WO2017006573A1 - Method for producing side chain precursor of paclitaxel and docetaxel - Google Patents

Method for producing side chain precursor of paclitaxel and docetaxel Download PDF

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WO2017006573A1
WO2017006573A1 PCT/JP2016/051372 JP2016051372W WO2017006573A1 WO 2017006573 A1 WO2017006573 A1 WO 2017006573A1 JP 2016051372 W JP2016051372 W JP 2016051372W WO 2017006573 A1 WO2017006573 A1 WO 2017006573A1
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compound
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PCT/JP2016/051372
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忠勝 萬代
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忠勝 萬代
塩水港精糖株式会社
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Priority to CN201680039925.4A priority Critical patent/CN107848990B/en
Priority to JP2017525638A priority patent/JP6205530B2/en
Priority to KR1020187003624A priority patent/KR20180027559A/en
Publication of WO2017006573A1 publication Critical patent/WO2017006573A1/en

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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
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a method for producing side chain precursors of paclitaxel and docetaxel.
  • Paclitaxel is a compound obtained by extraction from yew bark, and is known as an anticancer agent having cell growth inhibitory action. Paclitaxel has low solubility in water, and docetaxel is known as a compound that improves this.
  • Patent Document 1 discloses that (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) is converted to N-allyloxycarbonyl- (2R, 3S) -3-phenyl as shown in the following chemical reaction formula.
  • docetaxel can be obtained after reacting the obtained carboxylic acid (IV) with 7,10-diallyloxycarbonyl-10-deacetylbaccatin III (VI).
  • the starting compound (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) usually requires a multi-step synthesis, which may increase the cost.
  • the yield of the step of obtaining methyl ester (III) was also low, and improvement was desired.
  • Non-Patent Document 1 discloses (2R, 3S) -3-phenylisoserine hydrochloride in which the ester moiety in the above (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) is a carboxylic acid. The method of obtaining is described.
  • isopropyl cinnamate is used as a starting compound, osmium catalyst K 2 [OsO 2 (OH) 4 ], and ligand (DHQ) 2
  • osmium catalyst K 2 [OsO 2 (OH) 4 ] osmium catalyst K 2 [OsO 2 (OH) 4 ]
  • ligand (DHQ) 2 By reacting with PHAL or the like, isopropyl (2R, 3S) -3- (acetylamino) -2-hydroxy-3-phenylpropanoate is obtained and then hydrolyzed to give (2R, 3S)- It is said that 3-phenylisoserine hydrochloride is obtained.
  • the osmium catalyst and ligand are expensive and the osmium catalyst is toxic, a method that does not use such a catalyst or ligand has been desired.
  • the present invention has been made to solve the above-described problems, and an object of the present invention is to provide a side chain precursor of paclitaxel and docetaxel with high purity, high yield and low cost. Another object of the present invention is to provide paclitaxel and docetaxel that are useful as anticancer agents by using the side chain precursor thus obtained.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • a compound represented by formula (3) is used as a starting compound: [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ] It is solved by providing the manufacturing method of the compound shown by these.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 2 is an aryl group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 2 is an aryl group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 2 is an aryl group
  • R 3 is an alkoxy group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is hydrogen An atom or a methyl group.
  • side chain precursors of paclitaxel and docetaxel can be provided with high purity, high yield and low cost.
  • the side chain precursor thus obtained can be used to provide paclitaxel and docetaxel that are useful as anticancer agents.
  • the production method of the present invention comprises a compound represented by the following formula (3) (hereinafter referred to as “carboxylic acid compound”) using a compound represented by the following formula (1) (hereinafter sometimes referred to as “diazo compound”) as a starting compound. It may be called).
  • the compound represented by the following formula (3) is a side chain precursor of docetaxel, and the production method of the present invention is employed because docetaxel that is useful as an anticancer agent can be obtained using the side chain precursor thus obtained. The significance of doing is great.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2).
  • Y is a hydrogen atom or a methyl group.
  • R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group.
  • R 1 is preferably an alkoxy group, an arylalkyloxy group or an alkoxycarbonyloxy group, and more preferably an alkoxy group or an alkoxycarbonyloxy group. And more preferably an alkoxy group.
  • alkoxy group examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an isopentyloxy group.
  • These alkoxy groups may have a substituent.
  • a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 1 .
  • arylalkyloxy group examples include phenylmethyloxy group, phenylethyloxy group, phenylbutyloxy group, phenylpentyloxy group, phenylhexyloxy group, naphthylmethyloxy group, and the like. These arylalkyloxy groups may have a substituent.
  • alkylsilyloxy group examples include a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, a tert-butyldimethylsilyloxy group, and a tert-butyldiphenylsilyloxy group. These alkylsilyloxy groups may have a substituent.
  • alkoxycarbonyloxy group examples include a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, an isopropoxycarbonyloxy group, an n-butoxycarbonyloxy group, an isobutoxycarbonyloxy group, and a sec-butoxycarbonyl group.
  • examples thereof include an oxy group, a tert-butoxycarbonyloxy group, a pentyloxycarbonyloxy group, a hexyloxycarbonyloxy group, a heptyloxycarbonyloxy group, and an octyloxycarbonyloxy group.
  • These alkoxycarbonyloxy groups may have a substituent.
  • R 2 is an aryl group.
  • the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. These aryl groups may have a substituent. Among them, a phenyl group or a naphthyl group are preferably used as R 2.
  • X is one selected from the group consisting of substituents represented by the following formula (2).
  • X is preferably one selected from the group consisting of substituents represented by the following formula (2a) from the viewpoint of relatively easy preparation.
  • Y is a hydrogen atom or a methyl group. Among them, Y is preferably a methyl group.
  • R 2 is an aryl group.
  • the same substituents as those exemplified in the description of R 2 in the above formula (1) can be used. Among them, a phenyl group or a naphthyl group are preferably used as R 2.
  • R 3 is an alkoxy group.
  • the alkoxy group those similar to the substituents exemplified in the description of R 1 in the above formula (1) can be used. Of these, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 3 .
  • the method for obtaining the compound represented by the formula (1) is not particularly limited, and the compound represented by the formula (8) (hereinafter referred to as “oxime compound”) as shown in the following chemical reaction formula (I).
  • oxime compound the compound represented by the formula (8) (hereinafter referred to as “oxime compound”) as shown in the following chemical reaction formula (I).
  • a method for obtaining a compound represented by the formula (1) using a starting compound as a starting compound is preferably employed.
  • R 1, R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 1, R 2 and Y in the formula (1), X
  • the substituent represented by the formula (2a) exemplified in the description of the above formula (2) can be preferably used.
  • a diazotizing agent such as tosyl azide and a basic catalyst such as 1,8-diazabicyclo [5.4.0] undecene (DBU) with respect to the oxime compound represented by formula (8)
  • DBU 1,8-diazabicyclo [5.4.0] undecene
  • the diazo compound shown by Formula (1) can be suitably obtained by making it react using.
  • the amount of the diazotizing agent used is preferably 1 to 10 mol, more preferably 1 to 4 mol, relative to 1 mol of the oxime compound represented by the formula (8).
  • the amount of the basic catalyst used is preferably 0.01 to 1 mol, preferably 0.05 to 0.5 mol, with respect to 1 mol of the oxime compound represented by the formula (8). More preferred.
  • the method for obtaining the compound represented by the above formula (8) is not particularly limited, and the compound represented by the formula (9) (hereinafter referred to as “ester compound”) as shown in the chemical reaction formula (II-1) below.
  • a method for obtaining a compound represented by the formula (8) using as a starting compound is preferably employed. Therefore, as shown in the following chemical reaction formula (II-2), a compound represented by the formula (8) is obtained using the compound represented by the formula (9) as a starting compound, and the obtained formula (8) is obtained.
  • a method for obtaining a compound represented by the formula (1) from a compound is a preferred embodiment of the present invention.
  • R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1).
  • R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1).
  • R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2)
  • the substituent represented by the formula (2a) exemplified in the description of can be preferably used.
  • the ester compound represented by the formula (9) is reacted with an oximation agent such as 0-methylhydroxylamine hydrochloride to give a formula (8)
  • the oxime compound shown by can be obtained suitably.
  • the amount of the oximation agent to be used is preferably 1 to 10 mol, more preferably 1 to 4 mol, per 1 mol of the ester compound represented by the formula (9).
  • the method for obtaining the compound represented by the formula (9) is not particularly limited, and the compound represented by the formula (10) and the alcohol represented by the formula (11) are represented by the following chemical reaction formula (III-1). Is preferably employed to obtain a compound represented by the formula (9). Accordingly, as shown in the following chemical reaction formula (III-2), a compound represented by the formula (9) is obtained by reacting a compound represented by the formula (10) with an alcohol represented by the formula (11). A method for obtaining a compound represented by formula (8) from the obtained compound represented by formula (9) and obtaining a compound represented by formula (1) from the obtained compound represented by formula (8) is described. It is a preferred embodiment of the invention.
  • R 2 is synonymous with Formula (1), R 4 is an alkyl group, and in Formula (11), X and Y are synonymous with Formula (1), 9) In the formula, R 2 , X and Y are as defined in the above formula (1). ]
  • R 2 is synonymous with Formula (1), R 4 is an alkyl group, and in Formula (11), X and Y are synonymous with Formula (1), 9) during, R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1). ]
  • R 4 is an alkyl group.
  • the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, Examples thereof include a tert-pentyl group, n-hexyl group, isohexyl group, 2-ethylhexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like. Among them, a methyl group, an ethyl group, an n-propyl group,
  • Y is preferably a methyl group as in the above formula (1), and X is one selected from the group consisting of substituents represented by the above formula (2a). It is preferable.
  • the alcohol represented by the formula (11) is more preferably L-menthol.
  • the ester compound represented by the formula (9) is suitably obtained by reacting the compound represented by the formula (10) with the alcohol represented by the formula (11). be able to.
  • the reaction temperature is preferably 60 to 150 ° C, more preferably 90 to 130 ° C.
  • the reaction time is preferably 2 to 20 hours.
  • the present invention is characterized in that a compound represented by the formula (3) is obtained using the compound represented by the formula (1) obtained as described above as a starting compound.
  • the compound represented by the formula (1) when used as a starting compound, the compound represented by the formula (4) (hereinafter referred to as “oxime alcohol compound”) as shown in the chemical reaction formula (IV-1) below. Is preferably used as an intermediate.
  • oxime alcohol compound as shown in the following chemical reaction formula (IV-2)
  • a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained.
  • a method for obtaining a compound represented by the formula (3) from a compound is a preferred embodiment of the present invention.
  • the compound represented by the formula (4) is also very useful as an intermediate compound.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2).
  • Y is a hydrogen atom or a methyl group.
  • R 1 , R 2 , X and Y are as defined in the formula (1).
  • R 2 is as defined in the formula (1), and R 3 is alkoxy. It is a group.
  • R 1, R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 1, R 2 and Y in the formula (1), X
  • the substituent represented by the formula (2a) exemplified in the description of the above formula (2) can be preferably used.
  • the diazo compound represented by the formula (1) is reacted with a carboxylic acid such as formic acid to obtain a carboxylic acid ester.
  • the oxime alcohol compound represented by the formula (4) can be suitably obtained by an ester exchange reaction using an alcohol and aqueous ammonia with respect to the acid ester. By such a method, the oxime alcohol compound represented by the formula (4) can be obtained as crystals.
  • a method of obtaining the compound represented by the formula (4) as an intermediate from the compound represented by the formula (1) is very useful. I understand that.
  • the amount of the carboxylic acid used is preferably 3 to 300 mol with respect to 1 mol of the diazo compound represented by the formula (1), and is 5 to 200 mol. It is more preferable.
  • the reaction temperature using carboxylic acid is preferably 20 to 100 ° C, more preferably 40 to 80 ° C.
  • the reaction time is preferably 1 to 10 hours.
  • the reaction temperature in the transesterification reaction is preferably 5 to 40 ° C., more preferably around room temperature.
  • the reaction time is preferably 0.5 to 5 hours.
  • the compound represented by the above formula (4) to the compound represented by the formula (5) (hereinafter sometimes referred to as “transaminoalcohol compound”) as shown in the chemical reaction formula (V-1) below.
  • a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained.
  • a preferred embodiment of the present invention is a method of obtaining a compound represented by the formula (5) from a compound and obtaining a compound represented by the formula (3) from the obtained compound represented by the formula (5).
  • the compound shown by Formula (5) is also very useful as an intermediate compound.
  • R 2 is an aryl group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 1, R 2, X and Y are as defined in the formula (1) wherein (5), R 2, X and Y are as defined in the formula (1).
  • R 1 , R 2 , X and Y are as defined in the formula (1), and in the formula (5), R 2 , X and Y are as defined in the formula (1),
  • R 3 is an alkoxy group.
  • R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2)
  • the substituent represented by the formula (2a) exemplified in the description of can be preferably used.
  • the transamino alcohol compound represented by the formula (5) can be suitably obtained.
  • the reaction time is preferably 1 to 10 hours, more preferably 2 to 8 hours.
  • the compound represented by the formula (5) to the compound represented by the formula (6) (hereinafter sometimes referred to as “carbamate compound”) is intermediated as shown in the chemical reaction formula (VI-1) below.
  • the method obtained as a body is preferably employed. Therefore, as shown in the following chemical reaction formula (VI-2), the compound represented by the formula (4) is obtained by using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained.
  • a compound represented by formula (5) is obtained from the compound, a compound represented by formula (6) is obtained from the obtained compound represented by formula (5), and the obtained formula (6) is obtained.
  • a method for obtaining a compound represented by the formula (3) from a compound is a preferred embodiment of the present invention.
  • the compound represented by the formula (6) is also very useful as an intermediate compound.
  • R 2 is an aryl group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is a hydrogen atom or a methyl group.
  • R 2, X and Y are as defined in the formula (1) wherein (6), R 2, X and Y are as defined in the formula (1).
  • R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2)
  • the substituent represented by the formula (2a) exemplified in the description of can be preferably used.
  • the trans amino alcohol compound represented by the formula (5) is reacted with allyl chloroformate to protect the amino group with an allyloxycarbonyl group (Alloc group).
  • the carbamate compound represented by the formula (6) can be suitably obtained.
  • the amount of allyl chloroformate to be used is preferably 1 to 10 mol, more preferably 1 to 4 mol, relative to 1 mol of the transaminoalcohol compound represented by the formula (5).
  • the reaction time is preferably 0.1 to 5 hours.
  • the compound represented by the above formula (6) to the compound represented by the formula (7) (hereinafter referred to as “N, O-acetal compound”) is represented by the following chemical reaction formula (VII-1). Is preferably employed as an intermediate. Therefore, as shown in the following chemical reaction formula (VII-2), a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained. A compound represented by formula (5) is obtained from the compound, a compound represented by formula (6) is obtained from the obtained compound represented by formula (5), and the obtained formula (6) is obtained.
  • a preferred embodiment of the present invention is a method of obtaining a compound represented by formula (7) from a compound and obtaining a compound represented by formula (3) from the obtained compound represented by formula (7).
  • the compound represented by the formula (7) is also very useful as an intermediate compound.
  • R 2 is an aryl group
  • R 3 is an alkoxy group
  • X is one selected from the group consisting of substituents represented by the following formula (2)
  • Y is hydrogen An atom or a methyl group.
  • R 2, X and Y are as defined in the formula (1) wherein (7), R 2, X and Y are as defined in the formula (1), R 3 is An alkoxy group; ]
  • R 1 , R 2 , X and Y are as defined in the formula (1), and in the formula (5), R 2 , X and Y are as defined in the formula (1), In formula (6), R 2 , X and Y have the same meaning as in formula (1), and in formula (7), R 2 , X and Y have the same meaning as in formula (1), and R 3 represents alkoxy. In the formula (3), R 2 has the same meaning as the formula (1), and R 3 is an alkoxy group. ]
  • R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1)
  • X is the formula (2)
  • the substituent represented by the formula (2a) exemplified in the description of can be preferably used.
  • R 3 is an alkoxy group.
  • the alkoxy group those similar to the substituents exemplified in the description of R 1 in the above formula (1) can be used. Of these, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 3 .
  • the carbamate compound represented by the formula (6) is acetalized using an anisaldehyde dimethyl acetal and an acid catalyst such as pyridinium p-toluenesulfonate (PPTS).
  • An N, O-acetal compound represented by the formula (7) can be preferably obtained.
  • the amount of anisaldehyde dimethyl acetal to be used is preferably 1 to 5 mol, more preferably 1.2 to 4 mol, relative to 1 mol of the carbamate compound represented by the formula (6).
  • the amount of the acid catalyst used is preferably 0.005 to 0.5 mol, more preferably 0.01 to 0.2 mol, relative to 1 mol of the carbamate compound represented by the formula (6). preferable.
  • the reaction time is preferably 0.5 to 10 hours.
  • an alcohol represented by the formula (11) can be suitably recovered by adding an organic solvent such as toluene or ethyl acetate and water after the reaction and concentrating the organic layer. Therefore, a method for producing a compound represented by the following formula (3), which comprises using a compound represented by the following formula (1) as a starting compound and recovering an alcohol represented by the following formula (11), is also disclosed in the present invention. This is a preferred embodiment.
  • R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group
  • R 2 is an aryl group
  • X is a substituent represented by the following formula (2).
  • Y is a hydrogen atom or a methyl group.
  • R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group.
  • docetaxel and paclitaxel can be suitably obtained using the compound represented by the formula (3) obtained as described above, and docetaxel can be more suitably obtained.
  • a method for obtaining paclitaxel will be described with reference to the following chemical reaction formula (VIII-1).
  • Z 1 is allyloxycarbonyl group or triethylsilyl group
  • R 2 is synonymous with the formula (1)
  • R 3 is an alkoxy group
  • R 2 has the same meaning as in the above formula (1)
  • R 3 is an alkoxy group
  • Z 2 is an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom.
  • a paclitaxel precursor represented by the formula (13) obtained by subjecting a baccatin III derivative represented by the formula (12) and a carboxylic acid compound represented by the formula (3) to a condensation reaction
  • the process of obtaining is preferably employed.
  • Z 1 in the formula (12) is an allyloxycarbonyl group or a triethylsilyl group.
  • R 2 and R 3 in the formula (13) has the same meaning as R 2 and R 3 in the formula (3).
  • Z 2 in formula (13) is an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom.
  • condensing agent preferably used in the condensation reaction examples include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl-carbodiimide hydrochloride (EDCI), etc.
  • Amount of condensing agent used Is preferably from 1 to 10 mol, more preferably from 1.2 to 6 mol, based on 1 mol of the baccatin III derivative represented by the formula (12).
  • the baccatin III derivative represented by the formula (12) is Robert A. Holton, Zhuming Zhang, Paul A. Clarke, Hossain Nadizadeh, D. John Procter, Tetrahedron Letters, 1998, 39. , p.2883-2886.
  • paclitaxel precursor represented by the formula (13) for example, when Z 2 is a triethylsilyl group, the triethylsilyl group is deprotected by reacting with hydrochloric acid or the like, and Z 2 is a hydrogen atom.
  • a paclitaxel precursor represented by the formula (13) can also be obtained.
  • Debenzoylcarbonyl paclitaxel can be suitably obtained by reacting the paclitaxel precursor represented by the formula (13) in which Z 2 is a hydrogen atom with palladium acetate as a catalyst together with triphenylphosphine. .
  • the amount of the catalyst used is preferably 0.005 to 0.5 mol, preferably 0.01 to 0, relative to 1 mol of the paclitaxel precursor represented by the formula (13) in which Z 2 is a hydrogen atom. More preferably, it is 3 mol.
  • the reaction time is preferably 0.5 to 10 hours.
  • paclitaxel represented by the formula (14) can be suitably obtained by carrying out a reaction for protecting the amino group in debenzoylcarbonyl paclitaxel using benzoyl chloride or the like.
