as rastamide (HMPT), preferably dimethylformamide], at ⁇ 10 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.).
  • HMPT rastamide
  • the reaction is carried out by reacting an amino acid hydrazide produced by the reaction with a nitrite compound, converting it to an azide compound, and then treating it with ammonia.
  • the nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite.
  • the reaction is suitably carried out in an inert solvent and the solvents used are amides such as, for example, formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide; dimethylsulfoxide or It can be a sulfoxide such as a sulfolane; or a pyrrolidone such as N-methylpyrrolidone, and preferably an amide (particularly, dimethylformamide).
  • amides such as, for example, formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide
  • dimethylsulfoxide or It can be a sulfoxide such as a sulfolane
  • a pyrrolidone such as N-methylpyrrolidone
  • the reaction temperature varies depending on the raw material compounds, reagents, etc., but usually the azidation step is from 170 ° C. to 50 ° (preferably from ⁇ 50 ° C. to 0 ° C.).
  • the temperature is from 70 ° C to 50 ° C (preferably from 10 ° C to 10 ° C).
  • the time required for the reaction varies depending on the starting compounds, the reagents, and the reaction temperature.
  • the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia is usually performed. 5 hours to 7 days (preferably 10 hours to 5 days).
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the active ester method, the mixed acid anhydride method and the condensation method can be performed under the same conditions as in Step C8.
  • Method D is a step of producing a compound having the general formula (IId), which is a raw material compound of Method A. Step D 1 (Amidation)
  • Step C9 the compound (lib) obtained in Step C9 is reacted with aminoacetoaldehyde dimethyl acetal in an inert solvent in the presence of a condensing agent to form a compound having the general formula (XVI).
  • Step D2 formylation
  • the compound (XVI) is reacted with paratosylic acid in an inert solvent to produce a compound having the general formula (XVII).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether Hydrogens; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Jethyl ether, diisopropyl propyl Ethers such as tetra, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; -toro compounds such as nitromethane; acetonitrile or isobutyronitrile Nitriles; formamide Amides such as dimethylformamide, di
  • the reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 110 ° C to 150 ° C.
  • the temperature is preferably 50 ° C. to 100 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 4 hours.
  • Step D 3 Ring-closure reaction
  • This step is a step of reacting the compound (XVII) with iodine and triphenylphosphine in an inert solvent to produce the compound (Idd).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene
  • getyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether
  • ketones such as acetone or methyl ethyl ketone
  • dinitro compounds such as nitromethane
  • acetonitrile or isobbutyronitrile Nitriles formami Amides such as dimethylformamide, dimethylacetamide,
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 120 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours.
  • Method E is a process for producing a compound having the general formula (IIf) and a compound having the general formula (IIg), which are the starting compounds of the method A.
  • the compound (IIe) obtained by the method B is reacted with a tetrahalogenated carbon (preferably carbon tetrabromide or carbon tetrachloride) in an inert solvent in the presence of trifylphosphine, This is a step of producing a compound having the formula (XVIII).
  • a tetrahalogenated carbon preferably carbon tetrabromide or carbon tetrachloride
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be the same as in the Al (1) step, and Genated hydrocarbons (preferably dichloromethane).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 to 100 ° C, preferably from 0 to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
  • Step E2 (amination)
  • This step is a step of producing a compound (IIf) by reacting the compound (XVIII) with a compound having the general formula (XIX) in an inert solvent in the presence of sodium iodide.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, it may be the same as in the Al (1) step, (Particularly dimethylformamide).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C to 150 ° C, preferably 60 ° C to 120 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent eg, benzene, ether , Ethyl acetate, etc.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • the solvent used in the step E3 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • hexane, heptane, lignin, or petroleum ether Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or cyclobenzene; Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol dimethyl ether; -nitro compounds such as tromethane; nitriles such as acetonitrile or isobutyrrotrile; formamide , Dimethylformamide, dimethyl Amides such as
  • the reaction temperature of the step E3 (1) varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time of the step E3 (1) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
  • the target compound of Step E3 (1) is collected from the reaction mixture according to a conventional method, similarly to Step B4.
  • the solvent used in the step E3 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxetane or diethylene glycol dimethyl ether, or alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, preferably alcohols (preferably alcohols) Ethanol).
  • the reducing agent used in the step E3 (2) can be, for example, hydrogen (using Pd or the like as a catalyst), and is preferably hydrogen in the presence of a Pd catalyst.
  • the reaction temperature of the step E3 (2) varies depending on the starting compounds, reagents and the like, but is usually from 10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.
  • the reaction time of the step E3 (2) varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 1 hour to 15 hours.
  • the target compound of Step E3 (2) is collected from the reaction mixture by a conventional method.
  • the catalyst is removed by filtration and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • This step is a step of reacting compound (XX) with a compound having the general formula (XXI) in an inert solvent in the presence of a base to produce compound (I Ig).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be the same as in the Al (1) step, and Genated hydrocarbons (particularly dichloromethane).
  • the bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium acetate such as sodium acetate.
  • Alkali metal acetic acid Salts or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-ethylethylamine, 1,5-diazabicyclo [4.3.0] nonane 5-ene, 1,4-diazabicyclo [2.2.2] octane (D AB CO) or 1,8-diazabicyclo [5.4.0] It can be an organic amine such as 7-ene (DBU), preferably an organic amine (especially triethylamine).
  • DBU 7-ene
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method as in Step E2.
  • dimethylaminopyridine or pyridine can be used as a catalyst.
