WO2017006573A1 - Procédé de production d'un précurseur à chaîne latérale de paclitaxel et de docétaxel - Google Patents

Procédé de production d'un précurseur à chaîne latérale de paclitaxel et de docétaxel 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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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/zh
Priority to KR1020187003624A priority patent/KR20180027559A/ko
Priority to JP2017525638A priority patent/JP6205530B2/ja
Publication of WO2017006573A1 publication Critical patent/WO2017006573A1/fr

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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

L'invention concerne un précurseur à chaîne latérale de paclitaxel et de docétaxel présentant un niveau de pureté élevé, un haut rendement, et un faible coût au moyen d'un procédé de production d'un composé représenté par la formule (3) à l'aide d'un composé représenté par la formule (1) en tant que composé de départ. L'utilisation du précurseur à chaîne latérale ainsi obtenu permet de fournir le paclitaxel et le docétaxel qui sont utiles en tant qu'agents anticancéreux. (Dans la formule (1), R1 est un groupe alcoxy, un groupe arylalkyloxy, un groupe alkylsilyloxy, ou un groupe alcoxycarbonyloxy, R2 est un groupe aryle, X est un élément choisi dans le groupe constitué par les substituants représentés par la formule (2), et Y est un atome d'hydrogène ou un groupe méthyle.) (Dans la formule (3), R2 est défini de la même manière que dans la formule (1), et R3 est un groupe alcoxy.)
PCT/JP2016/051372 2015-07-07 2016-01-19 Procédé de production d'un précurseur à chaîne latérale de paclitaxel et de docétaxel WO2017006573A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000500437A (ja) * 1995-10-27 2000-01-18 ソシエテ・デテユード・エ・ド・ルシエルシユ・アン・アンジエニエリ・フアルマスーテイツク・セリフアルム タキサンの半合成のための中間体およびそれらの製造方法
JP2001089464A (ja) * 1999-09-17 2001-04-03 Yokohama Kokusai Bio Kenkyusho:Kk タキソイド化合物の製造法
JP2004531498A (ja) * 2001-03-23 2004-10-14 ジョージ シュレーマー タキサン誘導体の製造方法
CN101033216A (zh) * 2007-04-20 2007-09-12 北京诺瑞医药技术有限公司 用于合成紫杉烷类药物侧链的噁唑烷化合物及制备方法
WO2008054233A2 (fr) * 2006-10-31 2008-05-08 Instytut Farmaceutyczny Procédé de préparation de docétaxel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000500437A (ja) * 1995-10-27 2000-01-18 ソシエテ・デテユード・エ・ド・ルシエルシユ・アン・アンジエニエリ・フアルマスーテイツク・セリフアルム タキサンの半合成のための中間体およびそれらの製造方法
JP2001089464A (ja) * 1999-09-17 2001-04-03 Yokohama Kokusai Bio Kenkyusho:Kk タキソイド化合物の製造法
JP2004531498A (ja) * 2001-03-23 2004-10-14 ジョージ シュレーマー タキサン誘導体の製造方法
WO2008054233A2 (fr) * 2006-10-31 2008-05-08 Instytut Farmaceutyczny Procédé de préparation de docétaxel
CN101033216A (zh) * 2007-04-20 2007-09-12 北京诺瑞医药技术有限公司 用于合成紫杉烷类药物侧链的噁唑烷化合物及制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MANDAI, T. ET AL.: "Synthesis and biological evaluation of water soluble taxoids bearing sugar moieties", HETEROCYCLES, vol. 54, no. 2, 2001, pages 561 - 566, XP001536935, ISSN: 0385-5414, DOI: doi:10.3987/COM-00-S(I)34 *
MICHALAK, O. ET AL.: "A novel synthesis of antineoplastic drug docetaxel", PRZEMYSL CHEMICZNY, vol. 86, no. 8, 2007, pages 783 - 788, ISSN: 0033-2496 *

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