  • R 2 is synonymous with Formula (1), R 3 is an alkoxy group, and in Formula (13 ′), R 2 is synonymous with Formula (1), and R 3 Is an alkoxy group. ]
  • a 7,10-Dialloc-baccatin III derivative represented by the formula (12 ′) and a carboxylic acid compound represented by the formula (3) are subjected to a condensation reaction, and the formula ( The process of obtaining the docetaxel precursor shown by 13 ') is employ
  • R 2 and R 3 in the formula (13 ') has the same meaning as R 2 and R 3 in the formula (3).
  • the condensing agent preferably used in the condensation reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl-carbodiimide hydrochloride (EDCI), etc.
  • Amount of condensing agent used Is preferably 1 to 10 moles, more preferably 1.2 to 6 moles per mole of the 7,10-Dialloc-baccatin III derivative represented by the formula (12 ′).
  • the time is preferably 0.5 to 10 hours, and the 7,10-Dialoc-baccatin III derivative represented by the formula (12 ′) can be synthesized by the method described in WO2008 / 054233A2. it can.
  • the allyloxycarbonyl group is deprotected, and debutoxycarbonyl docetaxel is converted into debutoxycarbonyl docetaxel. It can be suitably obtained.
  • the amount of the catalyst used is preferably 0.005 to 0.5 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of the docetaxel precursor represented by the formula (13 ′). Is more preferable.
  • the reaction time is preferably 0.5 to 10 hours.
  • docetaxel represented by the formula (14 ') can be suitably obtained by carrying out a reaction for protecting the amino group in debutoxycarbonyl docetaxel using di-tert-dibutyl dicarbonate or the like.
  • the side chain precursors of paclitaxel and docetaxel can be provided by a simple method with high purity, high yield and low cost. And the paclitaxel and docetaxel which are considered useful as an anticancer agent from the obtained side chain precursor can be provided. Therefore, it turns out that the manufacturing method of this invention and the intermediate compound used for the method are very useful.
  • the ester compound represented by the formula (9a) (15.1 g, 49.9 mmol) was dissolved in methanol (20 mL), and then O-methylhydroxylamine hydrochloride (4.59 g, 55 mmol) was added. Subsequently, pyridine (4.85 mL, 60 mL) was added dropwise at room temperature over 5 minutes. After dropping, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, then dissolved in toluene (50 ml), washed 3 times with water (50 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a pale yellow oil. Distillation under reduced pressure (155-165 ° C./0.8 mmHg) gave a pale yellow oil (15.1 kg, 91% in total over 2 steps) which is an oxime compound represented by the formula (8a).
  • the precipitated tosylamide was removed by filtration, dried over anhydrous magnesium sulfate, and filtered.
  • the solvent was distilled off under reduced pressure to obtain a dark yellow oily substance (29 g, 90%) which is a diazo compound represented by the formula (1a).
  • N, N-dimethylaminopyridine (36.7 mg, 0.3 mmol) and N, N-diisopropylethylamine (3.14 mL, 18 mmol) were added to this, and then dichloromethane (30 mL) was added.
  • Triethylchlorosilane (1.0 mL, 6.0 mL) was added dropwise and stirred at room temperature for 21 hours.
  • the paclitaxel precursor (7-triethylsilyl precursor) represented by the formula (13a) (453 mg, 0.42 mmol) is dissolved in a mixed solvent of EtOH (10 mL) and THF (5 mL), and 0.5% HCl (3 mL) ) was added and stirred at room temperature for 24 hours.
  • the reaction mixture was diluted with ethyl acetate (30 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted.
  • the organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure.
  • the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained white solid was dispersed in hot hexane and allowed to stand at room temperature for 30 minutes, and then a white solid was collected by filtration.
  • This was purified by silica gel column chromatography using chloroform / methanol (50 / 1-30 / 1-20 / 1) and paclitaxel represented by the formula (14) (184 mg, 60%, represented by the formula (13a). From the paclitaxel precursor (7-triethylsilyl precursor).
  • 7,10-Dialloc-baccatin III represented by the formula (12 ') was prepared. Subsequently, 7,10-Dialloc-baccatin III (713 mg, 1.0 mmol) represented by the formula (12 '), dicyclohexylcarbodiimide (DCC) (619 mg, 3.0 mmol), 4-dimethylaminopyridine (122 mg, 1.0 mmol) )
  • DCC dicyclohexylcarbodiimide
  • 4-dimethylaminopyridine 122 mg, 1.0 mmol
  • Dichloromethane (10 ⁇ mL) was added to the solution, and the carboxylic acid compound of formula (3a) (575 mg, 1.5 mmol) was dissolved in dichloromethane (15 mL) and stirred at room temperature using a dropping funnel.
  • Triphenylphosphine 63 mg, 0.24 mmol
  • diethylamine (0.75 mL, 7.26 mmol)
  • THF 10 mL
  • palladium acetate 13.5 mg, 0.06 mmol
  • methanol 30 mL
  • paratoluenesulfonic acid / pyridine salt 608 mg, 2.42 mmol

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Abstract

A side chain precursor of paclitaxel and docetaxel is provided at high purity, high yield, and low cost through a method for producing a compound shown by formula (3) using a compound shown by formula (1) as a starting compound. Using the side chain precursor thus obtained makes it possible to provide paclitaxel and docetaxel that are useful as anticancer agents. (In formula (1), R1 is an alkoxy group, arylalkyloxy group, alkylsilyloxy group, or alkoxycarbonyloxy group, R2 is an aryl group, X is one selected from the group consisting of substituents shown by formula (2), and Y is a hydrogen atom or methyl group.) (In formula (3), R2 is defined in the same way as in formula (1), and R3 is an alkoxy group.)

Description

パクリタキセル及びドセタキセルの側鎖前駆体の製造方法Method for producing side chain precursor of paclitaxel and docetaxel
　本発明は、パクリタキセル及びドセタキセルの側鎖前駆体の製造方法に関する。 The present invention relates to a method for producing side chain precursors of paclitaxel and docetaxel.
　パクリタキセル（Ｐａｃｌｉｔａｘｅｌ）は、イチイの樹皮から抽出されて得られる化合物であり、細胞増殖抑制作用を有する抗癌剤として知られている。パクリタキセルは水に対する溶解性が低く、これを改善した化合物として、ドセタキセル（Ｄｏｃｅｔａｘｅｌ）が知られている。 Paclitaxel is a compound obtained by extraction from yew bark, and is known as an anticancer agent having cell growth inhibitory action. Paclitaxel has low solubility in water, and docetaxel is known as a compound that improves this.
　特許文献１には、下記化学反応式で示されるように、（２Ｒ，３Ｓ）－３－フェニルイソセリンメチルエステル塩酸塩（Ｉ）からＮ－アリルオキシカルボニル－（２Ｒ，３Ｓ）－３－フェニルイソセリンメチルエステル（II）を得て、得られた前記メチルエステル（II）に対して、ｐ－アニスアルデヒドジメチルアセタール等を反応させて、（４Ｓ，５Ｒ）－Ｎ－アリルオキシカルボニル－２－（４－メトキシフェニル）－４－フェニルオキサゾリジン－５－カルボン酸メチルエステル（III）を得て、次いで加水分解することで、（４Ｓ，５Ｒ）－Ｎ－アリルオキシカルボニル－２－（４－メトキシフェニル）－４－フェニルオキサゾリジン－５－カルボン酸（IV）を得ることが記載されている。そして、得られた前記カルボン酸（IV）と７，１０－ジアリルオキシカルボニル－１０－デアセチルバッカチンIII（VI）とを反応させた後に、ドセタキセルを得ることができるとされている。しかしながら、出発化合物である（２Ｒ，３Ｓ）－３－フェニルイソセリンメチルエステル塩酸塩（Ｉ）は、通常、多工程の合成が必要となるためコスト高となる場合があり、また、前記カルボン酸メチルエステル（III）を得る工程の収率も低く、改善が望まれていた。 Patent Document 1 discloses that (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) is converted to N-allyloxycarbonyl- (2R, 3S) -3-phenyl as shown in the following chemical reaction formula. Isoserine methyl ester (II) was obtained, and the obtained methyl ester (II) was reacted with p-anisaldehyde dimethyl acetal or the like to give (4S, 5R) -N-allyloxycarbonyl-2- (4-Methoxyphenyl) -4-phenyloxazolidine-5-carboxylic acid methyl ester (III) was obtained and then hydrolyzed to give (4S, 5R) -N-allyloxycarbonyl-2- (4-methoxy It is described to obtain (phenyl) -4-phenyloxazolidine-5-carboxylic acid (IV). It is said that docetaxel can be obtained after reacting the obtained carboxylic acid (IV) with 7,10-diallyloxycarbonyl-10-deacetylbaccatin III (VI). However, the starting compound (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) usually requires a multi-step synthesis, which may increase the cost. The yield of the step of obtaining methyl ester (III) was also low, and improvement was desired.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　一方、非特許文献１には、上記（２Ｒ，３Ｓ）－３－フェニルイソセリンメチルエステル塩酸塩（Ｉ）におけるエステル部分がカルボン酸である（２Ｒ，３Ｓ）－３－フェニルイソセリン塩酸塩を得る方法が記載されている。具体的には、下記化学反応式で示されるように、ケイ皮酸イソプロピル（ｉｓｏｐｒｏｐｙｌ　ｃｉｎｎａｍａｔｅ）を出発化合物として、オスミウム触媒であるＫ２［ＯｓＯ２（ＯＨ）４]、リガンドである（ＤＨＱ）２ＰＨＡＬ等を用いて反応させることにより、（２Ｒ，３Ｓ）－３－（アセチルアミノ）－２－ヒドロキシ－３－フェニルプロパン酸イソプロピルを得て、次いで加水分解することで、（２Ｒ，３Ｓ）－３－フェニルイソセリン塩酸塩が得られるとされている。しかしながら、上記オスミウム触媒やリガンドは高価であり、またオスミウム触媒は有毒であるため、このような触媒やリガンドを使用しない方法が望まれていた。 On the other hand, Non-Patent Document 1 discloses (2R, 3S) -3-phenylisoserine hydrochloride in which the ester moiety in the above (2R, 3S) -3-phenylisoserine methyl ester hydrochloride (I) is a carboxylic acid. The method of obtaining is described. Specifically, as shown by the following chemical reaction formula, isopropyl cinnamate is used as a starting compound, osmium catalyst K 2 [OsO 2 (OH) 4 ], and ligand (DHQ) 2 By reacting with PHAL or the like, isopropyl (2R, 3S) -3- (acetylamino) -2-hydroxy-3-phenylpropanoate is obtained and then hydrolyzed to give (2R, 3S)- It is said that 3-phenylisoserine hydrochloride is obtained. However, since the osmium catalyst and ligand are expensive and the osmium catalyst is toxic, a method that does not use such a catalyst or ligand has been desired.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
ＷＯ２００８／０５４２３３Ａ２WO2008 / 054233A2
　本発明は上記課題を解決するためになされたものであり、高純度、高収率かつ安価にパクリタキセル及びドセタキセルの側鎖前駆体を提供することを目的とするものである。また、こうして得られる側鎖前駆体を用いて、抗癌剤として有用とされるパクリタキセル及びドセタキセルを提供することを目的とするものである。 The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a side chain precursor of paclitaxel and docetaxel with high purity, high yield and low cost. Another object of the present invention is to provide paclitaxel and docetaxel that are useful as anticancer agents by using the side chain precursor thus obtained.
　上記課題は、下記式（１）：
Figure JPOXMLDOC01-appb-C000035
 ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000036
 で示される化合物を出発化合物として用いることを特徴とする下記式（３）：
Figure JPOXMLDOC01-appb-C000037
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
で示される化合物の製造方法を提供することによって解決される。 The above problem is solved by the following formula (1):
Figure JPOXMLDOC01-appb-C000035
 [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000036
 A compound represented by formula (3) is used as a starting compound:
Figure JPOXMLDOC01-appb-C000037
 [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
It is solved by providing the manufacturing method of the compound shown by these.
　このとき、前記式（１）で示される化合物を出発化合物として下記式（４）：
Figure JPOXMLDOC01-appb-C000038
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得る工程を有することが好適である。 At this time, using the compound represented by the formula (1) as a starting compound, the following formula (4):
Figure JPOXMLDOC01-appb-C000038
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1). ]
It is preferable to have the process of obtaining the compound shown by these.
　また、このとき、前記得られた式（４）で示される化合物から下記式（５）：
Figure JPOXMLDOC01-appb-C000039
 ［式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得る工程を有することが好適である。 Further, at this time, from the compound represented by the obtained formula (4), the following formula (5):
Figure JPOXMLDOC01-appb-C000039
 Wherein (5), R 2, X and Y are as defined in the formula (1). ]
It is preferable to have the process of obtaining the compound shown by these.
　また、このとき、前記得られた式（５）で示される化合物から下記式（６）：
Figure JPOXMLDOC01-appb-C000040
 ［式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得る工程を有することが好適である。 Further, at this time, from the compound represented by the obtained formula (5), the following formula (6):
Figure JPOXMLDOC01-appb-C000040
 Wherein (6), R 2, X and Y are as defined in the formula (1). ]
It is preferable to have the process of obtaining the compound shown by these.
　また、このとき、前記得られた式（６）で示される化合物から下記式（７）：
Figure JPOXMLDOC01-appb-C000041
 ［式（７）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
で示される化合物を得る工程を有することが好適である。 Further, at this time, from the compound represented by the obtained formula (6), the following formula (7):
Figure JPOXMLDOC01-appb-C000041
 Wherein (7), R 2, X and Y are as defined in the formula (1), R 3 is an alkoxy group. ]
It is preferable to have the process of obtaining the compound shown by these.
　また、このとき、下記式（８）：
Figure JPOXMLDOC01-appb-C000042
 ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を出発化合物として前記式（１）で示される化合物を得る工程を有することが好適である。 At this time, the following formula (8):
Figure JPOXMLDOC01-appb-C000042
 [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
It is preferable to have a step of obtaining a compound represented by the formula (1) using a compound represented by the formula (1) as a starting compound.
　また、このとき、下記式（９）：
Figure JPOXMLDOC01-appb-C000043
 ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を出発化合物として下記式（８）：
Figure JPOXMLDOC01-appb-C000044
 ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得て、該得られた式（８）で示される化合物から前記式（１）で示される化合物を得る工程を有することが好適である。 At this time, the following formula (9):
Figure JPOXMLDOC01-appb-C000043
 Wherein (9), R 2, X and Y are as defined in the formula (1). ]
A compound represented by the following formula (8):
Figure JPOXMLDOC01-appb-C000044
 [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
It is preferable to have a step of obtaining the compound represented by the formula (1) from the obtained compound represented by the formula (8).
　また、このとき、下記式（１０）：
Figure JPOXMLDOC01-appb-C000045
 ［式（１０）中、Ｒ２は前記式（１）と同義であり、Ｒ４はアルキル基である。］
で示される化合物と下記式（１１）：
Figure JPOXMLDOC01-appb-C000046
 ［式（１１）中、Ｘ及びＹは前記式（１）と同義である。］
で示されるアルコールとを反応させて下記式（９）：
Figure JPOXMLDOC01-appb-C000047
 ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得て、該得られた式（９）で示される化合物から下記式（８）：
Figure JPOXMLDOC01-appb-C000048
 ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
で示される化合物を得て、該得られた式（８）で示される化合物から前記式（１）で示される化合物を得る工程を有することが好適である。 At this time, the following formula (10):
Figure JPOXMLDOC01-appb-C000045
 Wherein (10), R 2 has the same meaning as the formula (1), R 4 is an alkyl group. ]
And a compound represented by the following formula (11):
Figure JPOXMLDOC01-appb-C000046
 [In Formula (11), X and Y are synonymous with said Formula (1). ]
Is reacted with an alcohol represented by the following formula (9):
Figure JPOXMLDOC01-appb-C000047
 Wherein (9), R 2, X and Y are as defined in the formula (1). ]
A compound represented by the following formula (8) is obtained from the compound represented by the formula (9) thus obtained:
Figure JPOXMLDOC01-appb-C000048
 [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
It is preferable to have a step of obtaining the compound represented by the formula (1) from the obtained compound represented by the formula (8).
　また、下記式（３）：
Figure JPOXMLDOC01-appb-C000049
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
で示される化合物と下記式（１２）：
Figure JPOXMLDOC01-appb-C000050
 ［式（１２）中、Ｚ１はアリルオキシカルボニル基又はトリエチルシリル基である。］
で示されるバッカチンIII誘導体とを反応させて、下記式（１３）：
Figure JPOXMLDOC01-appb-C000051
 ［式（１３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基であり、Ｚ２はアリルオキシカルボニル基、トリエチルシリル基又は水素原子である。］
で示されるパクリタキセル前駆体を得る工程を有する下記式（１４）：
Figure JPOXMLDOC01-appb-C000052
 で示されるパクリタキセルの製造方法が好適な実施態様である。 Moreover, following formula (3):
Figure JPOXMLDOC01-appb-C000049
 [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
And a compound represented by the following formula (12):
Figure JPOXMLDOC01-appb-C000050
 Wherein (12), Z 1 is allyloxycarbonyl group or triethylsilyl group. ]
Is reacted with a baccatin III derivative represented by the following formula (13):
Figure JPOXMLDOC01-appb-C000051
 [In formula (13), R 2 has the same meaning as in formula (1), R 3 represents an alkoxy group, and Z 2 represents an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom. ]
The following formula (14) having a step of obtaining a paclitaxel precursor represented by:
Figure JPOXMLDOC01-appb-C000052
 The method for producing paclitaxel represented by is a preferred embodiment.
　また、下記式（３）：
Figure JPOXMLDOC01-appb-C000053
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
で示される化合物と下記式（１２’）：
Figure JPOXMLDOC01-appb-C000054
 で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII誘導体とを反応させて、下記式（１３’）：
Figure JPOXMLDOC01-appb-C000055
 ［式（１３’）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
で示されるドセタキセル前駆体を得る工程を有する下記式（１４’）：
Figure JPOXMLDOC01-appb-C000056
 で示されるドセタキセルの製造方法が好適な実施態様である。 Moreover, following formula (3):
Figure JPOXMLDOC01-appb-C000053
 [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
And a compound represented by the following formula (12 ′):
Figure JPOXMLDOC01-appb-C000054
 Is reacted with a 7,10-Dialloc-baccatin III derivative represented by the following formula (13 ′):
Figure JPOXMLDOC01-appb-C000055
 [In Formula (13 ′), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
The following formula (14 ′) having a step of obtaining a docetaxel precursor represented by:
Figure JPOXMLDOC01-appb-C000056
 The method for producing docetaxel represented by the formula is a preferred embodiment.
　また、上記課題は、下記式（１）で示される化合物を提供することによっても解決される。
Figure JPOXMLDOC01-appb-C000057
 ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000058
 Moreover, the said subject is also solved by providing the compound shown by following formula (1).
Figure JPOXMLDOC01-appb-C000057
 [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000058
　また、上記課題は、下記式（４）で示される化合物を提供することによっても解決される。
Figure JPOXMLDOC01-appb-C000059
 ［式（４）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000060
 Moreover, the said subject is also solved by providing the compound shown by following formula (4).
Figure JPOXMLDOC01-appb-C000059
 [In formula (4), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000060
　また、上記課題は、下記式（５）で示される化合物を提供することによっても解決される。
Figure JPOXMLDOC01-appb-C000061
 ［式（５）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000062
 Moreover, the said subject is also solved by providing the compound shown by following formula (5).
Figure JPOXMLDOC01-appb-C000061
 Wherein (5), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000062
　また、上記課題は、下記式（６）で示される化合物を提供することによっても解決される。
Figure JPOXMLDOC01-appb-C000063
 ［式（６）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000064
 Moreover, the said subject is also solved by providing the compound shown by following formula (6).