  • Method F is a process for producing a compound having the general formula (IIh), which is a starting compound of Method A. Step F 1 (condensation)
  • a compound having the general formula (XXIV) is reacted with a compound having the general formula (XXIII) in an inert solvent in the presence of a base to produce a compound having the general formula (XXIV) It is a process.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.For example, it may be the same as that in Step Al (1), and preferably, Halogenated hydrocarbons (preferably dichloromethane).
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, hydrogen carbonate or lithium hydrogen carbonate; sodium acetate.
  • Alkali metals such as sodium hydroxide, potassium hydroxide or lithium hydroxide Hydroxides; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium t-butoxide or lithium methoxide; mercaptan alkaline metals such as methyl mercaptan natrium or ethyl mercaptan natrium; triethylamine , Triptyluamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylylaniline, N, N-Jetylaniline, 1,5-diazabicyclo [4.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 112 hours, preferably 3 hours to 10 hours.
  • Step F 2 Mitsubishi reaction
  • This process is inert according to the Mitsunobu reaction described in Bulletin Chemical 'Sociati' Japan, Vol. 40, p. 2380 (1 967) [Bull. Chem. Soc. Jap., 40, 2380 (1967).
  • This is a step of producing a compound having the general formula (XXV) by subjecting the compound (XXIV) to a dehydration condensation reaction with the corresponding compound (IIe) in a solvent in the presence of a phosphine and an azo compound.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • examples thereof include aliphatic hydrocarbons such as hexane, heptane, rigoin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, or dichlorobenzene; or Jethyl ether, diisopropane It can be an ether such as mouth pill, tetrahydrofuran, dioxane, dimethyloxetane or dimethylene glycol dimethyl ether, preferably an aliphatic hydrocarbon.
  • aromatic hydrocarbons or ethers more preferably aromatic hydrocarbons (particularly benzene).
  • the phosphines used include, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexynolephosphine, and other tri-C ⁇ -C6a / lequinolephosphine; triphenylenophosphine; Tri-C 6 -C 10 arylphosphine such as triindenylphosphine or trinaphthylphosphine; or tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl.
  • C 4 alkyl birds which may have as substituents C 6 - C ⁇ be 0 ⁇ reel phosphine, preferably tri C ⁇ is - C 6 alkyl Le phosphines (especially trimethyl Phosphine, triethylphosphine, Tripropyl phosphine or tributyl phosphine) or tri C 6 —C 10 aryl phosphine (especially triphenyl phosphine, triindul phosphine or trinaphthyl phosphine), and more preferably tri C 6 — C ⁇ 0 aryl phosphine (especially triphenyl phosphine).
  • the azo compound used can be a di-C4 alkyl azodicarboxylate such as, for example, dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate, preferably dimethyl azodicarboxylate or azodicarboxylate This is Jechil.
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 10 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C.
  • the reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours, preferably 10 minutes to 4 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if any insolubles are present, they are filtered off and the solvent is distilled off to give the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step F3 (elimination reaction) This step is a step of reacting compound (XXV) with a base in an inert solvent to produce compound (IIh).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be the same as in the Al (1) step, and is preferably a halo.
  • Genated hydrocarbons particularly dichloromethane).
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, water Alkali metal hydroxides such as potassium oxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; sodium metal ethoxide, such as methyl mercaptan sodium or ethyl mercaptan Mercaptan alkali metals: propylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4_
  • N N-dimethylamino
  • pyridine N, N-dimethylaniline, N, N-ethylaniline, 1,5-diazabicyclo [4.3.0] nona 5-ene, 1,4-diazabicyclo [ 2.2.2]
  • Organic amines such as octane (DAB CO) or 1,8-diazabicyclo [5.4.0] pendeic 7-ene (DBU), and preferably, organic amines ( Preferably propylamine).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 to 100 ° C, preferably from 0 to 50 ° C.
  • the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 1 hour to 72 hours, preferably 24 hours to 36 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method as in Step E2.
  • Method G produces a compound having the general formula (IIi), a compound having the general formula (IIj) which is a starting compound of the method A, and a compound having a general formula (Ilia) which is a starting compound of the method B. Is the way.
  • Step G 1 (Wittig reaction)
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples thereof include aromatic hydrocarbons such as benzene; getyl ether, tetrahydrofuran, dioxane or Ethers such as dimethoxetane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; or sulfoxides such as dimethylsulfoxide or sulfolane.
  • aromatic hydrocarbons such as benzene
  • getyl ether, tetrahydrofuran, dioxane or Ethers such as dimethoxetane
  • amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide
  • sulfoxides such as dimethylsulfoxide or sulfolane.
  • ethers especially tetrahydrofuran
  • amides especially dimethylformamide
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, and is, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride. And preferably lithium hydride or sodium hydride.
  • the reaction temperature varies depending on the solvent, the starting material, the reagent and the like, but is usually from -20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the solvent, raw materials, reagents, reaction temperature and the like, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 2 hours.
  • Step G2 (reduction of double bond)
  • This step is a step of reacting compound (XXVI) with a reducing agent in an inert solvent to produce compound (IIla), and is carried out under the same conditions as in step E3 (2).
  • Step G3 hydrolysis
  • Step G 4 (condensation)
  • Step C8 in an inert solvent in the presence a condensing agent, the compound (II i) ammonia, mono (CI - CQ alkyl) Amin or di (C; L -C 6 alkyl) is reacted with Amin, compound (II j ), And is performed under the same conditions as in Step C8.
  • Method H is a method for separately producing a compound having the general formula (Villa) in which R 4 is a methyl group in compound (VIII) which is an intermediate compound of method C.
  • Step H 1 protection of hydroxyl group and esterification of carboxylic acid
  • This step is a step of producing a compound having the general formula (XXIX) by reacting the compound (XXVIII) with a reducing agent in an inert solvent, and is carried out under the same conditions as in the step B1.
  • This step is a step of reacting compound (XXIX) with an oxidizing agent in an inert solvent to produce compound (VIIIa), and is performed under the same conditions as in step B2.
  • Example 1 Example 1