Figure JPOXMLDOC01-appb-C000063
 Wherein (6), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000064
　また、上記課題は、下記式（７）で示される化合物を提供することによっても解決される。
Figure JPOXMLDOC01-appb-C000065
 ［式（７）中、Ｒ２はアリール基であり、Ｒ３はアルコキシ基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000066
 Moreover, the said subject is also solved by providing the compound shown by following formula (7).
Figure JPOXMLDOC01-appb-C000065
 [In formula (7), R 2 is an aryl group, R 3 is an alkoxy group, X is one selected from the group consisting of substituents represented by the following formula (2), and Y is hydrogen An atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000066
　本発明の製造方法によれば、高純度、高収率かつ安価にパクリタキセル及びドセタキセルの側鎖前駆体を提供することができる。こうして得られる側鎖前駆体を用いて、抗癌剤として有用とされるパクリタキセル及びドセタキセルを提供することができる。 According to the production method of the present invention, side chain precursors of paclitaxel and docetaxel can be provided with high purity, high yield and low cost. The side chain precursor thus obtained can be used to provide paclitaxel and docetaxel that are useful as anticancer agents.
　本発明の製造方法は、下記式（１）で示される化合物（以下、「ジアゾ化合物」と呼ぶことがある）を出発化合物として下記式（３）で示される化合物（以下、「カルボン酸化合物」と呼ぶことがある）を得ることを特徴とする。下記式（３）で示される化合物はドセタキセルの側鎖前駆体であり、こうして得られる側鎖前駆体を用いて、抗癌剤として有用とされるドセタキセルを得ることができるため本発明の製造方法を採用する意義が大きいものである。 The production method of the present invention comprises a compound represented by the following formula (3) (hereinafter referred to as “carboxylic acid compound”) using a compound represented by the following formula (1) (hereinafter sometimes referred to as “diazo compound”) as a starting compound. It may be called). The compound represented by the following formula (3) is a side chain precursor of docetaxel, and the production method of the present invention is employed because docetaxel that is useful as an anticancer agent can be obtained using the side chain precursor thus obtained. The significance of doing is great.
Figure JPOXMLDOC01-appb-C000067
 ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000067
 [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000069
 [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
　上記式（１）において、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基である。中でも、１級アミノ基への変換が容易である観点から、Ｒ１がアルコキシ基、アリールアルキルオキシ基又はアルコキシカルボニルオキシ基であることが好ましく、アルコキシ基又はアルコキシカルボニルオキシ基であることがより好ましく、アルコキシ基であることが更に好ましい。 In the above formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group. Among these, from the viewpoint of easy conversion to a primary amino group, R 1 is preferably an alkoxy group, an arylalkyloxy group or an alkoxycarbonyloxy group, and more preferably an alkoxy group or an alkoxycarbonyloxy group. And more preferably an alkoxy group.
　上記アルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペンチルオキシ基、イソペンチルオキシ基、ネオペンチルオキシ基、ｎ－ヘキシルオキシ基、イソヘキシルオキシ基、２－エチルヘキシルオキシ基、ｎ－ヘプチルオキシ基、ｎ－オクチルオキシ基、ｎ－ノニルオキシ基、ｎ－デシルオキシ基等が挙げられる。これらアルコキシ基は置換基を有していてもよい。中でも、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基又はイソブトキシ基がＲ１として好適に使用される。 Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an isopentyloxy group. Group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, 2-ethylhexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group and the like. These alkoxy groups may have a substituent. Of these, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 1 .
　上記アリールアルキルオキシ基としては、例えば、フェニルメチルオキシ基、フェニルエチルオキシ基、フェニルブチルオキシ基、フェニルペンチルオキシ基、フェニルヘキシルオキシ基、ナフチルメチルオキシ基等が挙げられる。これらアリールアルキルオキシ基は置換基を有していてもよい。 Examples of the arylalkyloxy group include phenylmethyloxy group, phenylethyloxy group, phenylbutyloxy group, phenylpentyloxy group, phenylhexyloxy group, naphthylmethyloxy group, and the like. These arylalkyloxy groups may have a substituent.
　上記アルキルシリルオキシ基としては、例えば、トリメチルシリルオキシ基、トリエチルシリルオキシ基、トリイソプロピルシリルオキシ基、ｔｅｒｔ－ブチルジメチルシリルオキシ基、ｔｅｒｔ－ブチルジフェニルシリルオキシ基等が挙げられる。これらアルキルシリルオキシ基は置換基を有していてもよい。 Examples of the alkylsilyloxy group include a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, a tert-butyldimethylsilyloxy group, and a tert-butyldiphenylsilyloxy group. These alkylsilyloxy groups may have a substituent.
　上記アルコキシカルボニルオキシ基としては、例えば、メトキシカルボニルオキシ基、エトキシカルボニルオキシ基、ｎ－プロポキシカルボニルオキシ基、イソプロポキシカルボニルオキシ基、ｎ－ブトキシカルボニルオキシ基、イソブトキシカルボニルオキシ基、ｓｅｃ－ブトキシカルボニルオキシ基、ｔｅｒｔ－ブトキシカルボニルオキシ基、ペンチルオキシカルボニルオキシ基、ヘキシルオキシカルボニルオキシ基、ヘプチルオキシカルボニルオキシ基、オクチルオキシカルボニルオキシ基等が挙げられる。これらアルコキシカルボニルオキシ基は置換基を有していてもよい。 Examples of the alkoxycarbonyloxy group include a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, an isopropoxycarbonyloxy group, an n-butoxycarbonyloxy group, an isobutoxycarbonyloxy group, and a sec-butoxycarbonyl group. Examples thereof include an oxy group, a tert-butoxycarbonyloxy group, a pentyloxycarbonyloxy group, a hexyloxycarbonyloxy group, a heptyloxycarbonyloxy group, and an octyloxycarbonyloxy group. These alkoxycarbonyloxy groups may have a substituent.
　上記式（１）において、Ｒ２はアリール基である。アリール基としては、例えば、フェニル基、ナフチル基、アントリル基、フェナントリル基等が挙げられる。これらアリール基は置換基を有していてもよい。中でも、フェニル基又はナフチル基がＲ２として好適に使用される。 In the above formula (1), R 2 is an aryl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. These aryl groups may have a substituent. Among them, a phenyl group or a naphthyl group are preferably used as R 2.
　上記式（１）において、Ｘは下記式（２）で示される置換基からなる群から選択される１種である。 In the above formula (1), X is one selected from the group consisting of substituents represented by the following formula (2).
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　中でも、調製が比較的簡単である観点から、Ｘは下記式（２ａ）で示される置換基からなる群から選択される１種であることが好ましい。 Among these, X is preferably one selected from the group consisting of substituents represented by the following formula (2a) from the viewpoint of relatively easy preparation.
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　上記式（１）において、Ｙは水素原子又はメチル基である。中でも、Ｙとしてはメチル基であることが好ましい。 In the above formula (1), Y is a hydrogen atom or a methyl group. Among them, Y is preferably a methyl group.
　上記式（３）において、Ｒ２はアリール基である。アリール基としては、上記式（１）におけるＲ２の説明のところで例示された置換基と同様のものを用いることができる。中でも、フェニル基又はナフチル基がＲ２として好適に使用される。 In the above formula (3), R 2 is an aryl group. As the aryl group, the same substituents as those exemplified in the description of R 2 in the above formula (1) can be used. Among them, a phenyl group or a naphthyl group are preferably used as R 2.
　上記式（３）において、Ｒ３はアルコキシ基である。アルコキシ基としては、上記式（１）におけるＲ１の説明のところで例示された置換基と同様のものを用いることができる。中でも、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基又はイソブトキシ基がＲ３として好適に使用される。 In the above formula (3), R 3 is an alkoxy group. As the alkoxy group, those similar to the substituents exemplified in the description of R 1 in the above formula (1) can be used. Of these, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 3 .
　本発明において、式（１）で示される化合物を得る方法としては特に限定されず、下記化学反応式（Ｉ）のように、式（８）で示される化合物（以下、「オキシム化合物」と呼ぶことがある）を出発化合物として式（１）で示される化合物を得る方法が好適に採用される。 In the present invention, the method for obtaining the compound represented by the formula (1) is not particularly limited, and the compound represented by the formula (8) (hereinafter referred to as “oxime compound”) as shown in the following chemical reaction formula (I). A method for obtaining a compound represented by the formula (1) using a starting compound as a starting compound is preferably employed.
Figure JPOXMLDOC01-appb-C000072
 ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000072
 [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
　上記式（８）において、Ｒ１、Ｒ２及びＹは上記式（１）におけるＲ１、Ｒ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記化学反応式（Ｉ）のように、式（８）で示されるオキシム化合物に対して、トシルアジド等のジアゾ化剤及び1,8-ジアザビシクロ[5.4.0]ウンデセン（ＤＢＵ）等の塩基性触媒を用いて反応させることにより、式（１）で示されるジアゾ化合物を好適に得ることができる。ジアゾ化剤の使用量としては、式（８）で示されるオキシム化合物１モルに対して、１～１０モルであることが好ましく、１～４モルであることがより好ましい。また、塩基性触媒の使用量としては、式（８）で示されるオキシム化合物１モルに対して、０．０１～１モルであることが好ましく、０．０５～０．５モルであることがより好ましい。 In the above formula (8), R 1, R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 1, R 2 and Y in the formula (1), X The substituent represented by the formula (2a) exemplified in the description of the above formula (2) can be preferably used. As shown in the above chemical reaction formula (I), a diazotizing agent such as tosyl azide and a basic catalyst such as 1,8-diazabicyclo [5.4.0] undecene (DBU) with respect to the oxime compound represented by formula (8) The diazo compound shown by Formula (1) can be suitably obtained by making it react using. The amount of the diazotizing agent used is preferably 1 to 10 mol, more preferably 1 to 4 mol, relative to 1 mol of the oxime compound represented by the formula (8). The amount of the basic catalyst used is preferably 0.01 to 1 mol, preferably 0.05 to 0.5 mol, with respect to 1 mol of the oxime compound represented by the formula (8). More preferred.
　上記式（８）で示される化合物を得る方法としては特に限定されず、下記化学反応式（II－１）のように、式（９）で示される化合物（以下、「エステル化合物」と呼ぶことがある）を出発化合物として式（８）で示される化合物を得る方法が好適に採用される。したがって、下記化学反応式（II－２）のように、式（９）で示される化合物を出発化合物として式（８）で示される化合物を得て、該得られた式（８）で示される化合物から式（１）で示される化合物を得る方法が本発明の好適な実施態様である。 The method for obtaining the compound represented by the above formula (8) is not particularly limited, and the compound represented by the formula (9) (hereinafter referred to as “ester compound”) as shown in the chemical reaction formula (II-1) below. A method for obtaining a compound represented by the formula (8) using as a starting compound is preferably employed. Therefore, as shown in the following chemical reaction formula (II-2), a compound represented by the formula (8) is obtained using the compound represented by the formula (9) as a starting compound, and the obtained formula (8) is obtained. A method for obtaining a compound represented by the formula (1) from a compound is a preferred embodiment of the present invention.
Figure JPOXMLDOC01-appb-C000073
 ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000073
 Wherein (9), R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1). ]
Figure JPOXMLDOC01-appb-C000074
 ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000074
 Wherein (9), R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1). ]
　上記式（９）において、Ｒ２及びＹは上記式（１）におけるＲ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記化学反応式（II－１）のように、式（９）で示されるエステル化合物に対して、０－メチルヒドロキシルアミン塩酸塩等のオキシム化剤を用いて反応させることにより、式（８）で示されるオキシム化合物を好適に得ることができる。オキシム化剤の使用量としては、式（９）で示されるエステル化合物１モルに対して、１～１０モルであることが好ましく、１～４モルであることがより好ましい。 In the formula (9), R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2) The substituent represented by the formula (2a) exemplified in the description of can be preferably used. As shown in the chemical reaction formula (II-1), the ester compound represented by the formula (9) is reacted with an oximation agent such as 0-methylhydroxylamine hydrochloride to give a formula (8) The oxime compound shown by can be obtained suitably. The amount of the oximation agent to be used is preferably 1 to 10 mol, more preferably 1 to 4 mol, per 1 mol of the ester compound represented by the formula (9).
　上記式（９）で示される化合物を得る方法としては特に限定されず、下記化学反応式（III－１）のように、式（１０）で示される化合物と式（１１）で示されるアルコールとを反応させて式（９）で示される化合物を得る方法が好適に採用される。したがって、下記化学反応式（III－２）のように、式（１０）で示される化合物と式（１１）で示されるアルコールとを反応させて式（９）で示される化合物を得て、該得られた式（９）で示される化合物から式（８）で示される化合物を得て、該得られた式（８）で示される化合物から式（１）で示される化合物を得る方法が本発明の好適な実施態様である。 The method for obtaining the compound represented by the formula (9) is not particularly limited, and the compound represented by the formula (10) and the alcohol represented by the formula (11) are represented by the following chemical reaction formula (III-1). Is preferably employed to obtain a compound represented by the formula (9). Accordingly, as shown in the following chemical reaction formula (III-2), a compound represented by the formula (9) is obtained by reacting a compound represented by the formula (10) with an alcohol represented by the formula (11). A method for obtaining a compound represented by formula (8) from the obtained compound represented by formula (9) and obtaining a compound represented by formula (1) from the obtained compound represented by formula (8) is described. It is a preferred embodiment of the invention.
Figure JPOXMLDOC01-appb-C000075
 ［式（１０）中、Ｒ２は前記式（１）と同義であり、Ｒ４はアルキル基であり、式（１１）中、Ｘ及びＹは前記式（１）と同義であり、式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000075
 [In Formula (10), R 2 is synonymous with Formula (1), R 4 is an alkyl group, and in Formula (11), X and Y are synonymous with Formula (1), 9) In the formula, R 2 , X and Y are as defined in the above formula (1). ]
Figure JPOXMLDOC01-appb-C000076
 ［式（１０）中、Ｒ２は前記式（１）と同義であり、Ｒ４はアルキル基であり、式（１１）中、Ｘ及びＹは前記式（１）と同義であり、式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000076
 [In Formula (10), R 2 is synonymous with Formula (1), R 4 is an alkyl group, and in Formula (11), X and Y are synonymous with Formula (1), 9) during, R 2, X and Y are as defined in the formula (1) wherein (8), R 1, R 2, X and Y are as defined in the formula (1). ]
　上記式（１０）において、Ｒ２は上記式（１）におけるＲ２の説明のところで例示された置換基と同様のものを好適に用いることができる。上記式（１０）において、Ｒ４はアルキル基である。アルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、ｎ－ヘキシル基、イソヘキシル基、２－エチルヘキシル基、ｎ－ヘプチル基、ｎ－オクチル基、ｎ－ノニル基、ｎ－デシル基等が挙げられる。中でも、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基又はイソブチル基がＲ４として好適に使用される。 In the above formula (10), as R 2 , those similar to the substituents exemplified in the description of R 2 in the above formula (1) can be suitably used. In the above formula (10), R 4 is an alkyl group. Examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, Examples thereof include a tert-pentyl group, n-hexyl group, isohexyl group, 2-ethylhexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like. Among them, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or an isobutyl group is preferably used as R 4 .
　上記式（１１）において、Ｙは上記式（１）と同様にメチル基であることが好ましく、Ｘとしては、上記式（２ａ）で示される置換基からなる群から選択される１種であることが好ましい。中でも、式（１１）で示されるアルコールがＬ－メントールであることがより好ましい。上記化学反応式（III－１）のように、式（１０）で示される化合物と式（１１）で示されるアルコールとを反応させることにより、式（９）で示されるエステル化合物を好適に得ることができる。反応温度としては、６０～１５０℃であることが好ましく、９０～１３０℃であることがより好ましい。反応時間としては、２～２０時間であることが好ましい。 In the above formula (11), Y is preferably a methyl group as in the above formula (1), and X is one selected from the group consisting of substituents represented by the above formula (2a). It is preferable. Of these, the alcohol represented by the formula (11) is more preferably L-menthol. As in the chemical reaction formula (III-1), the ester compound represented by the formula (9) is suitably obtained by reacting the compound represented by the formula (10) with the alcohol represented by the formula (11). be able to. The reaction temperature is preferably 60 to 150 ° C, more preferably 90 to 130 ° C. The reaction time is preferably 2 to 20 hours.
　本発明は、上述のようにして得られた式（１）で示される化合物を出発化合物として式（３）で示される化合物を得ることを特徴とする。ここで、式（１）で示される化合物を出発化合物とする場合、下記化学反応式（IV－１）のように、式（４）で示される化合物（以下、「オキシムアルコール化合物」と呼ぶことがある）を中間体として得る方法が好適に採用される。したがって、下記化学反応式（IV－２）のように、式（１）で示される化合物を出発化合物として式（４）で示される化合物を得て、該得られた式（４）で示される化合物から式（３）で示される化合物を得る方法が本発明の好適な実施態様である。また、式（４）で示される化合物も中間体化合物として非常に有用である。 The present invention is characterized in that a compound represented by the formula (3) is obtained using the compound represented by the formula (1) obtained as described above as a starting compound. Here, when the compound represented by the formula (1) is used as a starting compound, the compound represented by the formula (4) (hereinafter referred to as “oxime alcohol compound”) as shown in the chemical reaction formula (IV-1) below. Is preferably used as an intermediate. Accordingly, as shown in the following chemical reaction formula (IV-2), a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained. A method for obtaining a compound represented by the formula (3) from a compound is a preferred embodiment of the present invention. In addition, the compound represented by the formula (4) is also very useful as an intermediate compound.
Figure JPOXMLDOC01-appb-C000077
 ［式（４）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000077
 [In formula (4), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000079
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000079
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1). ]
Figure JPOXMLDOC01-appb-C000080
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000080
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1). In the formula (3), R 2 is as defined in the formula (1), and R 3 is alkoxy. It is a group. ]
　上記式（４）において、Ｒ１、Ｒ２及びＹは上記式（１）におけるＲ１、Ｒ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記化学反応式（IV－１）のように、式（１）で示されるジアゾ化合物に対して、ギ酸等のカルボン酸を用いて反応させることによりカルボン酸エステルを得て、該得られたカルボン酸エステルに対して、アルコールとアンモニア水を用いたエステル交換反応により式（４）で示されるオキシムアルコール化合物を好適に得ることができる。このような方法により、式（４）で示されるオキシムアルコール化合物を結晶で得ることができる。そして、精製することなく次の反応に使用することができるため、式（１）で示される化合物を出発化合物として、式（４）で示される化合物を中間体として得る方法が非常に有用であることが分かる。 In the above formula (4), R 1, R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 1, R 2 and Y in the formula (1), X The substituent represented by the formula (2a) exemplified in the description of the above formula (2) can be preferably used. As shown in the chemical reaction formula (IV-1), the diazo compound represented by the formula (1) is reacted with a carboxylic acid such as formic acid to obtain a carboxylic acid ester. The oxime alcohol compound represented by the formula (4) can be suitably obtained by an ester exchange reaction using an alcohol and aqueous ammonia with respect to the acid ester. By such a method, the oxime alcohol compound represented by the formula (4) can be obtained as crystals. And since it can be used for the next reaction without purification, a method of obtaining the compound represented by the formula (4) as an intermediate from the compound represented by the formula (1) is very useful. I understand that.
　上記化学反応式（IV－１）において、カルボン酸の使用量としては、式（１）で示されるジアゾ化合物１モルに対して、３～３００モルであることが好ましく、５～２００モルであることがより好ましい。カルボン酸を用いた反応温度としては、２０～１００℃であることが好ましく、４０～８０℃であることがより好ましい。反応時間としては、１～１０時間であることが好ましい。また、上記エステル交換反応における反応温度としては、５～４０℃であることが好ましく、室温付近であることがより好ましい。反応時間としては、０．５～５時間であることが好ましい。 In the above chemical reaction formula (IV-1), the amount of the carboxylic acid used is preferably 3 to 300 mol with respect to 1 mol of the diazo compound represented by the formula (1), and is 5 to 200 mol. It is more preferable. The reaction temperature using carboxylic acid is preferably 20 to 100 ° C, more preferably 40 to 80 ° C. The reaction time is preferably 1 to 10 hours. The reaction temperature in the transesterification reaction is preferably 5 to 40 ° C., more preferably around room temperature. The reaction time is preferably 0.5 to 5 hours.
　本発明では、下記化学反応式（Ｖ－１）のように、上記式（４）で示される化合物から式（５）で示される化合物（以下、「トランスアミノアルコール化合物」と呼ぶことがある）を中間体として得る方法が好適に採用される。したがって、下記化学反応式（Ｖ－２）のように、式（１）で示される化合物を出発化合物として式（４）で示される化合物を得て、該得られた式（４）で示される化合物から式（５）で示される化合物を得て、該得られた式（５）で示される化合物から式（３）で示される化合物を得る方法が本発明の好適な実施態様である。また、式（５）で示される化合物も中間体化合物として非常に有用である。 In the present invention, the compound represented by the above formula (4) to the compound represented by the formula (5) (hereinafter sometimes referred to as “transaminoalcohol compound”) as shown in the chemical reaction formula (V-1) below. Is preferably employed as an intermediate. Therefore, as shown in the chemical reaction formula (V-2) below, a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained. A preferred embodiment of the present invention is a method of obtaining a compound represented by the formula (5) from a compound and obtaining a compound represented by the formula (3) from the obtained compound represented by the formula (5). Moreover, the compound shown by Formula (5) is also very useful as an intermediate compound.
Figure JPOXMLDOC01-appb-C000081
 ［式（５）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000081
 Wherein (5), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000083
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000083
 Wherein (4), R 1, R 2, X and Y are as defined in the formula (1) wherein (5), R 2, X and Y are as defined in the formula (1). ]
Figure JPOXMLDOC01-appb-C000084
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000084
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1), and in the formula (5), R 2 , X and Y are as defined in the formula (1), In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 is an alkoxy group. ]
　上記式（５）において、Ｒ２及びＹは上記式（１）におけるＲ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記化学反応式（Ｖ－１）のように、式（４）で示されるオキシムアルコール化合物に対して、酢酸／メタノール溶媒下、１０％Ｐｄ／Ｃ等のパラジウム触媒を用いて水素添加する反応を行って、式（５）で示されるトランスアミノアルコール化合物を好適に得ることができる。反応時間としては、１～１０時間であることが好ましく、２～８時間であることがより好ましい。 In the above formula (5), R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2) The substituent represented by the formula (2a) exemplified in the description of can be preferably used. As in the chemical reaction formula (V-1), a reaction in which an oxime alcohol compound represented by the formula (4) is hydrogenated using a palladium catalyst such as 10% Pd / C in an acetic acid / methanol solvent. The transamino alcohol compound represented by the formula (5) can be suitably obtained. The reaction time is preferably 1 to 10 hours, more preferably 2 to 8 hours.
　本発明では、下記化学反応式（VI－１）のように、上記式（５）で示される化合物から式（６）で示される化合物（以下、「カーバメイト化合物」と呼ぶことがある）を中間体として得る方法が好適に採用される。したがって、下記化学反応式（VI－２）のように、式（１）で示される化合物を出発化合物として式（４）で示される化合物を得て、該得られた式（４）で示される化合物から式（５）で示される化合物を得て、該得られた式（５）で示される化合物から式（６）で示される化合物を得て、該得られた式（６）で示される化合物から式（３）で示される化合物を得る方法が本発明の好適な実施態様である。また、式（６）で示される化合物も中間体化合物として非常に有用である。 In the present invention, the compound represented by the formula (5) to the compound represented by the formula (6) (hereinafter sometimes referred to as “carbamate compound”) is intermediated as shown in the chemical reaction formula (VI-1) below. The method obtained as a body is preferably employed. Therefore, as shown in the following chemical reaction formula (VI-2), the compound represented by the formula (4) is obtained by using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained. A compound represented by formula (5) is obtained from the compound, a compound represented by formula (6) is obtained from the obtained compound represented by formula (5), and the obtained formula (6) is obtained. A method for obtaining a compound represented by the formula (3) from a compound is a preferred embodiment of the present invention. In addition, the compound represented by the formula (6) is also very useful as an intermediate compound.
Figure JPOXMLDOC01-appb-C000085
 ［式（６）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000085
 Wherein (6), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
 ［式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000087
 Wherein (5), R 2, X and Y are as defined in the formula (1) wherein (6), R 2, X and Y are as defined in the formula (1). ]
Figure JPOXMLDOC01-appb-C000088
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000088
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1), and in the formula (5), R 2 , X and Y are as defined in the formula (1), In formula (6), R 2 , X and Y have the same meaning as in formula (1), in formula (3), R 2 has the same meaning as in formula (1), and R 3 is an alkoxy group. ]
　上記式（６）において、Ｒ２及びＹは上記式（１）におけるＲ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記化学反応式（VI－１）のように、式（５）で示されるトランスアミノアルコール化合物に対して、クロルギ酸アリルを反応させることにより、アミノ基がアリルオキシカルボニル基（Ａｌｌｏｃ基）で保護された式（６）で示されるカーバメイト化合物を好適に得ることができる。クロルギ酸アリルの使用量としては、式（５）で示されるトランスアミノアルコール化合物１モルに対して、１～１０モルであることが好ましく、１～４モルであることがより好ましい。反応時間としては、０．１～５時間であることが好ましい。 In the above formula (6), R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2) The substituent represented by the formula (2a) exemplified in the description of can be preferably used. As shown in the above chemical reaction formula (VI-1), the trans amino alcohol compound represented by the formula (5) is reacted with allyl chloroformate to protect the amino group with an allyloxycarbonyl group (Alloc group). The carbamate compound represented by the formula (6) can be suitably obtained. The amount of allyl chloroformate to be used is preferably 1 to 10 mol, more preferably 1 to 4 mol, relative to 1 mol of the transaminoalcohol compound represented by the formula (5). The reaction time is preferably 0.1 to 5 hours.
　本発明では、下記化学反応式（VII－１）のように、上記式（６）で示される化合物から式（７）で示される化合物（以下、「Ｎ，Ｏ－アセタール化合物」と呼ぶことがある）を中間体として得る方法が好適に採用される。したがって、下記化学反応式（VII－２）のように、式（１）で示される化合物を出発化合物として式（４）で示される化合物を得て、該得られた式（４）で示される化合物から式（５）で示される化合物を得て、該得られた式（５）で示される化合物から式（６）で示される化合物を得て、該得られた式（６）で示される化合物から式（７）で示される化合物を得て、該得られた式（７）で示される化合物から式（３）で示される化合物を得る方法が本発明の好適な実施態様である。また、式（７）で示される化合物も中間体化合物として非常に有用である。 In the present invention, the compound represented by the above formula (6) to the compound represented by the formula (7) (hereinafter referred to as “N, O-acetal compound”) is represented by the following chemical reaction formula (VII-1). Is preferably employed as an intermediate. Therefore, as shown in the following chemical reaction formula (VII-2), a compound represented by the formula (4) is obtained using the compound represented by the formula (1) as a starting compound, and the obtained formula (4) is obtained. A compound represented by formula (5) is obtained from the compound, a compound represented by formula (6) is obtained from the obtained compound represented by formula (5), and the obtained formula (6) is obtained. A preferred embodiment of the present invention is a method of obtaining a compound represented by formula (7) from a compound and obtaining a compound represented by formula (3) from the obtained compound represented by formula (7). In addition, the compound represented by the formula (7) is also very useful as an intermediate compound.
Figure JPOXMLDOC01-appb-C000089
 ［式（７）中、Ｒ２はアリール基であり、Ｒ３はアルコキシ基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000089
 Wherein (7), R 2 is an aryl group, R 3 is an alkoxy group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is hydrogen An atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000091
 ［式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（７）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000091
 Wherein (6), R 2, X and Y are as defined in the formula (1) wherein (7), R 2, X and Y are as defined in the formula (1), R 3 is An alkoxy group; ]
Figure JPOXMLDOC01-appb-C000092
 ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、式（７）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、Ｒ３はアルコキシ基であり、式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000092
 [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1), and in the formula (5), R 2 , X and Y are as defined in the formula (1), In formula (6), R 2 , X and Y have the same meaning as in formula (1), and in formula (7), R 2 , X and Y have the same meaning as in formula (1), and R 3 represents alkoxy. In the formula (3), R 2 has the same meaning as the formula (1), and R 3 is an alkoxy group. ]
　上記式（７）において、Ｒ２及びＹは上記式（１）におけるＲ２及びＹの説明のところで例示された置換基と同様のものを好適に用いることができ、Ｘは上記式（２）の説明のところで例示された式（２ａ）で示される置換基を好適に用いることができる。上記式（７）において、Ｒ３はアルコキシ基である。アルコキシ基としては、上記式（１）におけるＲ１の説明のところで例示された置換基と同様のものを用いることができる。中でも、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基又はイソブトキシ基がＲ３として好適に使用される。上記化学反応式（VII－１）のように、式（６）で示されるカーバメイト化合物に対して、アニスアルデヒドジメチルアセタールとともに、ｐ－トルエンスルホン酸ピリジニウム（ＰＰＴＳ）等の酸触媒を用いてアセタール化し、式（７）で示されるＮ，Ｏ－アセタール化合物を好適に得ることができる。アニスアルデヒドジメチルアセタールの使用量としては、式（６）で示されるカーバメイト化合物１モルに対して、１～５モルであることが好ましく、１．２～４モルであることがより好ましい。酸触媒の使用量としては、式（６）で示されるカーバメイト化合物１モルに対して、０．００５～０．５モルであることが好ましく、０．０１～０．２モルであることがより好ましい。反応時間としては、０．５～１０時間であることが好ましい。 In the above formula (7), R 2 and Y may be suitably used those similar to the substituents exemplified in the description of R 2 and Y in the formula (1), X is the formula (2) The substituent represented by the formula (2a) exemplified in the description of can be preferably used. In the above formula (7), R 3 is an alkoxy group. As the alkoxy group, those similar to the substituents exemplified in the description of R 1 in the above formula (1) can be used. Of these, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, or an isobutoxy group is preferably used as R 3 . Like the chemical reaction formula (VII-1), the carbamate compound represented by the formula (6) is acetalized using an anisaldehyde dimethyl acetal and an acid catalyst such as pyridinium p-toluenesulfonate (PPTS). An N, O-acetal compound represented by the formula (7) can be preferably obtained. The amount of anisaldehyde dimethyl acetal to be used is preferably 1 to 5 mol, more preferably 1.2 to 4 mol, relative to 1 mol of the carbamate compound represented by the formula (6). The amount of the acid catalyst used is preferably 0.005 to 0.5 mol, more preferably 0.01 to 0.2 mol, relative to 1 mol of the carbamate compound represented by the formula (6). preferable. The reaction time is preferably 0.5 to 10 hours.
　次いで、上記化学反応式（VII－２）のように、式（７）で示されるＮ，Ｏ－アセタール化合物に対して、水酸化リチウム等を用いることにより、式（７）で示されるＮ，Ｏ－アセタール化合物における２’位の異性化とエステル部分の加水分解が同時に進行し、式（３）で示されるカルボン酸化合物を好適に得ることができる。反応時間としては、１～１０時間であることが好ましい。また、反応後に出発化合物の一つである式（１１）で示されるアルコールを回収することもできるため、上記製造方法を採用する意義が大きい。具体的には、反応後にトルエン、酢酸エチル等の有機溶媒と水とを加え、有機層を濃縮することにより式（１１）で示されるアルコールを好適に回収することができる。したがって、下記式（１）で示される化合物を出発化合物として用い、下記式（１１）で示されるアルコールを回収することを特徴とする下記式（３）で示される化合物の製造方法も本発明の好適な実施態様である。 Next, as shown in the chemical reaction formula (VII-2), by using lithium hydroxide or the like for the N, O-acetal compound represented by the formula (7), N, represented by the formula (7) In the O-acetal compound, the isomerization at the 2 ′ position and the hydrolysis of the ester moiety proceed simultaneously, and a carboxylic acid compound represented by the formula (3) can be suitably obtained. The reaction time is preferably 1 to 10 hours. Moreover, since the alcohol shown by Formula (11) which is one of the starting compounds can also be collect | recovered after reaction, the significance which employ | adopts the said manufacturing method is large. Specifically, an alcohol represented by the formula (11) can be suitably recovered by adding an organic solvent such as toluene or ethyl acetate and water after the reaction and concentrating the organic layer. Therefore, a method for producing a compound represented by the following formula (3), which comprises using a compound represented by the following formula (1) as a starting compound and recovering an alcohol represented by the following formula (11), is also disclosed in the present invention. This is a preferred embodiment.
Figure JPOXMLDOC01-appb-C000093
 ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
Figure JPOXMLDOC01-appb-C000093
 [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000095
 ［式（１１）中、Ｘ及びＹは前記式（１）と同義である。］
Figure JPOXMLDOC01-appb-C000095
 [In Formula (11), X and Y are synonymous with said Formula (1). ]
Figure JPOXMLDOC01-appb-C000096
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000096
 [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
　本発明では、上述のようにして得られた式（３）で示される化合物を用いて、ドセタキセルやパクリタキセルを好適に得ることができ、ドセタキセルをより好適に得ることができる。以下、パクリタキセルを得る方法について下記化学反応式（VIII－１）を参照しながら説明する。 In the present invention, docetaxel and paclitaxel can be suitably obtained using the compound represented by the formula (3) obtained as described above, and docetaxel can be more suitably obtained. Hereinafter, a method for obtaining paclitaxel will be described with reference to the following chemical reaction formula (VIII-1).
Figure JPOXMLDOC01-appb-C000097
 ［式（１２）中、Ｚ１はアリルオキシカルボニル基又はトリエチルシリル基であり、式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基であり、式（１３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基であり、Ｚ２はアリルオキシカルボニル基、トリエチルシリル基又は水素原子である。］
Figure JPOXMLDOC01-appb-C000097
 Wherein (12), Z 1 is allyloxycarbonyl group or triethylsilyl group, wherein (3), R 2 is synonymous with the formula (1), R 3 is an alkoxy group, the formula ( In 13), R 2 has the same meaning as in the above formula (1), R 3 is an alkoxy group, and Z 2 is an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom. ]
　上記化学反応式（VIII－１）のように、式（１２）で示されるバッカチンIII誘導体と式（３）で示されるカルボン酸化合物とを縮合反応させて式（１３）で示されるパクリタキセル前駆体を得る工程が好適に採用される。式（１２）におけるＺ１はアリルオキシカルボニル基又はトリエチルシリル基である。式（１３）におけるＲ２及びＲ３は、式（３）におけるＲ２及びＲ３と同義である。また、式（１３）におけるＺ２はアリルオキシカルボニル基、トリエチルシリル基又は水素原子である。縮合反応の際に好適に用いられる縮合剤としては、ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３’－ジメチルアミノプロピル－カルボジイミド塩酸塩（EDCI）等が挙げられる。縮合剤の使用量としては、式（１２）で示されるバッカチンIII誘導体１モルに対して、１～１０モルであることが好ましく、１．２～６モルであることがより好ましい。反応時間としては、０．５～１５時間であることが好ましい。なお、式（１２）で示されるバッカチンIII誘導体は、Robert A. Holton, Zhuming Zhang, Paul A. Clarke, Hossain Nadizadeh, D. John Procter, Tetrahedron Letters, 1998, 39, p.2883-2886に記載された方法により合成することができる。 As in the chemical reaction formula (VIII-1), a paclitaxel precursor represented by the formula (13) obtained by subjecting a baccatin III derivative represented by the formula (12) and a carboxylic acid compound represented by the formula (3) to a condensation reaction The process of obtaining is preferably employed. Z 1 in the formula (12) is an allyloxycarbonyl group or a triethylsilyl group. R 2 and R 3 in the formula (13) has the same meaning as R 2 and R 3 in the formula (3). Z 2 in formula (13) is an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom. Examples of the condensing agent preferably used in the condensation reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl-carbodiimide hydrochloride (EDCI), etc. Amount of condensing agent used Is preferably from 1 to 10 mol, more preferably from 1.2 to 6 mol, based on 1 mol of the baccatin III derivative represented by the formula (12). Preferably, the baccatin III derivative represented by the formula (12) is Robert A. Holton, Zhuming Zhang, Paul A. Clarke, Hossain Nadizadeh, D. John Procter, Tetrahedron Letters, 1998, 39. , p.2883-2886.
　得られた式（１３）で示されるパクリタキセル前駆体において、例えば、Ｚ２がトリエチルシリル基である場合、塩酸等を用いて反応させることで、トリエチルシリル基が脱保護され、Ｚ２が水素原子である式（１３）で示されるパクリタキセル前駆体を得ることもできる。Ｚ２が水素原子である式（１３）で示されるパクリタキセル前駆体に対して、トリフェニルホスフィンとともに触媒である酢酸パラジウム等を用いて反応させることにより、デベンゾイルカルボニルパクリタキセルを好適に得ることができる。前記触媒の使用量としては、Ｚ２が水素原子である式（１３）で示されるパクリタキセル前駆体１モルに対して、０．００５～０．５モルであることが好ましく、０．０１～０．３モルであることがより好ましい。反応時間としては、０．５～１０時間であることが好ましい。 In the obtained paclitaxel precursor represented by the formula (13), for example, when Z 2 is a triethylsilyl group, the triethylsilyl group is deprotected by reacting with hydrochloric acid or the like, and Z 2 is a hydrogen atom. A paclitaxel precursor represented by the formula (13) can also be obtained. Debenzoylcarbonyl paclitaxel can be suitably obtained by reacting the paclitaxel precursor represented by the formula (13) in which Z 2 is a hydrogen atom with palladium acetate as a catalyst together with triphenylphosphine. . The amount of the catalyst used is preferably 0.005 to 0.5 mol, preferably 0.01 to 0, relative to 1 mol of the paclitaxel precursor represented by the formula (13) in which Z 2 is a hydrogen atom. More preferably, it is 3 mol. The reaction time is preferably 0.5 to 10 hours.
　次いで、塩化ベンゾイル等を用いて、デベンゾイルカルボニルパクリタキセルにおけるアミノ基を保護する反応を行うことにより、式（１４）で示されるパクリタキセルを好適に得ることができる。 Subsequently, paclitaxel represented by the formula (14) can be suitably obtained by carrying out a reaction for protecting the amino group in debenzoylcarbonyl paclitaxel using benzoyl chloride or the like.
　以下、ドセタキセルを得る方法について下記化学反応式（VIII－２）を参照しながら説明する。 Hereinafter, a method for obtaining docetaxel will be described with reference to the following chemical reaction formula (VIII-2).
Figure JPOXMLDOC01-appb-C000098
 ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基であり、式（１３’）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
Figure JPOXMLDOC01-appb-C000098
 [In Formula (3), R 2 is synonymous with Formula (1), R 3 is an alkoxy group, and in Formula (13 ′), R 2 is synonymous with Formula (1), and R 3 Is an alkoxy group. ]
　上記化学反応式（VIII－２）のように、式（１２’）で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII誘導体と式（３）で示されるカルボン酸化合物とを縮合反応させて、式（１３’）で示されるドセタキセル前駆体を得る工程が好適に採用される。式（１３’）におけるＲ２及びＲ３は、式（３）におけるＲ２及びＲ３と同義である。縮合反応の際に好適に用いられる縮合剤としては、ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３’－ジメチルアミノプロピル－カルボジイミド塩酸塩（EDCI）等が挙げられる。縮合剤の使用量としては、式（１２’）で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII誘導体１モルに対して、１～１０モルであることが好ましく、１．２～６モルであることがより好ましい。反応時間としては、０．５～１０時間であることが好ましい。なお、式（１２’）で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII誘導体は、ＷＯ２００８／０５４２３３Ａ２に記載された方法により合成することができる。 Like the above chemical reaction formula (VIII-2), a 7,10-Dialloc-baccatin III derivative represented by the formula (12 ′) and a carboxylic acid compound represented by the formula (3) are subjected to a condensation reaction, and the formula ( The process of obtaining the docetaxel precursor shown by 13 ') is employ | adopted suitably. R 2 and R 3 in the formula (13 ') has the same meaning as R 2 and R 3 in the formula (3). Examples of the condensing agent preferably used in the condensation reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl-carbodiimide hydrochloride (EDCI), etc. Amount of condensing agent used Is preferably 1 to 10 moles, more preferably 1.2 to 6 moles per mole of the 7,10-Dialloc-baccatin III derivative represented by the formula (12 ′). The time is preferably 0.5 to 10 hours, and the 7,10-Dialoc-baccatin III derivative represented by the formula (12 ′) can be synthesized by the method described in WO2008 / 054233A2. it can.
　得られた式（１３’）で示されるドセタキセル前駆体に対して、トリフェニルホスフィンとともに触媒である酢酸パラジウム等を用いて反応させることにより、アリルオキシカルボニル基が脱保護され、デブトキシカルボニルドセタキセルを好適に得ることができる。前記触媒の使用量としては、式（１３’）で示されるドセタキセル前駆体１モルに対して、０．００５～０．５モルであることが好ましく、０．０１～０．１モルであることがより好ましい。反応時間としては、０．５～１０時間であることが好ましい。 By reacting the obtained docetaxel precursor represented by the formula (13 ′) with triphenylphosphine using palladium acetate as a catalyst, the allyloxycarbonyl group is deprotected, and debutoxycarbonyl docetaxel is converted into debutoxycarbonyl docetaxel. It can be suitably obtained. The amount of the catalyst used is preferably 0.005 to 0.5 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of the docetaxel precursor represented by the formula (13 ′). Is more preferable. The reaction time is preferably 0.5 to 10 hours.
　次いで、二炭酸-tert-ジブチル等を用いて、デブトキシカルボニルドセタキセルにおけるアミノ基を保護する反応を行うことにより、式（１４’）で示されるドセタキセルを好適に得ることができる。 Subsequently, docetaxel represented by the formula (14 ') can be suitably obtained by carrying out a reaction for protecting the amino group in debutoxycarbonyl docetaxel using di-tert-dibutyl dicarbonate or the like.
　上述のように、簡便な方法により、高純度、高収率かつ安価にパクリタキセル及びドセタキセルの側鎖前駆体を提供することができる。そして、得られた側鎖前駆体から抗癌剤として有用とされるパクリタキセル及びドセタキセルを提供することができる。したがって、本発明の製造方法、及びその方法に使用される中間体化合物は非常に有用であることが分かる。 As described above, the side chain precursors of paclitaxel and docetaxel can be provided by a simple method with high purity, high yield and low cost. And the paclitaxel and docetaxel which are considered useful as an anticancer agent from the obtained side chain precursor can be provided. Therefore, it turns out that the manufacturing method of this invention and the intermediate compound used for the method are very useful.
　以下、実施例を用いて本発明を更に具体的に説明する。 Hereinafter, the present invention will be described more specifically using examples.
実施例１
［式（９ａ）で示されるエステル化合物の合成］ Example 1
[Synthesis of ester compound represented by formula (9a)]
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　式（10a）で示されるベンゾイル酢酸エチル（9.61 g, 50 mmol）とL-メントール（10.2 g, 65 mmol）の混合物を100℃に加熱し、エタノールを減圧下に留去（<20 mmHg）しながら8時間反応させた。未反応のベンゾイル酢酸エチルとL-メントールを蒸留（油浴温度125℃、＜0.5 mmHg）で取り除き、式（9a）で示されるエステル化合物である淡黄色の液体（15.1 g）を得た。 A mixture of ethyl benzoylacetate (9.61 g, 50 mmol) and L-menthol (10.2 g, 65 mmol) represented by formula (10a) is heated to 100 ° C, and ethanol is distilled off under reduced pressure (<20 mmHg). The reaction was continued for 8 hours. Unreacted ethyl benzoyl acetate and L-menthol were removed by distillation (oil bath temperature 125 ° C., <0.5 mmHg) to obtain a pale yellow liquid (15.1 kg) which is an ester compound represented by the formula (9a).
　分析用サンプルはシリカゲルカラムクロマトで精製し、白色固体を得た。式（9a）で示されるエステル化合物の分析データを以下に示す。
　TLC: ヘキサン/酢酸エチル=10/1, Rf=0.50, UV active;
　1H NMR (500 MHz, CDCl3) δ: 12.7 (bs, 0.3H), 7.94-7.40 (m, 5H), 4.82 (dt, J=10.9 Hz, 4.37 Hz, 0.36H),4.72 (dt, J=10.9, 4.37 Hz, 0.64H), 4.00(d, J=15.5 Hz,0.64 H), 3.94(d, J=15.5 Hz, 0.64 H), 2.04-1.98 (m, 1H), 1.78-1.29 (m, 4H), 1.06-0.78 (m, 3H), 0.89(d, J=6.7 Hz, 3H), 0.81 (d, J=7.0 Hz, 3H), 0.68 (d, J=6.8 Hz,3H);
　13C NMR (125 MHz, CDCl3) δ: 192.5, 172.9, 171.3, 167.1, 136.1, 133.6, 131.1, 128.7, 128.5, 126.0, 87.7, 75.6, 74.2, 47.1, 46.8, 46.5, 41.1, 40.6, 34.2, 34.1,31.43, 31.4, 26.3, 25.9, 23.6, 23.2, 22.0, 21.9, 20.7, 16.4, 16.0;
　m.p. 37.7-38.3 ℃（無溶媒状態から固化）;
　比旋光度 [α]D 23 -60.1 (C 1.44, CHCl3) The analytical sample was purified by silica gel column chromatography to obtain a white solid. Analytical data of the ester compound represented by the formula (9a) is shown below.
TLC: Hexane / ethyl acetate = 10/1, R f = 0.50, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 12.7 (bs, 0.3H), 7.94-7.40 (m, 5H), 4.82 (dt, J = 10.9 Hz, 4.37 Hz, 0.36H), 4.72 (dt, J = 10.9, 4.37 Hz, 0.64H), 4.00 (d, J = 15.5 Hz, 0.64 H), 3.94 (d, J = 15.5 Hz, 0.64 H), 2.04-1.98 (m, 1H), 1.78-1.29 (m , 4H), 1.06-0.78 (m, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 192.5, 172.9, 171.3, 167.1, 136.1, 133.6, 131.1, 128.7, 128.5, 126.0, 87.7, 75.6, 74.2, 47.1, 46.8, 46.5, 41.1, 40.6, 34.2, 34.1, 31.43, 31.4, 26.3, 25.9, 23.6, 23.2, 22.0, 21.9, 20.7, 16.4, 16.0;
mp 37.7-38.3 ° C (solidification from solvent-free state);
Specific rotation [α] D 23 -60.1 (C 1.44, CHCl 3 )
［式（８ａ）で示されるオキシム化合物の合成］ [Synthesis of Oxime Compound represented by Formula (8a)]
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　式（9a）で示されるエステル化合物（15.1 g, 49.9 mmol）をメタノール（20 mL）に溶かし、続いてO-メチルヒドロキシルアミン塩酸塩（4.59 g, 55 mmol）を加えた。続いて、ピリジン（4.85 mL, 60 mmol）を室温で5分掛けて滴下した。滴下後、室温で2時間撹拌した。溶媒を減圧下に留去した後、トルエン（50ml）に溶解し、水（50 ml）で3回洗浄、無水硫酸マグネシウムで乾燥、濾過した。減圧下に溶媒を留去し、淡黄色のオイルを得た。減圧蒸留（155-165 ℃/0.8 mmHg）し、式（8a）で示されるオキシム化合物である淡黄色の油状物（15.1 g, 2工程通算で91%）を得た。 The ester compound represented by the formula (9a) (15.1 g, 49.9 mmol) was dissolved in methanol (20 mL), and then O-methylhydroxylamine hydrochloride (4.59 g, 55 mmol) was added. Subsequently, pyridine (4.85 mL, 60 mL) was added dropwise at room temperature over 5 minutes. After dropping, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, then dissolved in toluene (50 ml), washed 3 times with water (50 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a pale yellow oil. Distillation under reduced pressure (155-165 ° C./0.8 mmHg) gave a pale yellow oil (15.1 kg, 91% in total over 2 steps) which is an oxime compound represented by the formula (8a).
　式（8a）で示されるオキシム化合物の分析データを以下に示す。
　TLC: Hexane/EtOAc=10/1, Rf=0.53, yellow-green, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.65-7.30 (m, 5H), 4.70-4.40 (m, 1H), 3.99(s, 3H), 3.75(d, J=15.9 Hz, 1H), 3.71(d, J=15.9 Hz, 1H), 1.98-1.93 (m, 1H), 1.79-1.27 (m, 6H), 1.06-0.77 (m, 3H), 0.88(d, J=6.7 Hz, 3H), 0.84 (d, J=7.1 Hz, 3H), 0.69 (d, J=7.1 Hz, 3H);
　13C NMR (125 MHz, CDCl3) δ: 168.4, 151.5, 135.5, 129.2, 126.2, 75.0, 62.1, 46.8, 40.5, 34.1, 33.7, 31.3, 25.9, 23.2, 21.9, 20.7, 16.1;
　比旋光度 [α]D 25 -40.4 (C 1.03, CHCl3) Analytical data of the oxime compound represented by the formula (8a) is shown below.
TLC: Hexane / EtOAc = 10/1, R f = 0.53, yellow-green, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.65-7.30 (m, 5H), 4.70-4.40 (m, 1H), 3.99 (s, 3H), 3.75 (d, J = 15.9 Hz, 1H), 3.71 (d, J = 15.9 Hz, 1H), 1.98-1.93 (m, 1H), 1.79-1.27 (m, 6H), 1.06-0.77 (m, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 7.1 Hz, 3H), 0.69 (d, J = 7.1 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 168.4, 151.5, 135.5, 129.2, 126.2, 75.0, 62.1, 46.8, 40.5, 34.1, 33.7, 31.3, 25.9, 23.2, 21.9, 20.7, 16.1;
Specific rotation [α] D 25 -40.4 (C 1.03, CHCl 3 )
［式（１ａ）で示されるジアゾ化合物の合成］ [Synthesis of diazo compound represented by formula (1a)]
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　式（8a）で示されるオキシム化合物（30 g, 90.4 mmol）のアセトニトリル溶液（100 ml）に、トシルアジド（21.4 g, 108.5 mmol）を加えた。続いて1,8-ジアザビシクロ[5.4.0]ウンデセン（DBU）（2.76 g,18.1 mmol）を20分掛けて滴下した。室温で12時間撹拌した後、溶媒を減圧下に留去し、トルエン（100 mL）と水（50 mL）とを加えて分液した。有機層を水(50 ml)で3回洗浄した。析出したトシルアミドをろ過で除いた後、無水硫酸マグネシウムで乾燥、濾過した。溶媒を減圧下に留去し、式（1a）で示されるジアゾ化合物である濃い黄色の油状物（29 g,90%）を得た。 Tosyl azide (21.4 g, 108.5 mmol) was added to an acetonitrile solution (100 ml) of the oxime compound (30 g, 90.4 mmol) represented by the formula (8a). Subsequently, 1,8-diazabicyclo [5.4.0] undecene (DBU) (2.76 g, 18.1 mmol) was added dropwise over 20 minutes. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and toluene (100 mL) and water (50 mL) were added to separate the layers. The organic layer was washed 3 times with water (50 ml). The precipitated tosylamide was removed by filtration, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain a dark yellow oily substance (29 g, 90%) which is a diazo compound represented by the formula (1a).
　分析用サンプルはシリカゲルカラムクロマトで精製した。式（1a）で示されるジアゾ化合物の分析データを以下に示す。
　TLC: トルエン/EtOAc=50/1, Rf=0.50, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.55-7.35 (m, 5H), 4.65-4.55 (m, 1H), 4.05(s, 3H), 1.98-0.75 (m, 9H), 0.85(d, J=6.4 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H), 0.68(d, J=7.0 Hz, 3H);
　13C NMR (125 MHz, CDCl3) δ: 163.6, 144.4, 134.0, 129.4, 128.2, 127.7, 75.6, 62.6, 60.3, 58.0, 46.8, 40.8, 34.0, 31.3, 25.9, 23.2, 21.9, 20.7, 16.2;
　比旋光度 [α]D 23.5 -50.7 (C 1.43, CHCl3) The analytical sample was purified by silica gel column chromatography. Analytical data of the diazo compound represented by the formula (1a) is shown below.
TLC: Toluene / EtOAc = 50/1, R f = 0.50, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.55-7.35 (m, 5H), 4.65-4.55 (m, 1H), 4.05 (s, 3H), 1.98-0.75 (m, 9H), 0.85 (d, J = 6.4 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 163.6, 144.4, 134.0, 129.4, 128.2, 127.7, 75.6, 62.6, 60.3, 58.0, 46.8, 40.8, 34.0, 31.3, 25.9, 23.2, 21.9, 20.7, 16.2;
Specific rotation [α] D 23.5 -50.7 (C 1.43, CHCl 3 )
［式（４ａ）で示されるオキシムアルコール化合物の合成］ [Synthesis of an oxime alcohol compound represented by the formula (4a)]
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　ギ酸（11.3 mL, 0.3 mol）を60°Cに加熱しておき、式（1a）で示されるジアゾ化合物（3.57 g,10 mmol）を酢酸エチル（50 mL）に溶かした溶液を3時間掛けて滴下した。この温度で2時間撹拌をした後、減圧下に溶媒を留去した。残渣にメタノール（50 mL）、続いて28%アンモニア水（5 mL）を加えて室温で1時間撹拌した。減圧下に溶媒を留去し、残渣にトルエン/酢酸エチル（50 mL/50 mL）、水（50 mL）を加えて分液した。有機層を無水硫酸マグネシウムで乾燥、濾過、減圧下に濃縮し、淡黄色の油状物（3.08 g）を得た。ヘキサン（50 mL）を加えて溶解し、室温で48時間放置して式（4a）で示されるオキシムアルコール化合物である白色結晶（1.27g, 36.6%）を得た。 Formic acid (11.3 mL, 0.3 mol) was heated to 60 ° C, and a solution of diazo compound (3.57 g, 10 mmol) represented by formula (1a) in ethyl acetate (50 mL) was added over 3 hours. It was dripped. After stirring at this temperature for 2 hours, the solvent was distilled off under reduced pressure. Methanol (50 mL) was added to the residue, followed by 28% aqueous ammonia (5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and toluene / ethyl acetate (50 mL / 50 mL) and water (50 mL) were added to the residue for liquid separation. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a pale yellow oil (3.08 g). Hexane (50 mL) was added and dissolved, and the mixture was allowed to stand at room temperature for 48 hours to obtain white crystals (1.27 g,） 36.6%) which is an oxime alcohol compound represented by the formula (4a).
　式（4a）で示されるオキシムアルコール化合物の分析データを以下に示す。
　TLC: ヘキサン/酢酸エチル＝5/1, Rf=0.50, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.62-7.57(m, 2H), 7.41-7.36 (m, 3H), 5.30 (d, J=7.9 Hz, 1H), 4.81-4.75(m, 1H), 4.00(s, 3H), 3.66 (d, J=7.9 Hz, 1H), 1.85-1.78 (m, 2H), 1.68-1.63(m, 2H), 1.44 (br, 1H), 1.35-1.32 (m, 1H), 0.85-0.78 (m, 3H), 0.87 (d, J=7.0 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H);
　13C NMR (125 MHz, CDCl3) δ: 171.0, 155.1, 133.9, 129.4, 128.4, 126.8, 76.3, 67.5, 62.4, 46.6, 39.9, 33.9, 31.1, 26.2, 23.4, 21.8, 20.5, 16.3;
　m.p. 111.4-111.9 ℃（ヘキサン）;
　比旋光度: [α]D 23 +44.7 (C 1.41, CHCl3) Analytical data of the oxime alcohol compound represented by the formula (4a) is shown below.
TLC: Hexane / ethyl acetate = 5/1, R f = 0.50, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.62-7.57 (m, 2H), 7.41-7.36 (m, 3H), 5.30 (d, J = 7.9 Hz, 1H), 4.81-4.75 (m, 1H) , 4.00 (s, 3H), 3.66 (d, J = 7.9 Hz, 1H), 1.85-1.78 (m, 2H), 1.68-1.63 (m, 2H), 1.44 (br, 1H), 1.35-1.32 (m , 1H), 0.85-0.78 (m, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 171.0, 155.1, 133.9, 129.4, 128.4, 126.8, 76.3, 67.5, 62.4, 46.6, 39.9, 33.9, 31.1, 26.2, 23.4, 21.8, 20.5, 16.3;
mp 111.4-111.9 ° C (hexane);
Specific rotation: [α] D 23 +44.7 (C 1.41, CHCl 3 )
［式（５ａ）で示されるトランスアミノアルコール化合物の合成］ [Synthesis of transamino alcohol compound represented by formula (5a)]
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　式（4a）で示されるオキシムアルコール化合物(10.4 g, 30 mmol)と酢酸(2.86 mL, 50 mmol)の混合物にメタノール(100 mL)、続いて10% Pd/C (200 mg)を順次加え、１気圧で水素添加した。6時間攪拌した後、反応混合物をメタノール（30 mL）で希釈し、触媒をセライト545で濾去した。濾液を減圧下に濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液(50 mL)と固体の炭酸水素ナトリウムをゆっくりと加えて弱アルカリ性にした。クロロホルム(30 mL)で3回抽出を行なった。抽出液を飽和食塩水(30 ml)で洗浄した後、無水硫酸マグネシウムで乾燥、濾過した。減圧下に溶媒を留去して、淡黄色のオイル(10 g)を得た。ヘキサンに溶解し、室温で１２時間静置して式（5a）で示されるトランスアミノアルコール（8.15 g, 85 %）を白色個体として得た。 To a mixture of the oxime alcohol compound represented by the formula (4a) (10.4 g, 30 mmol) and acetic acid (2.86 mL, 50 mmol), methanol (100 mL) and then 10% Pd / C (200 mg) were sequentially added. Hydrogenated at 1 atm. After stirring for 6 hours, the reaction mixture was diluted with methanol (30 mL), and the catalyst was filtered off through Celite 545. The filtrate was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate (50 mL) and solid sodium hydrogen carbonate were slowly added to the resulting residue to make it weakly alkaline. Extraction was performed 3 times with chloroform (30 mL). The extract was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a pale yellow oil (10 g). The product was dissolved in hexane and allowed to stand at room temperature for 12 hours to obtain a transamino alcohol represented by the formula (5a) (8.15 式 g, 85%) as a white solid.
　式（5a）で示されるトランスアミノアルコール化合物の分析データを以下に示す。
　TLC: CHCl3/MeOH=9/1, Rf=0.33, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.35-7.21(m, 5H), 4.73-4.60 (m, 1H), 4.46(d, J=4.0 Hz,1H), 4.30(d, J=4.0 Hz, 1H), 3.22-3.02(br, 1H), 1.80-0.75 (m,12H), 0.88(d, J=6.4 Hz, 3H, 0.82 (d, J=7.0 Hz, 3H), 0.66(d, J=6.8 Hz, 3H);
　13C NMR (125 MHz, CDCl3) δ: 171.9, 140.5, 128.0, 127.4, 75.5, 74.6, 58.0, 46.7, 40.6, 33.9, 31.1, 25.8, 23.1, 21.8, 20.5, 16.1;
　m.p. 82.0-83.1 ℃（ヘキサン）;
　比旋光度 [α]D 24 -57.7 (C 1.41, CHCl3) Analytical data of the transamino alcohol compound represented by the formula (5a) is shown below.