Abstract

L'invention concerne des dérivés de phénol représentés par la formule générale (I) ou leurs sels acceptables du point de vue pharmacologique, ces dérivés présentant une excellente activité dépressive contre l'oxydation de LDL et une activité inhibitrice contre ACAT et s'utilisant donc comme médicaments thérapeutiques et préventifs contre les affections artérioscléreuses. Dans la formule générale (I), R1a est hydroxyle, R?1b et R1c¿ sont chacun indépendamment hydrogène ou alkyle (à condition que R?1b ou R1c¿ soit alkyle); R2 est alkyle; et R3 est un groupe hétérocyclique saturé, un hétéroaryle, un hétéroarylamino, un cyano, un hydroxyle, un hydroxyiminométhyle, un carboxy, un carbamoyle, un monoalkylcarbamoyle, un dialkylcarbamoyle ou un alcanoylamino; et A est une liaison simple ou un alkylène.
PCT/JP1998/003647 1997-08-18 1998-08-17 Derives de phenol WO1999009002A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU86498/98A AU8649898A (en) 1997-08-18 1998-08-17 Phenol derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/221324 1997-08-18
JP22132497 1997-08-18

Publications (1)

Publication Number Publication Date
WO1999009002A1 true WO1999009002A1 (fr) 1999-02-25

Family

ID=16765026

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003647 WO1999009002A1 (fr) 1997-08-18 1998-08-17 Derives de phenol

Country Status (2)