TLC: CHCl 3 / MeOH = 9/1, R f = 0.33, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.35-7.21 (m, 5H), 4.73-4.60 (m, 1H), 4.46 (d, J = 4.0 Hz, 1H), 4.30 (d, J = 4.0 Hz , 1H), 3.22-3.02 (br, 1H), 1.80-0.75 (m, 12H), 0.88 (d, J = 6.4 Hz, 3H, 0.82 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 171.9, 140.5, 128.0, 127.4, 75.5, 74.6, 58.0, 46.7, 40.6, 33.9, 31.1, 25.8, 23.1, 21.8, 20.5, 16.1;
mp 82.0-83.1 ° C (hexane);
Specific rotation [α] D 24 -57.7 (C 1.41, CHCl 3 )
［式（６ａ）で示されるカーバメイト化合物の合成］ [Synthesis of a carbamate compound represented by the formula (6a)]
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　式（5a）で示されるトランスアミノアルコール化合物（3.19 g, 10 mmol）、炭酸水素ナトリウム（2.18 g, 26 mmol）の混合物に酢酸エチル（40 ml）と水（20 ml）を加えた。室温下、激しく撹拌しながらクロルギ酸アリル（1.17 ml, 11 mmol）を滴下した。室温で３０分撹拌した後、トルエン（20 ml）を加え、分液した。有機層を飽和炭酸水素ナトリウム水溶液（20 ml）で2回洗浄し、無水硫酸マグネシウムで乾燥、濾過した。減圧下に溶媒を留去して、式（6a）で示されるアリルカーバメイト（4.0 g, 99%）を粘稠な淡黄色のオイルとして得た。 Ethyl acetate (40 ml) and water (20 ml) were added to a mixture of the transaminoalcohol compound represented by the formula (5a) (3.19 g, 10 mmol) and sodium bicarbonate (2.18 g, 26 mmol). Allyl chloroformate (1.17 ギ ml, 11 mmol) was added dropwise with vigorous stirring at room temperature. After stirring at room temperature for 30 minutes, toluene (20 ml) was added and the layers were separated. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution (20 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain allyl carbamate (4.0 g, 99%) represented by the formula (6a) as a viscous light yellow oil.
　式（6a）で示されるアリルカーバメイトの分析データを以下に示す。
　TLC: toluene/EtOAc=10/1, Rf=0.27, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.40-7.25 (m, 5H), 5.95-5.85 (m, 1H), 5.83 (d, J=9.2 Hz, 1H), 5.30 (d, J=17.4 Hz,1H),5.21 (d, J=10.4 Hz,1H), 5.13 (dd, J=9.0,3.1 Hz,1H), 4.76-4.50 (m,4H),3.01(d,J=6.1 Hz,1H), 1.75-1.63 (m, 4H), 1.44-1.33 (m, 2H),1.05-0.80 (m,9H), 0.68(d,J=6.7 Hz, 3H);
　13C NMR (125 MHz, CDCl3) δ: 171.1, 155.3, 136.6, 132.6, 128.1, 127.9, 117.6, 76.5, 72.7, 65.6, 56.6, 46.7, 40.5, 33.8, 31.2, 25.9, 23.1, 21.7, 20.5, 16.0;
　比旋光度:[α]D 22 -47.3 (C 1.25, CHCl3) Analytical data of allyl carbamate represented by the formula (6a) is shown below.
TLC: toluene / EtOAc = 10/1, R f = 0.27, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.40-7.25 (m, 5H), 5.95-5.85 (m, 1H), 5.83 (d, J = 9.2 Hz, 1H), 5.30 (d, J = 17.4 Hz , 1H), 5.21 (d, J = 10.4 Hz, 1H), 5.13 (dd, J = 9.0,3.1 Hz, 1H), 4.76-4.50 (m, 4H), 3.01 (d, J = 6.1 Hz, 1H) , 1.75-1.63 (m, 4H), 1.44-1.33 (m, 2H), 1.05-0.80 (m, 9H), 0.68 (d, J = 6.7 Hz, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 171.1, 155.3, 136.6, 132.6, 128.1, 127.9, 117.6, 76.5, 72.7, 65.6, 56.6, 46.7, 40.5, 33.8, 31.2, 25.9, 23.1, 21.7, 20.5, 16.0;
Specific rotation: [α] D 22 -47.3 (C 1.25, CHCl 3 )
［式（７ａ）で示されるＮ，Ｏ－アセタール化合物の合成］ [Synthesis of N, O-acetal compound represented by formula (7a)]
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　式（6a）で示されるカーバメイト化合物（4 g, 9.9 mmol）、アニスアルデヒドジメチルアセタール（3.61 g, 19.8 mmol）、PPTS（0.124 g, 0.5 mmol）のトルエン溶液（50 mL）を減圧下（約20 mmHg）にメタノールを留去しながら、100℃で加熱攪拌した。２時間後、室温まで冷却して飽和炭酸水素ナトリウム水溶液(10 mL)を加えて反応を停止した。分液操作を行い、有機層を無水硫酸マグネシウムで乾燥、ろ過、減圧下に溶媒を留去し、淡黄色の油状物を得た。熱ヘキサンに溶解した後、室温で一晩放置し、式（7a）で示されるＮ，Ｏ－アセタール化合物（4.65 g, 90 %）を白色個体として得た。 Carbamate compound represented by formula (6a) (4 g, 9.9 mmol), anisaldehyde dimethyl acetal (3.61 g, 19.8 mmol), PPTS (0.124 g, 0.5 mmol) in toluene solution (50 mL) under reduced pressure (about 20 mmHg) was stirred with heating at 100 ° C. while distilling off methanol. After 2 hours, the reaction was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (10 mL). Liquid separation operation was performed, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. After dissolving in hot hexane, the mixture was allowed to stand overnight at room temperature to obtain the N, O-acetal compound (4.65 g, 90%) represented by the formula (7a) as a white solid.
　式（7a）で示されるＮ，Ｏ－アセタール化合物の分析データを以下に示す。
　TLC: toluene/EtOAc=10/1, Rf=0.53, UV active;
　1H NMR (500 MHz, CDCl3) δ: 7.52-7.25 (m, 7H), 6.90 (d, J=8.6 Hz, 2H), 6.11(s, 1H), 5.74 (br, 1H), 5.31 (d, J=7.1 Hz, 1H), 5.14-5.05 (m,1H), 4.99 (d, J=7.1 Hz, 1H), 4.55-4.42 (m, 3H), 1.70-1.54 (m, 4H), 1.25-1.17 (m, 2H), 0.95-0.85 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.75-0.66 (m, 1H), 0.68 (d, J=6.4 Hz, 3H), 0.64 (d, J=7.1 Hz, 3H), 0.28-0.18 (m, 1H);
　13C NMR (125 MHz, CDCl3) δ: 165.8, 160.1, 153.8, 137.7, 131.9, 128.9, 128.7, 128.1, 117.3, 113.5, 90.6, 79.3, 75.1, 65.9, 62.3, 55.1, 46.5, 39.3, 33.8, 30.8, 26.0, 23.1, 21.6, 20.5,16.1;
　m.p. 108.9-110.0 ℃（ヘキサン）;
　比旋光度 [α]D 22 -52.6 (C 1.34, CHCl3), [α]D 22 -41.7 (C 1.12, CHCl3) Analytical data of the N, O-acetal compound represented by the formula (7a) is shown below.
TLC: toluene / EtOAc = 10/1, R f = 0.53, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 7.52-7.25 (m, 7H), 6.90 (d, J = 8.6 Hz, 2H), 6.11 (s, 1H), 5.74 (br, 1H), 5.31 (d , J = 7.1 Hz, 1H), 5.14-5.05 (m, 1H), 4.99 (d, J = 7.1 Hz, 1H), 4.55-4.42 (m, 3H), 1.70-1.54 (m, 4H), 1.25- 1.17 (m, 2H), 0.95-0.85 (m, 1H), 0.83 (d, J = 7.0 Hz, 3H), 0.75-0.66 (m, 1H), 0.68 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 7.1 Hz, 3H), 0.28-0.18 (m, 1H);
13 C NMR (125 MHz, CDCl 3 ) δ: 165.8, 160.1, 153.8, 137.7, 131.9, 128.9, 128.7, 128.1, 117.3, 113.5, 90.6, 79.3, 75.1, 65.9, 62.3, 55.1, 46.5, 39.3, 33.8, 30.8, 26.0, 23.1, 21.6, 20.5, 16.1;
mp 108.9-110.0 ° C (hexane);
Specific rotation [α] D 22 -52.6 (C 1.34, CHCl 3 ), [α] D 22 -41.7 (C 1.12, CHCl 3 )
［式（３ａ）で示されるカルボン酸化合物の合成］ [Synthesis of Carboxylic Acid Compound Represented by Formula (3a)]
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　式（7a）で示されるＮ，Ｏ－アセタール化合物（5.22 g, 10 mmol）に水酸化リチウム一水和物（629 mg,15 mmol）、メタノール(5 ml)、ジオキサン(30 ml)、水(5 ml)を加え,
50℃で5時間撹拌した。溶媒を減圧下に留去した後、残渣にトルエン(15 ml)、酢酸エチル(15 ml)、水(15 ml)を加え、よく撹拌した。有機層を分離し、食塩水（20 mL）で洗浄後、無水硫酸マグネシウムで乾燥、ろ過した後、減圧下に濃縮してメントール(1.48 g, 9.5 mmol)を回収した。一方、水層は再度トルエン(10 ml)と酢酸エチル（10 ml）を加えて洗浄し、分離した水層にトルエン(20 ml)と酢酸エチル(20 ml)を加えて、激しく撹拌しながら0.3M HCl(60 ml)をゆっくりと注いで弱酸性にした。有機層を水(20 ml)で3回洗浄し、無水硫酸マグネシウムで乾燥、ろ過した後、減圧下に濃縮して式（3a）で示されるカルボン酸を淡黄色の液体として得た(3.26g, 85%)。 To the N, O-acetal compound (5.22 g, 10 mmol) represented by the formula (7a), lithium hydroxide monohydrate (629 mg, 15 mmol), methanol (5 ml), dioxane (30 ml), water ( 5 ml)
Stir at 50 ° C. for 5 hours. After the solvent was distilled off under reduced pressure, toluene (15 ml), ethyl acetate (15 ml) and water (15 ml) were added to the residue and stirred well. The organic layer was separated, washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to recover menthol (1.48 g, 9.5 mmol). On the other hand, the aqueous layer was washed again with toluene (10 ml) and ethyl acetate (10 ml). To the separated aqueous layer was added toluene (20 ml) and ethyl acetate (20 ml), and the mixture was stirred vigorously with 0.3%. M HCl (60 ml) was slowly poured to make it weakly acidic. The organic layer was washed 3 times with water (20 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the carboxylic acid represented by formula (3a) as a pale yellow liquid (3.26 g). , 85%).
　式（3a）で示されるカルボン酸化合物の分析データを以下に示す。
　1H NMR (500 MHz, CDCl3) δ: 8.4-8.0 (br, 1H), 7.55-7.30 (m, 7H), 6.88 (d, J=8.6 Hz, 2H), 6.52 (s, 1H), 5.82-5.74 (m, 1H), 5.42 (bs, 1H), 5.15-5.06 (m, 2H), 4.92 (d, J=3.4, 1H),4.56 (d, J=5.5 HZ, 2H), 3.82 (s, 3H);
　13C NMR (125 MHz, CDCl3) δ: 173.9, 160.0, 154.5, 138.9, 131.8, 129.7, 128.7, 128.6, 128.1, 126.8, 117.7, 113.6, 91.3, 81.4, 66.4, 63.4, 55.1;
　比旋光度 [α]D 24 -28.4 (c 2.04, MeOH), [α]D 24 -29.6 (c 1.91, CHCl3) Analytical data of the carboxylic acid compound represented by the formula (3a) is shown below.
1 H NMR (500 MHz, CDCl 3 ) δ: 8.4-8.0 (br, 1H), 7.55-7.30 (m, 7H), 6.88 (d, J = 8.6 Hz, 2H), 6.52 (s, 1H), 5.82 -5.74 (m, 1H), 5.42 (bs, 1H), 5.15-5.06 (m, 2H), 4.92 (d, J = 3.4, 1H), 4.56 (d, J = 5.5 HZ, 2H), 3.82 (s , 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 173.9, 160.0, 154.5, 138.9, 131.8, 129.7, 128.7, 128.6, 128.1, 126.8, 117.7, 113.6, 91.3, 81.4, 66.4, 63.4, 55.1;
Specific rotation [α] D 24 -28.4 (c 2.04, MeOH), [α] D 24 -29.6 (c 1.91, CHCl 3 )
実施例２
［式（１２ａ）で示される７－トリエチルシリル－バッカチンIIIの合成］ Example 2
[Synthesis of 7-triethylsilyl-baccatin III represented by the formula (12a)]
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　10-デアセチルバッカチンIII(10-DAB)(1.63 g, 3.0 mmol)に無水塩化セリウム（25 mg, 0.1 mmol）、続いて乾燥テトラヒドロフラン（25 mL）を入れ、室温で10分間撹拌した。白く懸濁した混合物に無水酢酸（2.84 mL, 30 mmol）を加えた。室温で4.5時間撹拌したところ、透明な溶液の状態になった。水（20 mL）、飽和炭酸水素ナトリウム水溶液（20 mL）、酢酸エチル（50 mL）を加えて1時間撹拌して無水酢酸を分解した。有機層を分離した後、飽和炭酸水素ナトリウム水溶液（20 mL）で3回洗浄し、無水硫酸マグネシウムで乾燥、ろ過した後、減圧下に溶媒を留去して白色固体（1.98 g）を得た（Robert A. Holton, Zhuming Zhang, Paul A. Clarke, Hossain Nadizadeh, D. John Procter, Tetrahedron Letters, 1998, 39, p.2883-2886に記載された条件を採用した）。これにN,N-ジメチルアミノピリジン（36.7mg, 0.3 mmol）、N,N-ジイソプロピルエチルアミン（3.14 mL, 18 mmol）を加えた後、ジクロロメタン（30 mL）を加えた。トリエチルクロロシラン（1.0 mL, 6.0 mmol）を滴下して室温で21時間撹拌した。溶媒を減圧下に留去した後、残渣を酢酸エチル（30 mL）で希釈した後、飽和炭酸水素ナトリウム水溶液（30 mL）で2回、水（20 mL）で1回洗浄し、無水硫酸マグネシウムで乾燥してろ過後、減圧下に溶媒を留去し、白色固体（2.13 g）を得た。熱ヘキサン（20 mL）で2回洗浄して、式（12a）で示される７－トリエチルシリル－バッカチンIIIである灰白色固体（1.85 g, 88%）を得た。 Anhydrous cerium chloride (25 mg, 0.1 mol) was added to 10-deacetylbaccatin III (10-DAB) (1.63 g, 3.0 mol) followed by dry tetrahydrofuran (25 mL) and stirred at room temperature for 10 minutes. Acetic anhydride (2.84 mL, 30 mL) was added to the white suspension mixture. After stirring at room temperature for 4.5 hours, a clear solution was obtained. Water (20 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL), and ethyl acetate (50 mL) were added and stirred for 1 hour to decompose acetic anhydride. After separating the organic layer, it was washed 3 times with a saturated aqueous solution of sodium bicarbonate (20 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to obtain a white solid (1.98 mL). (The conditions described in Robert A. Holton, Zhuming Zhang, Paul A. Clarke, Hossain Nadizadeh, D. John Procter, Tetrahedron Letters, 1998, 39, p. 2883-2886 were adopted). N, N-dimethylaminopyridine (36.7 mg, 0.3 mmol) and N, N-diisopropylethylamine (3.14 mL, 18 mmol) were added to this, and then dichloromethane (30 mL) was added. Triethylchlorosilane (1.0 mL, 6.0 mL) was added dropwise and stirred at room temperature for 21 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate (30 mL), washed twice with saturated aqueous sodium bicarbonate (30 mL), and once with water (20 mL), and anhydrous magnesium sulfate After filtration and filtration, the solvent was distilled off under reduced pressure to obtain a white solid (2.13 g). Washing with hot hexane (20 mL) twice gave 7-triethylsilyl-baccatin III of the formula (12a) as an off-white solid (1.85 g, 88%).
　式（12a）で示される７－トリエチルシリル－バッカチンIIIの分析データを以下に示す。
　TLC: トルエン/酢酸エチル=2/1, Rf=0.40, UV active;
　1H NMR (500 MHz, CDCl3) δ: 8.11 (d, J=7.7 Hz, 2H), 7.61(t, J=7.3 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 6.46 (s, 1H), 5.64 (d, J=7.0 Hz, 1H), 4.96 (d, J=8.3 Hz, 1H), 4.88-4.81 (m, 1H), 4.49 (dd, J=10.7, 6.7 Hz, 1H), 4.31(d, J=8.2 Hz, 1H), 4.15 (d, J=8.2 Hz, 1H), 3.89 (d, J=7.0 Hz, 1H), 2.58-2.50 (m, 1H), 2.30-2.25(m, 1H), 2.29 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 2.05 (d, J=4.9 Hz, 1H), 1.92-1.85 (m, 1H), 1.68 (s, 3H), 1.63 (s, 1H), 1.20 (s, 3H), 1.04 (s, 3H), 0.93 (t, J=8.0 Hz, 9H), 0.65-0.55 (m, 6H);
　13C NMR (125 MHz, CDCl3) δ: 202.4, 170.5, 169.3, 166.9, 144.3, 133.5, 132.3, 130.0, 129.3, 128.5, 84.1, 80.6, 78.6, 76.4, 75.7, 74.7, 72.2, 67.6, 58.5, 47.2, 42.7, 38.3, 37.1, 26.7, 22.5, 20.8, 20.0, 14.8, 9.8, 6.6, 5.2;
　比旋光度 [α]D 22 -69.5 (C 1.17, CHCl3) Analytical data of 7-triethylsilyl-baccatin III represented by the formula (12a) is shown below.
TLC: Toluene / ethyl acetate = 2/1, R f = 0.40, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 8.11 (d, J = 7.7 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 6.46 ( s, 1H), 5.64 (d, J = 7.0 Hz, 1H), 4.96 (d, J = 8.3 Hz, 1H), 4.88-4.81 (m, 1H), 4.49 (dd, J = 10.7, 6.7 Hz, 1H ), 4.31 (d, J = 8.2 Hz, 1H), 4.15 (d, J = 8.2 Hz, 1H), 3.89 (d, J = 7.0 Hz, 1H), 2.58-2.50 (m, 1H), 2.30-2.25 (m, 1H), 2.29 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 2.05 (d, J = 4.9 Hz, 1H), 1.92-1.85 (m, 1H), 1.68 ( s, 3H), 1.63 (s, 1H), 1.20 (s, 3H), 1.04 (s, 3H), 0.93 (t, J = 8.0 Hz, 9H), 0.65-0.55 (m, 6H);
13 C NMR (125 MHz, CDCl 3 ) δ: 202.4, 170.5, 169.3, 166.9, 144.3, 133.5, 132.3, 130.0, 129.3, 128.5, 84.1, 80.6, 78.6, 76.4, 75.7, 74.7, 72.2, 67.6, 58.5, 47.2, 42.7, 38.3, 37.1, 26.7, 22.5, 20.8, 20.0, 14.8, 9.8, 6.6, 5.2;
Specific rotation [α] D 22 -69.5 (C 1.17, CHCl 3 )
［式（１３ａ）で示されるパクリタキセル前駆体（７－トリエチルシリル前駆体）の合成］ [Synthesis of Paclitaxel Precursor (7-Triethylsilyl Precursor) Represented by Formula (13a)]
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　式（12a）で示される７－トリエチルシリル－バッカチンIII（350 mg,0.5 mmol）、ジシクロヘキシルカルボジイミド（DCC）（413 mg, 2.0 mmol）、4-ジメチルアミノピリジン（61 mg, 0.5 mmol）にトルエン（20 ml）を加えて70℃に加熱した。これに式（3a）で示されるカルボン酸化合物（383 mg, 1.0 mmol）をトルエン（20 ml）に溶解して滴下ロートを使って1時間掛けて滴下した。12時間後にメタノール（0.5 ml）と酢酸（0.1 ml）を加えて室温で１時間撹拌した。続いて0.5M 塩酸（20 ml）と酢酸エチル（20 ml）を加え、30分撹拌を続けた。有機層を分離し、飽和炭酸水素ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥、ろ過した後、減圧下で溶媒を留去した。残渣の固形物をトルエン/酢酸エチル＝10/1-7/1で、シリカゲルカラムクロマトで精製し、式（13a）で示されるパクリタキセル前駆体（７－トリエチルシリル前駆体）である白色固体(453mg、85%)を得た。 7-triethylsilyl-baccatin III (350 mg, 0.5ammol), dicyclohexylcarbodiimide (DCC) (413 mg, 2.0 mmol), 4-dimethylaminopyridine (61 mg, 0.5 mmol) represented by the formula (12a) 20 ml) was added and heated to 70 ° C. To this, the carboxylic acid compound represented by the formula (3a) (383 mg, 1.0 mg) was dissolved in toluene (20 ml) and added dropwise over 1 hour using a dropping funnel. After 12 hours, methanol (0.5 ml) and acetic acid (0.1 ml) were added and stirred at room temperature for 1 hour. Subsequently, 0.5M hydrochloric acid (20 ml) and ethyl acetate (20 ml) were added, and stirring was continued for 30 minutes. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residual solid was purified by silica gel column chromatography with toluene / ethyl acetate = 10 / 1-7 / 1, and a white solid (453 mg) that was a paclitaxel precursor (7-triethylsilyl precursor) represented by the formula (13a) 85%).
　式（13a）で示されるパクリタキセル前駆体（７－トリエチルシリル前駆体）の分析データを以下に示す。
　TLC: トルエン/酢酸エチル=3/1, Rf=0.53, UV active;
　1H NMR (500 MHz, CDCl3) δ: 8.06 (d, J=7.4 Hz, 2H), 7.61(t, J=7.0 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.45-7.35(m, 6H), 6.91 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.47 (s, 1H), 6.31 (t, J=8.8 Hz, 1H), 5.82-5.72 (m, 1H), 5.68 (d, J=7.3 Hz, 1H), 5.42 (d, J=5.4 Hz, 1H), 5.14-5.04 (m, 2H), 4.94 (d, J=3.1 Hz, 1H), 4.89(d, J=8.3 Hz, 1H), 4.56-4.54 (m, 2H), 4.48 (dd, J=10.4, 6.7 Hz, 1H), 4.26 (d, J=8.2 Hz, 1H), 4.13 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.82 (d, J= 7.1 Hz, 1H), 2.57-2.48 (m, 1H), 2.28-2.22 (m, 2H), 2.19 (s, 3H), 2.11 (s, 3H), 1.93 (s, 3H), 1.92-1.85 (m, 1H), 1.71 (bs, 1H), 1.68 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 0.93 (t, J=7.9 Hz, 9H), 0.64-0.55 (m, 6H);
　13C NMR (125 MHz, CDCl3) δ: 201.6, 170.1, 169.9, 169.1, 166.9, 160.1, 154.0, 139.6, 138.9, 134.0, 133.6, 131.8, 130.0, 129.9, 129.2, 128.7, 128.6, 128.5, 128.1, 127.0, 117.7, 113.7, 91.5, 84.1, 80.7, 78.9, 76.4, 74.9, 74.8, 72.2, 71.6, 66.3, 63.9, 58.4, 55.2, 46.7, 43.2, 37.1, 35.4, 26.5, 21.8, 21.0, 20.8, 14.5, 10.0, 6.7, 5.2;
　比旋光度 [α]D 23 -59.7 (C 1.23, CHCl3) Analytical data of the paclitaxel precursor (7-triethylsilyl precursor) represented by the formula (13a) is shown below.
TLC: Toluene / ethyl acetate = 3/1, R f = 0.53, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 8.06 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.45- 7.35 (m, 6H), 6.91 (d, J = 8.6 Hz, 2H), 6.58 (s, 1H), 6.47 (s, 1H), 6.31 (t, J = 8.8 Hz, 1H), 5.82-5.72 (m , 1H), 5.68 (d, J = 7.3 Hz, 1H), 5.42 (d, J = 5.4 Hz, 1H), 5.14-5.04 (m, 2H), 4.94 (d, J = 3.1 Hz, 1H), 4.89 (d, J = 8.3 Hz, 1H), 4.56-4.54 (m, 2H), 4.48 (dd, J = 10.4, 6.7 Hz, 1H), 4.26 (d, J = 8.2 Hz, 1H), 4.13 (d, J = 8.2 Hz, 1H), 3.84 (s, 3H), 3.82 (d, J = 7.1 Hz, 1H), 2.57-2.48 (m, 1H), 2.28-2.22 (m, 2H), 2.19 (s, 3H ), 2.11 (s, 3H), 1.93 (s, 3H), 1.92-1.85 (m, 1H), 1.71 (bs, 1H), 1.68 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.64-0.55 (m, 6H);
13 C NMR (125 MHz, CDCl 3 ) δ: 201.6, 170.1, 169.9, 169.1, 166.9, 160.1, 154.0, 139.6, 138.9, 134.0, 133.6, 131.8, 130.0, 129.9, 129.2, 128.7, 128.6, 128.5, 128.1, 127.0, 117.7, 113.7, 91.5, 84.1, 80.7, 78.9, 76.4, 74.9, 74.8, 72.2, 71.6, 66.3, 63.9, 58.4, 55.2, 46.7, 43.2, 37.1, 35.4, 26.5, 21.8, 21.0, 20.8, 14.5, 10.0, 6.7, 5.2;
Specific rotation [α] D 23 -59.7 (C 1.23, CHCl 3 )
［式（１３ｂ）で示されるパクリタキセル前駆体（７－ヒドロキシ体）の合成］ [Synthesis of Paclitaxel Precursor (7-Hydroxy Compound) Represented by Formula (13b)]
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　式（13a）で示されるパクリタキセル前駆体（７－トリエチルシリル前駆体）(453 mg, 0.42 mmol)をEtOH(10 mL)とTHF(5 mL)の混合溶媒に溶解し、0.5% HCl(3 mL)を加えて室温で24時間撹拌した。反応混合物を酢酸エチル(30 mL)で希釈した後、飽和炭酸水素ナトリウム水溶液(10 mL)を加え、抽出した。有機層を飽和食塩水(20 mL)で洗浄後、無水硫酸マグネシウムで乾燥、濾過した後、減圧下に溶媒を留去した。得られた白色固体（440 mg）をシリカゲルカラムクロマト（トルエン/酢酸エチル＝5/1-2/1）で精製し、未反応の式（13a）で示されるパクリタキセル前駆体（43 mg,0.04）と式（13b）で示されるパクリタキセル前駆体（7－ヒドロキシ体）(344 mg, 消費原料換算で95%)を得た。 The paclitaxel precursor (7-triethylsilyl precursor) represented by the formula (13a) (453 mg, 0.42 mmol) is dissolved in a mixed solvent of EtOH (10 mL) and THF (5 mL), and 0.5% HCl (3 mL) ) Was added and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (30 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained white solid (440 mg) was purified by silica gel column chromatography (toluene / ethyl acetate = 5 / 1-2 / 1), and unreacted paclitaxel precursor represented by formula (13a) (43 mg, 0.04) And a paclitaxel precursor (7-hydroxy compound) represented by the formula (13b) (344 mg, 95% in terms of raw material consumed).
　式（13b）で示されるパクリタキセル前駆体（7－ヒドロキシ体）の分析データを以下に示す。
　1H NMR (500 MHz, CDCl3) δ: 8.05 (d, J=7.0 Hz, 2H), 7.62(t, J=7.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 2H), 7.46-7.35(m, 7H), 6.92 (d, J=8.6 Hz, 2H), 6.57 (s, 1H), 6.35 (t, J=8.3 Hz, 1H), 6.31 (s, 1H), 5.82-5.74 (m, 1H), 5.67 (d, J=7.0 Hz, 1H), 5.44 (d, J=3.7 Hz, 1H), 5.14-5.05 (m, 2H), 4.95-4.89 (m, 2H), 4.55 (d, J=5.2 Hz, 2H), 4.46-4.42 (m, 1H), 4.26 (d, J=8.2 Hz, 1H), 4.14 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.82 (d, J= 7.0 Hz, 1H), 2.60-2.52 (m, 1H), 2.48 (d, J=4.3 Hz, 1H), 2.32-2.20 (m, 2H), 2.26 (s, 3H), 1.99 (s, 3H), 1.93(s, 3H), 1.92-1.84 (m, 1H), 1.74 (bs, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.29 (s, 3H), 1.16 (s, 3H);
　13C NMR (125 MHz, CDCl3) δ: 203.6, 171.2, 170.2, 170.1, 166.9, 160.2, 154.1, 141.8, 138.9, 133.7, 133.3, 131.9, 130.0, 129.8, 129.1, 128.8, 128.64, 128.6, 128.2, 127.0, 117.7, 113.8, 91.6, 84.4, 82.0, 80.8, 79.2, 76.4, 75.5, 75.0, 72.1, 71.6, 66.4, 64.0, 58.5, 55.3, 45.6, 43.2, 35.7, 35.5, 26.8, 21.8, 20.8, 15.1, 9.5;
　比旋光度 [α]D 22 -81.0 (C 1.29, CHCl3) Analytical data of the paclitaxel precursor (7-hydroxy form) represented by the formula (13b) is shown below.
1 H NMR (500 MHz, CDCl 3 ) δ: 8.05 (d, J = 7.0 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.46- 7.35 (m, 7H), 6.92 (d, J = 8.6 Hz, 2H), 6.57 (s, 1H), 6.35 (t, J = 8.3 Hz, 1H), 6.31 (s, 1H), 5.82-5.74 (m , 1H), 5.67 (d, J = 7.0 Hz, 1H), 5.44 (d, J = 3.7 Hz, 1H), 5.14-5.05 (m, 2H), 4.95-4.89 (m, 2H), 4.55 (d, J = 5.2 Hz, 2H), 4.46-4.42 (m, 1H), 4.26 (d, J = 8.2 Hz, 1H), 4.14 (d, J = 8.2 Hz, 1H), 3.84 (s, 3H), 3.82 ( d, J = 7.0 Hz, 1H), 2.60-2.52 (m, 1H), 2.48 (d, J = 4.3 Hz, 1H), 2.32-2.20 (m, 2H), 2.26 (s, 3H), 1.99 (s , 3H), 1.93 (s, 3H), 1.92-1.84 (m, 1H), 1.74 (bs, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.29 (s, 3H), 1.16 ( s, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 203.6, 171.2, 170.2, 170.1, 166.9, 160.2, 154.1, 141.8, 138.9, 133.7, 133.3, 131.9, 130.0, 129.8, 129.1, 128.8, 128.64, 128.6, 128.2, 127.0, 117.7, 113.8, 91.6, 84.4, 82.0, 80.8, 79.2, 76.4, 75.5, 75.0, 72.1, 71.6, 66.4, 64.0, 58.5, 55.3, 45.6, 43.2, 35.7, 35.5, 26.8, 21.8, 20.8, 15.1, 9.5;
Specific rotation [α] D 22 -81.0 (C 1.29, CHCl 3 )
［式（１４）で示されるパクリタキセルの合成］ [Synthesis of paclitaxel represented by formula (14)]
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　式（13b）で示されるパクリタキセル前駆体（7－ヒドロキシ体）（344 mg, 0.36 mmol）にトリフェニルホスフィン（52.4 mg, 0.2 mmol）、ギ酸（0.068 mL, 1.8 mmol）トリエチルアミン（0.25 mL, 1.8 mmol）、THF（10 mL）を加えた。続いて、酢酸パラジウム（11.2 mg, 0.05 mmol）を加えて、室温で5時間撹拌した。減圧下に溶媒を留去した後、メタノール（30 mL）とパラトルエンスルホン酸・ピリジン塩（503 mg, 2.0 mmol）を加えて24時間撹拌した。飽和炭酸水素ナトリウム水溶液（60 mL）と酢酸エチル（50 mL）で希釈した後、有機層を分離した。これを飽和食塩水（30 mL）で洗浄、分離、無水硫酸マグネシウムで乾燥、ろ過した後、減圧下に濃縮して、デベンゾイルカルボニルパクリタキセルの粗生成物を泡状の固体として得た。これに酢酸エチル(20 mL)と飽和炭酸水素ナトリウム水溶液(3 ml)を加えて溶解し、塩化ベンゾイル(0.12ｍL, 1.0 mmol)を加えて室温で２時間撹拌した後、有機層を分離し、無水硫酸マグネシウムで乾燥、濾過した後、減圧下に濃縮した。得られた白色個体を熱ヘキサンに分散させて室温まで３０分放置した後、白色固体を濾取した。これをクロロホルム/メタノール(50/1-30/1-20/1)を用いて、シリカゲルカラムクロマトで精製して式（14）で示されるパクリタキセル（184 mg，60%，式（13a）で示されるパクリタキセル前駆体（７－トリエチルシリル前駆体）から通算）を得た。 Paclitaxel precursor (7-hydroxy compound) represented by formula (13b) (344 mg, 0.36 mmol) to triphenylphosphine (52.4 mg, 0.2 mmol), formic acid (0.068 mL, 1.8 mmol) triethylamine (0.25 mL, 1.8 mmol) ), THF (10 mL) was added. Subsequently, palladium acetate (11.2 mg, 0.05 mg mmol) was added and stirred at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, methanol (30 mL) and paratoluenesulfonic acid / pyridine salt (503 mg, 2.0 mol) were added and stirred for 24 hours. After diluting with a saturated aqueous solution of sodium bicarbonate (60 mL) and ethyl acetate (50 mL), the organic layer was separated. This was washed with saturated brine (30 mL), separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of debenzoylcarbonyl paclitaxel as a foamy solid. Ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (3 mL) were added and dissolved. Benzoyl chloride (0.12 mL, 1.0 mL) was added and stirred at room temperature for 2 hours, and then the organic layer was separated. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained white solid was dispersed in hot hexane and allowed to stand at room temperature for 30 minutes, and then a white solid was collected by filtration. This was purified by silica gel column chromatography using chloroform / methanol (50 / 1-30 / 1-20 / 1) and paclitaxel represented by the formula (14) (184 mg, 60%, represented by the formula (13a). From the paclitaxel precursor (7-triethylsilyl precursor).
　式（14）で示されるパクリタキセルの分析データを以下に示す。
　1H NMR (500 MHz, CDCl3) δ: 8.13 (d, J=7.9 Hz, 2H), 7.74(t, J=7.7 Hz, 2H), 7.61 (t, J=7.3 Hz, 1H), 7.54-7.32 (m, 10H), 6.99 (d, J=8.9 Hz, 1H), 6.27 (s, 1H), 6.23 (t, J=8.9 Hz, 1H), 5.79 (d, J=8.9 HZ, 1H), 5.68 (d, J=7.0 Hz, 1H), 4.95 (d, J=8.6 Hz, 1H), 4.81-4.79 (m, 1H), 4.44-4.38 (m,1H), 4.31 (d, J=8.3 Hz, 1H), 4.20 (d, J=8.3 Hz. 1H), 3.80 (d, J= 7.0 Hz, 1H), 3.57 (d, J= 5.2 Hz, 1H), 2.58-2.51 (m, 1H), 2.47 (d, J=4.0 Hz, 1H), 2.39 (s, 3H), 2.38-2.25 (m, 1H), 2.24 (s, 3H), 1.92-1.85 (m, 1H), 1.85 (bs, 1H), 1.80 (s, 3H), 1.69 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H) Analysis data of paclitaxel represented by the formula (14) is shown below.
1 H NMR (500 MHz, CDCl 3 ) δ: 8.13 (d, J = 7.9 Hz, 2H), 7.74 (t, J = 7.7 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.54- 7.32 (m, 10H), 6.99 (d, J = 8.9 Hz, 1H), 6.27 (s, 1H), 6.23 (t, J = 8.9 Hz, 1H), 5.79 (d, J = 8.9 HZ, 1H), 5.68 (d, J = 7.0 Hz, 1H), 4.95 (d, J = 8.6 Hz, 1H), 4.81-4.79 (m, 1H), 4.44-4.38 (m, 1H), 4.31 (d, J = 8.3 Hz , 1H), 4.20 (d, J = 8.3 Hz. 1H), 3.80 (d, J = 7.0 Hz, 1H), 3.57 (d, J = 5.2 Hz, 1H), 2.58-2.51 (m, 1H), 2.47 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H), 2.38-2.25 (m, 1H), 2.24 (s, 3H), 1.92-1.85 (m, 1H), 1.85 (bs, 1H), 1.80 (s, 3H), 1.69 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H)
実施例３
［式（１３’ａ）で示されるドセタキセル前駆体の合成］ Example 3
[Synthesis of Docetaxel Precursor Represented by Formula (13′a)]
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　WO2008/054233A2に記載の方法に従って式（12’）で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIIIを調製した。次いで、式（12’）で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII（713 mg,1.0 mmol）、ジシクロヘキシルカルボジイミド（DCC）（619 mg, 3.0 mmol）、４－ジメチルアミノピリジン（122 mg, 1.0 mmol）にジクロロメタン（10 mL）を加えてよく撹拌しながら、式（3a）で示されるカルボン酸化合物（575 mg, 1.5 mmol）をジクロロメタン（15 mL）に溶解して滴下ロートを使って室温で1時間掛けて滴下した。室温で3時間撹拌した後、減圧下に溶媒を留去し、残査にトルエン（30 mL）と0.5 M 塩酸（20 mL）を加えた。分離した有機層を飽和炭酸水素ナトリウム水溶液（20mL）で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧下に溶媒を留去した。残渣の固形物をで、シリカゲルカラムクロマト(トルエン/酢酸エチル＝20/1-8/1)で精製し、式（13’a）で示されるドセタキセル前駆体である白色固体（960 mg、89%）を得た。 According to the method described in WO2008 / 054233A2, 7,10-Dialloc-baccatin III represented by the formula (12 ') was prepared. Subsequently, 7,10-Dialloc-baccatin III (713 mg, 1.0 mmol) represented by the formula (12 '), dicyclohexylcarbodiimide (DCC) (619 mg, 3.0 mmol), 4-dimethylaminopyridine (122 mg, 1.0 mmol) ) Dichloromethane (10 に mL) was added to the solution, and the carboxylic acid compound of formula (3a) (575 mg, 1.5 mmol) was dissolved in dichloromethane (15 mL) and stirred at room temperature using a dropping funnel. It was dripped over time. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and toluene (30 mL) and 0.5 M hydrochloric acid (20 mL) were added to the residue. The separated organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residual solid was purified by silica gel column chromatography (toluene / ethyl acetate = 20 / 1-8 / 1), and a white solid (960 mg, 89%) which is a docetaxel precursor represented by the formula (13'a) )
　式（13’a）で示されるドセタキセル前駆体の分析データを以下に示す。
　TLC: toluene/EtOAc=3/1, Rf=0.50, UV active;
　1H NMR (500 MHz, CDCl3) δ: 8.05 (d, J=7.7 Hz, 2H), 7.66-7.30 (m, 10H), 6.93 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.37-6.32 (m, 1H), 6.25 (s, 1H), 6.05-5.94 (m, 2H), 5.82-5.74 (m, 1H), 5.67 (d, J=7.1 Hz, 1H), 5.55-5.21 (m, 6H), 5.15-5.05 (m, 2H), 4.96-4.89 (m, 2H), 4.70-4.60 (m, 4H), 4.56 (d, J=5.5 Hz, 2H), 4.28 (d, J=8.6 Hz, 1H), 4.13 (d, J=8.6 Hz, 1H), 3.93 (d, J= 6.7 Hz, 1H), 3.84 (s, 3H), 2.65-2.56 (m, 1H), 2.36-2.19 (m, 2H), 2.10 (s, 3H), 2.04-1.96 (m, 1H), 1.94 (s, 3H), 1.81 (s, 3H), 1.72 (bs, 1H), 1.27 (s, 3H), 1.19 (s, 3H);
　13C NMR (125 MHz, CDCl3) δ: 201.4, 170.1, 170.0, 166.8, 160.1, 154.1, 153.9, 153.8, 141.2, 138.8, 133.6, 132.7, 131.8131.7, 131.3, 129.9, 129.7, 129.0, 128.9, 128.6, 128.5, 128.1, 127.0, 119.0, 118.5, 117.7, 113.6, 91.4, 90.6, 79.3, 75.1, 65.9, 62.3, 55.1, 46.5, 39.3, 33.8, 30.8, 26.0, 23.1, 21.6, 20.5, 16.1;
　比旋光度 [α]D 21 -51.4 (C 1.39, CHCl3) Analytical data of the docetaxel precursor represented by the formula (13′a) is shown below.
TLC: toluene / EtOAc = 3/1, R f = 0.50, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 8.05 (d, J = 7.7 Hz, 2H), 7.66-7.30 (m, 10H), 6.93 (d, J = 8.6 Hz, 2H), 6.58 (s, 1H ), 6.37-6.32 (m, 1H), 6.25 (s, 1H), 6.05-5.94 (m, 2H), 5.82-5.74 (m, 1H), 5.67 (d, J = 7.1 Hz, 1H), 5.55- 5.21 (m, 6H), 5.15-5.05 (m, 2H), 4.96-4.89 (m, 2H), 4.70-4.60 (m, 4H), 4.56 (d, J = 5.5 Hz, 2H), 4.28 (d, J = 8.6 Hz, 1H), 4.13 (d, J = 8.6 Hz, 1H), 3.93 (d, J = 6.7 Hz, 1H), 3.84 (s, 3H), 2.65-2.56 (m, 1H), 2.36- 2.19 (m, 2H), 2.10 (s, 3H), 2.04-1.96 (m, 1H), 1.94 (s, 3H), 1.81 (s, 3H), 1.72 (bs, 1H), 1.27 (s, 3H) , 1.19 (s, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 201.4, 170.1, 170.0, 166.8, 160.1, 154.1, 153.9, 153.8, 141.2, 138.8, 133.6, 132.7, 131.8131.7, 131.3, 129.9, 129.7, 129.0, 128.9, 128.6, 128.5, 128.1, 127.0, 119.0, 118.5, 117.7, 113.6, 91.4, 90.6, 79.3, 75.1, 65.9, 62.3, 55.1, 46.5, 39.3, 33.8, 30.8, 26.0, 23.1, 21.6, 20.5, 16.1;
Specific rotation [α] D 21 -51.4 (C 1.39, CHCl 3 )
［式（１４’）で示されるドセタキセルの合成］ [Synthesis of Docetaxel represented by Formula (14 ')]
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　式（13’a）で示されるドセタキセル前駆体（1.30 g, 1.21 mmol）にトリフェニルホスフィン（63 mg, 0.24 mmol）、ジエチルアミン（0.75 mL,7.26 mmol）、THF（10 mL）を加えた。続いて、酢酸パラジウム（13.5 mg, 0.06 mmol）を加えて、室温で3時間撹拌した。減圧下に溶媒を留去した後、メタノール（30 mL）とパラトルエンスルホン酸・ピリジン塩（608 mg, 2.42 mmol）を加えて24時間撹拌した。飽和炭酸水素ナトリウム水溶液（60 mL）と酢酸エチル（50 mL）で希釈した後、有機層を分離した。これを飽和食塩水（30 ml）で洗浄、分離、無水硫酸マグネシウムで乾燥、ろ過、減圧下に濃縮して、デブトキシカルボニルドセタキセルの粗生成物を泡状の固体として得た。これにジクロロメタン(10 ml)と飽和炭酸水素ナトリウム水溶液(3 ml)を加えて溶解し、二炭酸-tert-ジブチル(290 mg, 1.33 mmol)のジクロロメタン(3 mL)溶液を室温で滴下した。１２時間撹拌した後、有機層を分離し、無水硫酸マグネシウムで乾燥、濾過、減圧下に濃縮した。得られた白色個体を熱ヘキサンに分散させて室温まで３０分放置した後、白色固体を濾取した。これをクロロホルム/メタノール(50/1-30/1-20/1)を用いて、カラムクロマトで精製して式（14’）で示されるドセタキセル（587 mg，通算収率60％）を得た。 Triphenylphosphine (63 mg, 0.24 mmol), diethylamine (0.75 mL, 7.26 mmol), and THF (10 mL) were added to the docetaxel precursor (1.30 g, 1.21 mmol) represented by the formula (13'a). Subsequently, palladium acetate (13.5 mg, 0.06 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, methanol (30 mL) and paratoluenesulfonic acid / pyridine salt (608 mg, 2.42 mmol) were added and stirred for 24 hours. After diluting with a saturated aqueous solution of sodium bicarbonate (60 mL) and ethyl acetate (50 mL), the organic layer was separated. This was washed with saturated brine (30 ml), separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of debutoxycarbonyl docetaxel as a foamy solid. Dichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate solution (3 ml) were added and dissolved, and a solution of tert-dibutyl dicarbonate (290 mg, 1.33 mmol) in dichloromethane (3 mL) was added dropwise at room temperature. After stirring for 12 hours, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained white solid was dispersed in hot hexane and allowed to stand at room temperature for 30 minutes, and then a white solid was collected by filtration. This was purified by column chromatography using chloroform / methanol (50 / 1-30 / 1-20 / 1) to obtain docetaxel (587 mg, total yield 60%) represented by the formula (14 ′). .
　式（14’）で示されるドセタキセルの分析データを以下に示す。
　TLC: CHCl3/MeOH=9/1, Rf=0.47, UV active;
　1H NMR (500 MHz, CDCl3) δ: 8.11(d, J=7.7 Hz, 2H), 7.65-7.23 (m, 8H), 6.21 (t, J=8.4 Hz, 1H), 5.67 (d, J=7.0 Hz 1H), 5.49 (d, J=8.8 Hz, 1H), 5.26 (d, J=8.3 Hz, 1H), 5.22 (s, 1H), 4.94 (d, J=8.0 Hz, 1H), 4.62(br s, 1H), 4.31 (d, J= 8.6 Hz, 1H), 4.30-4.20 (m 2H), 3.90 (d, J= 6.8 Hz, 1H),2.62-2.54 (m, 1H), 2.38 (s, 3H), 2.30-2.20 (m, 2H), 1.90-1.80 (m, 1H), 1.84 (s, 3H), 1.75 (s, 3H), 1.34 (s, 9H), 1.23 (s, 3H), 1.13 (s, 3H);
　13C NMR (125 MHz, CDCl3) δ: 211.3, 172.7, 170.3, 167.0, 155.3, 138.5, 138.3, 135.9, 133.7, 130.2, 129.1, 128.8, 128.7, 128.1,126.7, 84.1, 81.0, 80.2, 78.8, 76.6, 74.8, 74.5, 73.6, 72.5, 72.0, 57.6, 56.1, 46.5, 43.1, 37.0, 35.7, 28.2, 26.4, 22.6, 20.6, 14.4, 9.9;
　比旋光度 [α]D 21 -42.4 (C 1.21, EtOH) Analytical data of docetaxel represented by the formula (14 ′) is shown below.
TLC: CHCl 3 / MeOH = 9/1, R f = 0.47, UV active;
1 H NMR (500 MHz, CDCl 3 ) δ: 8.11 (d, J = 7.7 Hz, 2H), 7.65-7.23 (m, 8H), 6.21 (t, J = 8.4 Hz, 1H), 5.67 (d, J = 7.0 Hz 1H), 5.49 (d, J = 8.8 Hz, 1H), 5.26 (d, J = 8.3 Hz, 1H), 5.22 (s, 1H), 4.94 (d, J = 8.0 Hz, 1H), 4.62 (br s, 1H), 4.31 (d, J = 8.6 Hz, 1H), 4.30-4.20 (m 2H), 3.90 (d, J = 6.8 Hz, 1H), 2.62-2.54 (m, 1H), 2.38 ( s, 3H), 2.30-2.20 (m, 2H), 1.90-1.80 (m, 1H), 1.84 (s, 3H), 1.75 (s, 3H), 1.34 (s, 9H), 1.23 (s, 3H) , 1.13 (s, 3H);
13 C NMR (125 MHz, CDCl 3 ) δ: 211.3, 172.7, 170.3, 167.0, 155.3, 138.5, 138.3, 135.9, 133.7, 130.2, 129.1, 128.8, 128.7, 128.1,126.7, 84.1, 81.0, 80.2, 78.8, 76.6, 74.8, 74.5, 73.6, 72.5, 72.0, 57.6, 56.1, 46.5, 43.1, 37.0, 35.7, 28.2, 26.4, 22.6, 20.6, 14.4, 9.9;
Specific rotation [α] D 21 -42.4 (C 1.21, EtOH)

Claims (15)

  1. 　下記式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000002
     で示される化合物を出発化合物として用いることを特徴とする下記式（３）：
    Figure JPOXMLDOC01-appb-C000003
     ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
    で示される化合物の製造方法。     Following formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000002
     A compound represented by formula (3) is used as a starting compound:
    Figure JPOXMLDOC01-appb-C000003
     [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
    The manufacturing method of the compound shown by these.
  2. 　前記式（１）で示される化合物を出発化合物として下記式（４）：
    Figure JPOXMLDOC01-appb-C000004
     ［式（４）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得る工程を有する請求項１記載の式（３）で示される化合物の製造方法。     Starting from the compound represented by the formula (1) as a starting compound, the following formula (4):
    Figure JPOXMLDOC01-appb-C000004
     [In the formula (4), R 1 , R 2 , X and Y are as defined in the formula (1). ]
    The manufacturing method of the compound shown by Formula (3) of Claim 1 which has the process of obtaining the compound shown by these.
  3. 　前記得られた式（４）で示される化合物から下記式（５）：
    Figure JPOXMLDOC01-appb-C000005
     ［式（５）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得る工程を有する請求項２記載の式（３）で示される化合物の製造方法。     From the obtained compound represented by the formula (4), the following formula (5):
    Figure JPOXMLDOC01-appb-C000005
     Wherein (5), R 2, X and Y are as defined in the formula (1). ]
    The manufacturing method of the compound shown by Formula (3) of Claim 2 which has the process of obtaining the compound shown by these.
  4. 　前記得られた式（５）で示される化合物から下記式（６）：
    Figure JPOXMLDOC01-appb-C000006
     ［式（６）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得る工程を有する請求項３記載の式（３）で示される化合物の製造方法。     From the obtained compound represented by the formula (5), the following formula (6):
    Figure JPOXMLDOC01-appb-C000006
     Wherein (6), R 2, X and Y are as defined in the formula (1). ]
    The manufacturing method of the compound shown by Formula (3) of Claim 3 which has the process of obtaining the compound shown by these.
  5. 　前記得られた式（６）で示される化合物から下記式（７）：
    Figure JPOXMLDOC01-appb-C000007
     ［式（７）中、Ｒ２、Ｘ及びＹは前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
    で示される化合物を得る工程を有する請求項４記載の式（３）で示される化合物の製造方法。     From the obtained compound represented by the formula (6), the following formula (7):
    Figure JPOXMLDOC01-appb-C000007
     Wherein (7), R 2, X and Y are as defined in the formula (1), R 3 is an alkoxy group. ]
    The manufacturing method of the compound shown by Formula (3) of Claim 4 which has the process of obtaining the compound shown by these.
  6. 　下記式（８）：
    Figure JPOXMLDOC01-appb-C000008
     ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を出発化合物として前記式（１）で示される化合物を得る工程を有する請求項１～５のいずれか記載の式（３）で示される化合物の製造方法。     Following formula (8):
    Figure JPOXMLDOC01-appb-C000008
     [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
    A process for producing a compound represented by the formula (3) according to any one of claims 1 to 5, which comprises a step of obtaining a compound represented by the formula (1) using a compound represented by the formula:
  7. 　下記式（９）：
    Figure JPOXMLDOC01-appb-C000009
     ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を出発化合物として下記式（８）：
    Figure JPOXMLDOC01-appb-C000010
     ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得て、該得られた式（８）で示される化合物から前記式（１）で示される化合物を得る工程を有する請求項１～６のいずれか記載の式（３）で示される化合物の製造方法。     Following formula (9):
    Figure JPOXMLDOC01-appb-C000009
     Wherein (9), R 2, X and Y are as defined in the formula (1). ]
    A compound represented by the following formula (8):
    Figure JPOXMLDOC01-appb-C000010
     [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
    A compound represented by formula (3) according to any one of claims 1 to 6, further comprising the step of obtaining the compound represented by formula (1) from the compound represented by formula (8) thus obtained. Process for producing the indicated compound.
  8. 　下記式（１０）：
    Figure JPOXMLDOC01-appb-C000011
     ［式（１０）中、Ｒ２は前記式（１）と同義であり、Ｒ４はアルキル基である。］
    で示される化合物と下記式（１１）：
    Figure JPOXMLDOC01-appb-C000012
     ［式（１１）中、Ｘ及びＹは前記式（１）と同義である。］
    で示されるアルコールとを反応させて下記式（９）：
    Figure JPOXMLDOC01-appb-C000013
     ［式（９）中、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得て、該得られた式（９）で示される化合物から下記式（８）：
    Figure JPOXMLDOC01-appb-C000014
     ［式（８）中、Ｒ１、Ｒ２、Ｘ及びＹは前記式（１）と同義である。］
    で示される化合物を得て、該得られた式（８）で示される化合物から前記式（１）で示される化合物を得る工程を有する請求項１～７のいずれか記載の式（３）で示される化合物の製造方法。     Following formula (10):
    Figure JPOXMLDOC01-appb-C000011
     Wherein (10), R 2 has the same meaning as the formula (1), R 4 is an alkyl group. ]
    And a compound represented by the following formula (11):
    Figure JPOXMLDOC01-appb-C000012
     [In Formula (11), X and Y are synonymous with said Formula (1). ]
    Is reacted with an alcohol represented by the following formula (9):
    Figure JPOXMLDOC01-appb-C000013
     Wherein (9), R 2, X and Y are as defined in the formula (1). ]
    A compound represented by the following formula (8) is obtained from the compound represented by the formula (9) thus obtained:
    Figure JPOXMLDOC01-appb-C000014
     [In the formula (8), R 1 , R 2 , X and Y are as defined in the formula (1). ]
    The compound represented by formula (3) according to any one of claims 1 to 7, further comprising the step of obtaining the compound represented by formula (1) from the compound represented by formula (8) thus obtained. Process for producing the indicated compound.
  9. 　請求項１～８のいずれか記載の方法により得られた下記式（３）：
    Figure JPOXMLDOC01-appb-C000015
     ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
    で示される化合物と下記式（１２）：
    Figure JPOXMLDOC01-appb-C000016
     ［式（１２）中、Ｚ１はアリルオキシカルボニル基又はトリエチルシリル基である。］
    で示されるバッカチンIII誘導体とを反応させて、下記式（１３）：
    Figure JPOXMLDOC01-appb-C000017
     ［式（１３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基であり、Ｚ２はアリルオキシカルボニル基、トリエチルシリル基又は水素原子である。］
    で示されるパクリタキセル前駆体を得る工程を有する下記式（１４）：
    Figure JPOXMLDOC01-appb-C000018
     で示されるパクリタキセルの製造方法。     The following formula (3) obtained by the method according to any one of claims 1 to 8:
    Figure JPOXMLDOC01-appb-C000015
     [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
    And a compound represented by the following formula (12):
    Figure JPOXMLDOC01-appb-C000016
     [In the formula (12), Z 1 represents an allyloxycarbonyl group or a triethylsilyl group. ]
    Is reacted with a baccatin III derivative represented by the following formula (13):
    Figure JPOXMLDOC01-appb-C000017
     [In formula (13), R 2 has the same meaning as in formula (1), R 3 represents an alkoxy group, and Z 2 represents an allyloxycarbonyl group, a triethylsilyl group, or a hydrogen atom. ]
    The following formula (14) having a step of obtaining a paclitaxel precursor represented by:
    Figure JPOXMLDOC01-appb-C000018
     The manufacturing method of paclitaxel shown by this.
  10. 　請求項１～８のいずれか記載の方法により得られた下記式（３）：
    Figure JPOXMLDOC01-appb-C000019
     ［式（３）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
    で示される化合物と下記式（１２’）：
    Figure JPOXMLDOC01-appb-C000020
     で示される７，１０－Ｄｉａｌｌｏｃ－バッカチンIII誘導体とを反応させて、下記式（１３’）：
    Figure JPOXMLDOC01-appb-C000021
     ［式（１３’）中、Ｒ２は前記式（１）と同義であり、Ｒ３はアルコキシ基である。］
    で示されるドセタキセル前駆体を得る工程を有する下記式（１４’）：
    Figure JPOXMLDOC01-appb-C000022
     で示されるドセタキセルの製造方法。     The following formula (3) obtained by the method according to any one of claims 1 to 8:
    Figure JPOXMLDOC01-appb-C000019
     [In Formula (3), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
    And a compound represented by the following formula (12 ′):
    Figure JPOXMLDOC01-appb-C000020
     Is reacted with a 7,10-Dialloc-baccatin III derivative represented by the following formula (13 ′):
    Figure JPOXMLDOC01-appb-C000021
     [In Formula (13 ′), R 2 has the same meaning as in Formula (1), and R 3 represents an alkoxy group. ]
    The following formula (14 ′) having a step of obtaining a docetaxel precursor represented by:
    Figure JPOXMLDOC01-appb-C000022
     The manufacturing method of docetaxel shown by this.
  11. 　下記式（１）で示される化合物。
    Figure JPOXMLDOC01-appb-C000023
     ［式（１）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000024
         A compound represented by the following formula (1).
    Figure JPOXMLDOC01-appb-C000023
     [In the formula (1), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000024
  12. 　下記式（４）で示される化合物。
    Figure JPOXMLDOC01-appb-C000025
     ［式（４）中、Ｒ１はアルコキシ基、アリールアルキルオキシ基、アルキルシリルオキシ基又はアルコキシカルボニルオキシ基であり、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000026
         A compound represented by the following formula (4).
    Figure JPOXMLDOC01-appb-C000025
     [In formula (4), R 1 is an alkoxy group, an arylalkyloxy group, an alkylsilyloxy group or an alkoxycarbonyloxy group, R 2 is an aryl group, and X is a substituent represented by the following formula (2). Y is a hydrogen atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000026
  13. 　下記式（５）で示される化合物。
    Figure JPOXMLDOC01-appb-C000027
     ［式（５）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000028
         The compound shown by following formula (5).
    Figure JPOXMLDOC01-appb-C000027
     Wherein (5), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000028
  14. 　下記式（６）で示される化合物。
    Figure JPOXMLDOC01-appb-C000029
     ［式（６）中、Ｒ２はアリール基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000030
         A compound represented by the following formula (6).
    Figure JPOXMLDOC01-appb-C000029
     Wherein (6), R 2 is an aryl group, X is one selected from the group consisting of substituents represented by the following formula (2), Y is a hydrogen atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000030
  15. 　下記式（７）で示される化合物。
    Figure JPOXMLDOC01-appb-C000031
     ［式（７）中、Ｒ２はアリール基であり、Ｒ３はアルコキシ基であり、Ｘは下記式（２）で示される置換基からなる群から選択される１種であり、Ｙは水素原子又はメチル基である。］
    Figure JPOXMLDOC01-appb-C000032
           A compound represented by the following formula (7).
    Figure JPOXMLDOC01-appb-C000031
     [In formula (7), R 2 is an aryl group, R 3 is an alkoxy group, X is one selected from the group consisting of substituents represented by the following formula (2), and Y is hydrogen An atom or a methyl group. ]
    Figure JPOXMLDOC01-appb-C000032
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