Country Link
AU (1) AU8649898A (fr)
WO (1) WO1999009002A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0892222A (ja) * 1994-07-26 1996-04-09 Sankyo Co Ltd Ｎ−フェニルアミド及び尿素誘導体
JPH08325218A (ja) * 1994-11-10 1996-12-10 Sankyo Co Ltd Ｎ−フェニルプロピオン酸アミド及びｎ−フェネチル尿素体
JPH09143137A (ja) * 1995-09-18 1997-06-03 Sankyo Co Ltd アミド及び尿素誘導体
JPH09202775A (ja) * 1996-01-24 1997-08-05 Sankyo Co Ltd Ｎ−フェニルアミド及び尿素誘導体を含有する医薬
JPH09249628A (ja) * 1996-03-12 1997-09-22 Tanabe Seiyaku Co Ltd フェノール誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0892222A (ja) * 1994-07-26 1996-04-09 Sankyo Co Ltd Ｎ−フェニルアミド及び尿素誘導体
JPH08325218A (ja) * 1994-11-10 1996-12-10 Sankyo Co Ltd Ｎ−フェニルプロピオン酸アミド及びｎ−フェネチル尿素体
JPH09143137A (ja) * 1995-09-18 1997-06-03 Sankyo Co Ltd アミド及び尿素誘導体
JPH09202775A (ja) * 1996-01-24 1997-08-05 Sankyo Co Ltd Ｎ−フェニルアミド及び尿素誘導体を含有する医薬
JPH09249628A (ja) * 1996-03-12 1997-09-22 Tanabe Seiyaku Co Ltd フェノール誘導体

Also Published As

Publication number Publication date
AU8649898A (en) 1999-03-08

Similar Documents

Publication Publication Date Title
US7557110B2 (en) Pyrazolo[1,5-A] pyrimidine derivatives
JP7046968B2 (ja) ２－（置換フェニルヘテロ）芳香族カルボン酸系ｆｔｏ阻害剤、その製造方法およびその使用
US5883267A (en) Process for making phenyl heterocycles useful as cox-2 inhibitors
KR20020068388A (ko) 술폰아미드 함유 복소환 화합물
JPS6157587A (ja) 縮合複素環誘導体および抗潰瘍剤
Zhao et al. Design, synthesis, and biological evaluation of novel 4H-chromen-4-one derivatives as antituberculosis agents against multidrug-resistant tuberculosis
JP2010507674A (ja) マトリクスメタロプロテアーゼ阻害剤としての三環式化合物
WO2007036131A1 (fr) Dérivés de carzole sulfamide et leur procédé de préparation
CN107445896B (zh) 一种具有抗肿瘤活性的苯基异羟肟酸类化合物及其应用
KR20120080183A (ko) 신규 페놀 유도체
US6080876A (en) Process for making phenyl heterocycles useful as COX-2 inhibitors
CN115353508B (zh) 5-吡啶-1h-吲唑类化合物、药物组合物和应用
CN113330015A (zh) 已知四氢异喹啉衍生物的单磷酸盐水合物盐的多晶型物形式
KR101710740B1 (ko) 2-［［［2-［(히드록시아세틸)아미노］-4-피리디닐］메틸］티오］-ｎ-［4-(트리플루오로메톡시)페닐］-3-피리딘카르복사미드의 벤젠술폰산염, 이의 결정, 이의 결정 다형 및 이들의 제조 방법
WO2009131096A1 (fr) Composé possédant une activité d’antagoniste du récepteur y5 du npy
CN110872285A (zh) 作为受体相互作用蛋白1(rip1)激酶抑制剂的杂环化合物
Yamaoka et al. Structure–Activity Relationships of New 2-Acylamino-3-thiophenecarboxylic Acid Dimers as Plasminogen Activator Inhibitor-1 Inhibitors
JP5584696B2 (ja) Ｍｍｐ−１３阻害剤として有用なヘテロアリールジアミド化合物
JP2012505892A (ja) Ｍｍｐ−１３阻害剤として有用な縮合ヘテロアリールジアミド化合物
WO2020173417A1 (fr) Régulateur de transport nucléaire contenant de l'acryloyle et ses utilisations
CA2944805C (fr) Derive d'acide phosphonique de phenanthroline et son procede de preparation et d'utilisation
WO1999009002A1 (fr) Derives de phenol
CN101928259B (zh) 2-芳基噻唑衍生物及其药物组合物
KR20230078737A (ko) Fxr 저분자 작용제 및 이의 제조 방법과 용도
CZ391498A3 (cs) Způsob výroby fenylheterocyklů a sloučenina

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN CZ HU ID IL KR MX NO NZ PL RU TR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

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

Ref country code: KR

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA