WO2010131676A9 - ピリピロペン誘導体の製造法 - Google Patents
ピリピロペン誘導体の製造法 Download PDFInfo
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- WO2010131676A9 WO2010131676A9 PCT/JP2010/058040 JP2010058040W WO2010131676A9 WO 2010131676 A9 WO2010131676 A9 WO 2010131676A9 JP 2010058040 W JP2010058040 W JP 2010058040W WO 2010131676 A9 WO2010131676 A9 WO 2010131676A9
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- NGDUEKVGVYVTQU-MGFKOSKQSA-N C[C@@H]([C@H](CC[C@]1(C)[C@@H](C2O)[C@@](C)([C@H](C3)O)OC(C=C(c4cccnc4)O4)=C2C4=O)O)[C@@]13NCO Chemical compound C[C@@H]([C@H](CC[C@]1(C)[C@@H](C2O)[C@@](C)([C@H](C3)O)OC(C=C(c4cccnc4)O4)=C2C4=O)O)[C@@]13NCO NGDUEKVGVYVTQU-MGFKOSKQSA-N 0.000 description 1
- 0 C[C@](C(CC[C@]1(C)[C@@](C2O)[C@@](C)([C@](C3)O)OC(C=C(c4cccnc4)O4)=C2C4=O)O*)[C@@]13NO* Chemical compound C[C@](C(CC[C@]1(C)[C@@](C2O)[C@@](C)([C@](C3)O)OC(C=C(c4cccnc4)O4)=C2C4=O)O*)[C@@]13NO* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for producing a pyripyropene derivative useful as a pest control agent, and more specifically, a method for producing a pyripyropene derivative having acyloxy groups at the 1-position and 11-position and a hydroxyl group at the 7-position. It is about.
- a pyripyropene derivative having an acyloxy group at the 1st and 11th positions and a hydroxyl group at the 7th position is a compound having a controlling effect against pests as described in WO2006 / 129714.
- WO2006 / 129714 and JP-A-8-259568 are disclosed as raw materials of 1,7,11-triacyloxy compounds.
- a method for purifying or isolating from a plurality of products resulting from hydrolysis of a non-selective acyloxy group is disclosed.
- Japanese Patent Application Laid-Open No. 8-259568 describes the use of a protecting group in combination with the synthesis of a pyripyropene derivative
- JP-A-8-269065 disclose a synthesis example in which an acyl group is introduced at the 7-position using a protecting group. Yes.
- WO2009 / 022702 discloses a method for producing 1,11-diacyl-7-deacetylpyripyropene from 1,7,11-trideacetylpyripyropene using a protecting group.
- a pyripyropene derivative having an acyloxy group at the 1- and 11-positions and a hydroxyl group at the 7-position which has been known so far, includes non-selective hydrolysis and protection of the 1,7,11-position triacyloxy derivatives.
- the present inventors have prepared pyripyropene A substance obtained as a natural product and its analogs (Pure Appl. Chem., Vol.71, No6, pp.1059-1064, 1999 .; WO94 / 09147; JP-A-8-239385) Japanese Patent Laid-Open No. 8-259569, Bioorganic Medicinal Chemistry Letter 5, Vol. 22, No. 22, page 2683, 1995; ) To selectively and directly or stepwise acylate the hydroxyl groups at the 1 and 11 positions to obtain the desired useful 1 and 11 diacyloxy compounds in a short process. Completed the invention.
- the present invention is represented by the following formula C: [Wherein, R represents a linear, branched or cyclic C 2-6 alkylcarbonyl group (or a C 3-6 alkylcarbonyl group when the alkyl portion of this group is branched or cyclic)]
- the compound C1 is acylated from the compound B1 in one step. Is provided. That is, in this embodiment, the above 1.
- the compound C is obtained by acylating the hydroxyl groups at the 1-position and the 11-position of the compound B1 in one step.
- the hydroxyl group at the 11-position of compound B1 is represented by the following formula B2: [Wherein R is the same as in the above 1. As defined by formula C in FIG. Wherein the acylation is carried out in two steps, comprising the step of producing the compound B2 represented by formula (1) and the step of further acylating the hydroxyl group at the 1-position of the compound B2. Is provided. That is, in this embodiment, the above 1. In which the 11-position hydroxyl group of compound B1 is acylated with an acylating agent to produce compound B2, and the 1-position hydroxyl group of compound B2 is further acylated. Compound C is obtained by acylation in two steps.
- the step of producing the compound B2 by acylating the hydroxyl group at the 11th position of the compound B1 is obtained by transferring the acyl group at the 11th position of the compound B2 to the hydroxyl group at the 1st position.
- the step of preparing a compound of formula B1 comprises the following formula A1: [Wherein A 1 , A 7 and A 11 may be the same or different and each represents an acetyl group or a propionyl group] Comprising the step of hydrolyzing the acyl groups at the 1-position, 7-position and 11-position of the compound A1 represented by formula (1) with a base. ⁇ 4. Is provided. That is, in this embodiment, the above 1. ⁇ 4.
- the step of producing the compound of formula B1 further includes a step of hydrolyzing the acyl groups at the 1-position, 7-position and 11-position of compound A1 using a base.
- the above 1. ⁇ 5.
- a suitable solvent to the crude product of compound C obtained by concentrating the reaction solution containing compound C produced by the above method under reduced pressure.
- ⁇ 5. A method for isolating and purifying a solvate crystal of compound C precipitated by concentrating the ethyl acetate extract of the reaction solution containing compound C produced by the method of or adding a selected solvent. Provided.
- a method for isolating and purifying a solvate crystal of Compound C comprising: (A) Extraction treatment of the reaction solution containing Compound C with an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane And the step of concentrating the resulting extract after drying or without drying, (B) After obtaining a crude product by drying the reaction solution containing Compound C, the crude product was converted into methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, A step of dissolving in an organic solvent selected from the group consisting of diisopropy
- the resulting solution comprises heptane, hexane, and the step of adding a poor solvent selected from the group consisting of cyclohexane.
- a ′ the reaction solution containing the compound C is extracted with ethyl acetate, and the obtained extract is dried or not dried. It is set as the process of concentrating to.
- the step (b) obtains a crude product by drying a reaction solution containing (b ′) compound C
- the crude product is The step is to dissolve in ethyl acetate at room temperature or under heating.
- the crude product is It is a step of dissolving in ethyl acetate at room temperature or under heating, and adding hexane to the resulting solution.
- a method for producing compound C from compound B1, comprising the step of isolating and purifying compound C from a reaction solution containing compound C by crystallization.
- a method is provided. That is, in this embodiment, the above 1.
- the method described in 1) further comprises the step of isolating and purifying Compound C by crystallization from the reaction solution containing Compound C.
- a pyripyropene derivative having an acyloxy group at positions 1 and 11 and a hydroxyl group at position 7 that is useful as a pest control agent can be efficiently produced in a short process.
- alkyl as a substituent or a part of a substituent, unless otherwise defined, means linear, branched, cyclic, or a combination thereof. .
- C ab attached to a substituent means that the number of carbon atoms contained in the substituent is a to b.
- C ab as of "C ab alkylcarbonyl", excluding the carbon atom of the carbonyl moiety, the number of carbon atoms in the alkyl moiety means that from a number to a number b.
- linear, branched or cyclic C 2-6 alkylcarbonyl group represented by R (or a C 3-6 alkylcarbonyl group when the alkyl portion of this group is branched or cyclic) include cyclo A propanecarbonyl group, a propionyl group, etc. are mentioned.
- the acylation is carried out in the absence of a base. ⁇ 5.
- the method of description is mentioned.
- the base used for acylating the hydroxyl groups at the 1-position and 11-position of compound B1 is 2,4,6-collidine or 2,6-lutidine. ⁇ 5. The method of description is mentioned.
- Another preferred embodiment of the present invention is characterized in that the solvent used is different between the step of producing compound B2 and the step of further acylating the 1-position hydroxyl group of compound B2.
- the method of description is mentioned.
- Another preferred embodiment of the present invention is characterized in that the step of producing compound B3 from compound B2 is carried out in the presence of a base.
- the method of description is mentioned.
- the step of producing compound B3 from compound B2 is carried out in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) as a base. And 4.
- DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
- the C 2-6 alkylcarbonyl group in R is a cyclic C 3-6 alkylcarbonyl group, more preferably a cyclopropanecarbonyl group.
- step of producing compound B2 1.0 to 3.0 equivalents of a base is used relative to compound B1, and the step and the step of further acylating the hydroxyl group at position 1 of compound B2
- a total of 2.0 to 4.5 equivalents, more preferably 2.0 to 3.0 equivalents of base is used.
- Another preferred embodiment of the present invention includes a method using compound B2 as an intermediate compound for producing compound C from compound B1. That is, this embodiment provides the use of compound B2 in the manufacture of compound C.
- Another preferred embodiment of the present invention includes a method using Compound B2 and Compound B3 as intermediate compounds for producing Compound C from Compound B1. That is, this embodiment provides the use of Compound B3 in the manufacture of Compound C.
- the product in each step shown in the scheme may be used in the next step without post-treatment or isolation.
- pyripyropene A is used as the starting material for compound A1
- pyripyropene A produced by the method described in the Society of Synthetic Organic Chemistry of Japan (1998), Vol. 56, No. 6, pp. 478-488 or WO94 / 09147 is used. Can be used.
- the compound B1 for example, a derivative produced by the method described in JP-A-8-259569 and published technique 2008-50997 can be used.
- Examples of the method for producing compound B1 from compound A1 include the method described in WO2009 / 022702.
- Compound B1 is obtained by hydrolyzing the acyl groups at positions 1, 7, and 11 of compound A1 in the presence of a base. Can be manufactured.
- usable solvents include alcohol solvents having 1 to 4 carbon atoms such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, Examples thereof include aprotic polar organic solvents such as N-dimethylacetamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, water, and mixed solvents thereof.
- alcohol solvents having 1 to 4 carbon atoms such as methanol
- ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
- N N-dimethylformamide
- dimethyl sulfoxide N
- halogen solvents such as dichloromethane and chloroform
- Usable bases are sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide
- Inorganic bases such as lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkoxides of alkaline earth metals, 1,8-diazabicyclo [5.4.0] undeca Organic bases such as -7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, and the like are preferable, and 1,8-diazabicyclo [ 5.4.0] Undec-7 Emissions, 1,5-diazabicyclo [4.3.0] non-5-ene, sodium carbonate, potassium carbonate,
- the amount of base used is preferably 0.01 to 4.5 equivalents relative to compound A1
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 50 ° C.
- the reaction time is preferably 0.00. It ranges from 5 hours to 72 hours.
- ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, Aprotic polar organic solvents such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, halogen solvents such as dichloromethane and chloroform, toluene, etc.
- ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
- N, N-dimethylformamide dimethyl sulfoxide
- N, N-dimethylacetamide Aprotic polar organic solvents
- acetonitrile such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperaz
- Aromatic hydrocarbon solvents and mixed solvents thereof can be mentioned, and aprotic polar organic solvents are preferred.
- N-methyl-2-pyrrolidinone and N, N-dimethyl-2-imidazolidinone are more preferred, and N-methyl-2-pyrrolidinone is particularly preferred.
- the method is preferably carried out in the absence of a base, but usable bases in the presence of a base include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide. , Sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide and other inorganic bases, 1,8-diazabicyclo [5.4.0] undec-7 -Ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, collidine, 2,2'-bipyridyl, triphenylamine, quinoline, N, N -Organic bases such as dimethylaniline and N, N-diethylaniline
- Preferred examples include 2,6-lutidine, 2,4,6-collidine, triphenylamine, N, N-dimethylaniline, N, N-diethylaniline, and particularly preferred are 2,6-lutidine, 2, 4,6-collidine is mentioned.
- the amount of the base used is preferably 2.0 to 4.5 equivalents, more preferably 2.0 to 3.0 equivalents, relative to compound B1.
- R groups at the 1- and 11-positions can be achieved by using ROH, RCl, (R) 2 O, or mixed acid anhydrides, preferably RCl, (R) 2 as acylating agents corresponding to the desired R.
- O in the presence or absence of a base, or dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazolyl disulfide, 1,3 , 5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop, PyBrop and other condensing agents can be used.
- RCl or (R) 2 in the presence or absence of a base Preference is given to using O.
- More preferred acylating agents include cyclopropane carbonyl chloride, butyryl chloride, anhydrous cyclopropane carboxylic acid and the like.
- the amount of the acylating agent to be used is preferably 2.0 to 5.0 equivalents, more preferably 2.2 to 4.5 equivalents relative to Compound B1, and this can be used once or 2 to 5 equivalents. It is possible to use it in divided times.
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 50 ° C., more preferably ⁇ 10 ° C. to 50 ° C., and further preferably ⁇ 10 ° C. to room temperature.
- the reaction time is preferably in the range of 0.1 hour to 7 days, and more preferably in the range of 3 hours to 4 days.
- compound C can be obtained from compound B1 in a single step number with a yield of 40% or more.
- Solvents that can be used in the method for producing compound B2 from compound B1 are ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, Aprotic polar organic solvents such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, halogen solvents such as dichloromethane and chloroform, toluene, etc.
- Aromatic hydrocarbon solvents and mixed solvents thereof can be mentioned, and aprotic polar organic solvents are preferred. Particularly preferred is N-methyl-2-pyrrolidinone.
- usable bases when using a base include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, hydrogen Sodium base, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide and other inorganic bases, 1,8-diazabicyclo [5.4.0] undec-7-ene 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, collidine, 2,2′-bipyridyl, triphenylamine, quinoline, N, N-dimethyl Organic bases such as aniline and N, N-diethylaniline
- a condensing agent such as trichlorobenzoyl anhydride, PyBop, PyBrop, etc.
- More preferable acylating agents include cyclopropane carbonyl chloride, cyclopropane carboxylic anhydride and the like.
- the amount of the acylating agent to be used is preferably 1.0 to 3.5 equivalents, more preferably 1.1 to 3.0 equivalents, relative to compound B1.
- the amount of the base used is preferably 1.0 to 3.0 equivalents, more preferably 1.1 to 2.5 equivalents, relative to Compound B1.
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 50 ° C., more preferably ⁇ 10 ° C. to 50 ° C.
- the reaction time is preferably in the range of 0.1 hour to 7 days, more preferably 45 minutes to 48 hours.
- Solvents that can be used in the method for producing Compound C from Compound B2 include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, Aprotic polar organic solvents such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, halogen solvents such as dichloromethane and chloroform, toluene, etc.
- Aromatic hydrocarbon solvents and mixed solvents thereof can be mentioned, and aprotic polar organic solvents are preferred. Particularly preferred is N-methyl-2-pyrrolidinone.
- usable bases when using a base include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, hydrogen Sodium base, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide and other inorganic bases, 1,8-diazabicyclo [5.4.0] undec-7-ene 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, collidine, 2,2′-bipyridyl, triphenylamine, quinoline, N, N-dimethyl Organic bases such as aniline and N, N-diethylaniline
- acylating agent introduced as the group R, ROH, RCl, (R) 2 O, or a mixed acid anhydride, preferably RCl, (R) 2 O is used, in the presence or absence of a base.
- a condensing agent such as trichlorobenzoyl anhydride, PyBop, PyBrop, etc.
- More preferable acylating agents include cyclopropane carbonyl chloride, cyclopropane carboxylic anhydride and the like.
- the amount used is preferably 0.1 to 5.0 equivalents, more preferably 0.1 to 3.0 equivalents, more preferably 0.1 to 3.0 equivalents relative to Compound B2. And a total amount of 2.0 to 4.5 equivalents, more preferably 2.0 to 3.0 equivalents.
- the amount of the acylating agent used is preferably 1.0 to 3.0 equivalents relative to compound B1, more preferably 2.0 to 4.5 equivalents in total with the step described in (2). The method of doing is mentioned.
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 60 ° C.
- the reaction time is preferably in the range of 0.1 hour to 7 days.
- This step can be carried out continuously without taking out the product of the step described in (2) above.
- Solvents usable in the method for producing compound B3 from compound B2 include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, Aprotic polar organic solvents such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, halogen solvents such as dichloromethane and chloroform, toluene, chlorobenzene , Aromatic hydrocarbon solvents such as dichlorobenzene, and mixed solvents thereof, preferably aprotic polar organic solvents.
- ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
- N, N-dimethylformamide dimethyl sul
- Usable bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide,
- Inorganic bases such as calcium hydroxide, lithium hydroxide, barium hydroxide, t-butoxypotassium, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0 ]
- Organic bases such as non-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, collidine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, phosphazene, preferably potassium carbonate , Cesium carbonate, t-butoki Examples include potassium, 1,8-diazabicyclo [5.4.0] ⁇ undec-7-ene, 1,5-
- the amount of the base used is preferably 0.1 to 3.0 equivalents, more preferably 0.1 to 2.0 equivalents, relative to compound B2.
- the reaction temperature is preferably in the range of 0 ° C to 150 ° C.
- the reaction time is preferably in the range of 0.1 hour to 7 days.
- Solvents that can be used in the method for producing compound C from compound B3 are ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, Aprotic polar organic solvents such as acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, halogen solvents such as dichloromethane and chloroform, toluene, etc.
- Aromatic hydrocarbon solvents and mixed solvents thereof can be mentioned, and aprotic polar organic solvents are preferred. Particularly preferred is N-methyl-2-pyrrolidinone.
- usable bases when using a base include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, hydrogen Sodium base, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide and other inorganic bases, 1,8-diazabicyclo [5.4.0] undec-7-ene 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, collidine, 2,2′-bipyridyl, triphenylamine, quinoline, N, N-dimethyl Organic bases such as aniline and N, N-diethylaniline
- Acylating agents introduced as group R include ROH, RCl, (R) 2 O, or mixed anhydrides, preferably using RCl, (R) 2 O, in the presence of a base or In the absence, or dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazolyl disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3 , 5-trichlorobenzoyl anhydride, PyBop, PyBrop and other condensing agents can be used, preferably using RCl or (R) 2 O in the presence or absence of a base. .
- More preferable acylating agents include cyclopropane carbonyl chloride, cyclopropane carboxylic anhydride and the like.
- the amount used is preferably 1.0 to 3.0 equivalents relative to compound B2.
- the amount of the acylating agent used is preferably 1.0 to 2.5 equivalents relative to compound B1.
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 60 ° C.
- the reaction time is preferably in the range of 0.1 hour to 7 days.
- Compound C is purified and isolated from the reaction solution or crude product of Compound C obtained by the methods (1), (3) and (5) above.
- the method of obtaining the compound C by crystallization is mentioned.
- the crystal may be obtained as a solvated crystal in which a solvent is incorporated in the crystal lattice, and the obtained solvated crystal is dried or water obtained by dissolving the obtained solvated crystal in methanol.
- the precipitate produced by this is collected by filtration, and this is heated and dried under reduced pressure to obtain Compound C containing no solvent or water.
- the above-mentioned 1. ⁇ 5.
- the reaction solution containing Compound C obtained by the method described in 1. is extracted with an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, and ether.
- the obtained extract is dried or concentrated without drying, and crystallized as it is, or after the reaction solution is dried to obtain a crude product, the crude product is obtained by methyl acetate, ethyl acetate, butyl acetate.
- ether preferably selected from diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane.
- More specific examples of obtaining the crystals of compound C include adding ethyl acetate to the crude product obtained by distilling off the solvent from the reaction solution, or concentrating the ethyl acetate extract of the reaction solution at room temperature, Examples include a method of warming as necessary and isolating ethyl acetate solvated crystals. If necessary, acetic acid can be added by adding pentane, hexane, cyclohexane, preferably hexane to the ethyl acetate extract or its concentrated solution. A method for obtaining ethyl solvated crystals is mentioned. Further, after dissolving the obtained ethyl acetate crystals in methanol, water is added and the resulting precipitate is collected by filtration, heated and dried under reduced pressure to obtain compound C.
- step of producing compound B4 from compound B1 in the method can be carried out without a solvent, but usable solvents include ketone solvents such as acetone and diethyl ketone, diethyl ether, diisopropyl ether, tetrahydrofuran and the like.
- usable solvents include ketone solvents such as acetone and diethyl ketone, diethyl ether, diisopropyl ether, tetrahydrofuran and the like.
- Ether solvents such as ethyl acetate and butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone Aprotic polar organic solvents, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, and mixed solvents thereof.
- the acylating agent introduced as the group R includes ROH, RCl, (R) 2 O or a mixed acid anhydride, preferably RCl, (R) 2 O, in the presence or absence of a base.
- a base preferably RCl, (R) 2 O
- Usable bases include sodium carbonate, potassium carbonate, sodium hydride, tert-butoxypotassium, sodium methoxide, sodium ethoxide, pyridine, lutidine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo [5. 4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine and the like.
- the reaction temperature is preferably in the range of ⁇ 20 ° C. to 50 ° C.
- the reaction time is preferably in the range of 0.5 hour to 48 hours.
- Solvents that can be used in the step of producing compound C from compound B4 in the method of (1) include alcohol solvents having 1 to 4 carbon atoms such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N -Aprotic polar organic solvents such as dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone, halogen solvents such as dichloromethane and chloroform, or , Water, and mixed solvents thereof.
- alcohol solvents having 1 to 4 carbon atoms such as methanol
- ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
- N, N -Aprotic polar organic solvents such as dimethylformamide, dimethyl
- Usable bases are sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide
- Inorganic bases such as lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkoxides of alkaline earth metals, 1,8-diazabicyclo [5.4.0] undeca Organic bases such as -7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, and the like are preferable, and 1,8-diazabicyclo [ 5.4.0] Undec-7 Emissions, 1,5-diazabicyclo [4.3.0] non-5-ene, sodium carbonate, potassium carbonate,
- the amount of base used is preferably 0.01 to 24 equivalents relative to compound B4, the reaction temperature is preferably in the range of ⁇ 20 ° C. to 50 ° C., and the reaction time is preferably 0.5 hours. The range is up to 14 days.
- the purity described in the experimental examples refers to the area percentage of the target substance when measured under the following HPLC conditions, except for those specifically indicated.
- Example 1 Synthesis of 11-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 1.00 g of 1,7,11-trideacetylpyripyropene A synthesized according to the method described in WO2006 / 129714 is suspended in 5 ml of N-methyl-2-pyrrolidinone and 0.55 ml (2.2 eq) of 2,6-lutidine Then, 0.44 ml (2.2 eq) of cyclopropanecarbonyl chloride was added dropwise at room temperature. After 1 hour, the reaction solution was added dropwise to 200 ml of water.
- Example 2 Synthesis of 11-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 1.00 g of 1,7,11-trideacetylpyripyropene A was suspended in 5 ml of N-methyl-2-pyrrolidinone. , 6-lutidine (0.50 ml, 2.0 eq) was added, and cyclopropanecarbonyl chloride (0.33 ml, 1.7 eq) was added dropwise at room temperature. After 45 minutes, the reaction solution was added dropwise to 100 ml of water. 5 g of sodium chloride was added, and the mixture was stirred overnight.
- the precipitate was filtered, washed with water and dried, and 1.053 g of 11-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A was the main powder. It was. 526 mg (half amount) of the powder was subjected to silica gel chromatography (Kanto Chemical Co.
- Example 3 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 1.00 g of 1,7,11-trideacetylpyripyropene A into 5 ml of N-methyl-2-pyrrolidinone The suspension was suspended, 0.76 ml (2.6 eq) of 2,4,6-collidine was added, and the mixture was added dropwise to 0.50 ml (2.5 eq) of cyclopropanecarbonyl chloride at room temperature. After reacting for 8.5 hours, the reaction solution was added dropwise to 200 ml of water.
- Example 5 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 500 mg of 1,7,11-trideacetylpyripyropene A into 2.5 ml of N-methyl-2-pyrrolidinone The suspension was suspended, and 0.25 ml (2.5 eq) of cyclopropanecarbonyl chloride was added dropwise at room temperature. After reacting for 24 hours, the reaction solution was added dropwise to 50 ml of water. After adjusting the pH to 7.5 with 8% sodium bicarbonate water, 5 g of sodium chloride was added and stirred overnight, and then the precipitate was filtered and washed with water.
- the obtained powder was dried to obtain a main powder of 604 mg of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A.
- This 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A was purified by silica gel chromatography (Kanto Chemical Co. Silica gel C-60N 100 ml, ethyl acetate only, flow rate 5 ml / min. ) To obtain 338 mg (yield: 52.0%) (purity: 93.2%) of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A.
- Example 6 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 500 mg of 1,7,11-trideacetylpyripyropene A into 2.5 ml of N-methyl-2-pyrrolidinone After suspending and cooling to 0 ° C., 0.15 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise. After stirring at 0 ° C. for 20 hours, 0.1 ml (1.0 eq) of cyclopropanecarbonyl chloride was added, and after further stirring for 66 hours, 0.1 ml (1.0 eq) of cyclopropanecarbonyl chloride was added.
- Example 7 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 11-O-cyclopropanecarbonyl-1,7,11-trideacetylpyridine obtained in Example 1 200 mg (purity 95.6%) of pyropen A was suspended in 1.0 ml of N-methyl-2-pyrrolidinone, and 0.06 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise at room temperature.
- reaction mixture was added to 20 ml of water, adjusted to pH 7.5 with 8% aqueous sodium bicarbonate, 10 ml of ethyl acetate and 3 g of sodium chloride were added, and the mixture was washed with water.
- the aqueous layer was further extracted with 10 ml of ethyl acetate, extracted and washed with water. The previous ethyl acetate layer was combined, and the ethyl acetate was distilled off under reduced pressure.
- the main powder of 295 mg of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A obtained was purified by silica gel chromatography (100 ml of Kanto Chemical Co. Silica gel C-60N, Ethyl acetate only, flow rate 5 ml / min), 119 mg of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A (yield: 55.0%) (purity: 96.5%) Obtained.
- Example 8 Synthesis of 1,7,11-tri-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 500 mg of 1,7,11-trideacetylpyripyropene A 2.5 N-methyl-2-pyrrolidinone 2.5 Suspended in ml, 0.44 ml (5 eq) of pyridine was added, and 0.45 ml (4.5 eq) of cyclopropanecarbonyl chloride was added dropwise at room temperature. After reacting for 1.5 hours, the reaction solution was added dropwise to 50 ml of water. After stirring for 3 hours, 5 g of sodium chloride was added.
- Example 9 Synthesis of 1,11-O-dicyclopropanecarbonyl- 1,7,11-trideacetylpyripyropene A 1,7,11-O-tricyclopropanecarbonyl-1,7,11- synthesized in Example 8 Trideacetyl pyripyropene A (1.0 g) was dissolved in 95% aqueous methanol (30 mL), and tert-butoxypotassium (85 mg) was added at room temperature. After stirring at the same temperature for 16 hours, acetic acid was added, methanol was distilled off under reduced pressure, and the mixture was extracted with chloroform.
- Example 10 Synthesis of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A (method by crystallization) 1,7,11-O-Tricyclopropanecarbonyl-1,7,11-trideacetyl pyripyropene A (4 g) synthesized in Example 8 was dissolved by heating in methanol (100 mL), and potassium carbonate ( 420 mg) was added. After stirring at the same temperature for 6 hours, acetic acid (370 mg) and water (100 mL) were added, and the mixture was allowed to stand for 23 hours. The precipitated raw material was collected by filtration, water (50 mL) was added, and the mixture was allowed to stand for 20 hours.
- Example 11 Synthesis of 11-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 4.53 g of 1,7,11-trideacetylpyripyropene A is suspended in 22.5 g of N-methyl-2-pyrrolidinone, 1.51 g (1.51 eq) of triethylamine and 2.25 (1.47 eq) of cyclopropanecarboxylic acid anhydride are added at 60 ° C. For 23 hours. Then, it concentrated at the bath temperature of 70 degreeC under pressure reduction. The oily substance thus obtained was solidified by adding 10 ml of water, then washed with 10 ml of water three times and collected by filtration.
- Example 12 Synthesis of 1-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 199.7 mg (purity 95.6%) of 11-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A obtained in the same manner as in Example 1 was suspended in 2.0 ml of chlorobenzene, and 0.02 ml of DBU (ca0. 4eq) was added, and the mixture was stirred with heating at 80 ° C for 9 hours. Thereafter, the mixture was gradually brought to room temperature, stirred at room temperature for 2 days, 20 ml of ethyl acetate and 5 ml of water were added, and the organic layer was separated and concentrated under reduced pressure.
- DBU ca0. 4eq
- Example 14 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 1.00 g of 1,7,11-trideacetylpyripyropene A 7.0 ml of N-methyl-2-pyrrolidinone The mixture was cooled to 0 ° C., and 0.4 ml (2.0 eq) of cyclopropanecarbonyl chloride was added dropwise.
- Example 15 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 10.0 g of 1,7,11-trideacetylpyripyropene A 40.0 ml of N-methyl-2-pyrrolidinone And cooled to 0 ° C., and 3.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise.
- the crystals were filtered and washed with 50 ml of n-hexane-ethyl acetate (1: 1 (v / v)). The obtained crystals were dried at 60 ° C. for one day, and 8.83 g (weight yield: 67.9%) of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyridopopenene A (weight yield: 67.9%) (purity) 86.4%).
- Example 16 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11- trideacetylpyripyropene A 10.0 g of 1,7,11-trideacetylpyripyropene A 40.0 ml of N-methyl-2-pyrrolidinone And cooled to 0 ° C., and 7.0 ml (3.5 eq) of cyclopropanecarbonyl chloride was added dropwise.
- reaction solution was poured into 50 ml of ethyl acetate and 80 ml of ice water, and the mixture was stirred and separated at 7 ° C. or less.
- aqueous layer 30 ml of ethyl acetate was added, followed by liquid separation after stirring.
- 100 ml of ethyl acetate was added, neutralized with 72 ml of 1N sodium hydroxide and a small amount of 8% aqueous sodium bicarbonate solution, 15.0 g of sodium chloride was added at 10 to 15 ° C., and the mixture was allowed to stand and then separated.
- the organic layer was washed once with 30 ml of 5% brine and twice with 30 ml of water, concentrated under reduced pressure, added with 20 ml of ethyl acetate, heated to 60 ° C., and added with 14 ml of n-hexane. After dissolving 4.0 ml of ethyl acetate and cooling to 50 ° C., a very small amount of seed crystals was added. After 1.5 hours from the precipitation of crystals, 10 ml of n-hexane was added and stirred overnight. The obtained crystals were filtered and washed with 30 ml of n-hexane-ethyl acetate (1: 1 (v / v)).
- the ethyl acetate solution obtained in the above post-treatment was neutralized, washed with salt and water, dried under reduced pressure, and the crystal filtrate and washings were concentrated and dried (5.71 g). Methanol 30.0 ml Then, 5.16 ml of 5N sodium hydroxide solution was added dropwise at room temperature. After 1.5 hours, 2.0 ml of 5N sodium hydroxide solution was further added dropwise, followed by stirring at room temperature for 18 hours, followed by filtration and washing with 22 ml of methanol-water (1: 1 (v / v)). The obtained crystals were dried at 80 ° C. for 1 day to obtain 1.96 g (recovery rate: 19.6%) (purity: 94.5%) of the raw material 1,7,11-trideacetylpyripyropene A.
- the yield of the above-mentioned 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A including the recovery rate is 81.0%.
- Example 17 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 10.0 g of 1,7,11-trideacetylpyripyropene A 40.0 ml of N-methyl-2-pyrrolidinone And cooled to 3 ° C., 7.0 ml (3.5 eq) of cyclopropanecarbonyl chloride was added dropwise. Then, after reacting at 0 ° C. for 48 hours, the reaction solution was poured into 50 ml of ethyl acetate and 80 ml of ice water, and the mixture was stirred and separated at 10 ° C. or less.
- aqueous layer 100 ml of ethyl acetate was added, neutralized with 25 ml of 5N sodium hydroxide and a small amount of 8% aqueous sodium bicarbonate solution, 8 g of sodium chloride was added at 10 to 15 ° C., dissolved with stirring, allowed to stand, and then separated. did.
- the organic layer was washed once with 30 ml of 5% saline and twice with 30 ml of water, concentrated to 40 ml under reduced pressure, stirred at room temperature for 5 hours to precipitate crystals, and then 20 ml of n-hexane was added over 2 hours. Added and stirred overnight.
- the obtained crystals were filtered and washed with 30 ml of n-hexane-ethyl acetate (1: 1 (v / v)). The obtained crystals were dried at room temperature under reduced pressure for 30 minutes to obtain 7.31 g of crystals of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A.
- the obtained crystals were obtained by NMR spectrum (instrument: Lambda-400, solvent: CDCl 3, CH 3 COO CH 2 CH 3 ⁇ 4.12 integral of 2 protons and 1,11-di-O-cyclopropanecarbonyl- From the ratio of the integral value of one proton of 1,7,11-trideacetylpyripyropene A) to 1.0 mol of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A It contained 0.96 mol of ethyl acetate (weight yield (as ethyl acetate solvate): 49.1%) (purity 88.9%).
- the powder X-ray diffraction pattern of the crystal showed the following values.
- Powder X-ray diffraction pattern apparatus RINT 2200 (manufactured by Rigaku Corporation) Measurement conditions: X-ray: CuK ⁇ / 40 kV / 20 mA, sampling width: 0.020 °, scanning speed: 0.500 ° / min, scanning width: 2 ⁇ / ⁇ , scanning range: 3.0 to 40.0 °
- the characteristic peak is shown in the following diffraction angle [2 ⁇ (°)].
- Example 18 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 10.0 g of 1,7,11-trideacetylpyripyropene A 40.0 ml of N-methyl-2-pyrrolidinone And cooled to 0 ° C., and 3.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise. Thereafter, 2.0 ml (1.0 eq) of cyclopropanecarbonyl chloride was added dropwise at 0 ° C. after 4 hours.
- reaction solution was poured into 100 ml of ethyl acetate and 120 ml of ice water, followed by liquid separation after stirring.
- 100 ml of ethyl acetate was added, neutralized with 9.5 g of sodium bicarbonate, 8.0 g of sodium chloride was added, and the mixture was allowed to stand with stirring and then separated.
- the organic layer was washed once with 30 ml of 5% brine and twice with 30 ml of water, concentrated under reduced pressure, added with 35.0 ml of ethyl acetate, stirred for 1.5 hours at room temperature, and then 35.0 ml of n-hexane over 2 hours.
- Example 19 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 20.0 g of 1,7,11-trideacetylpyripyropene A 20.0 ml of N-methyl-2-pyrrolidinone 80.0 ml And cooled to ⁇ 10 ° C., 12.0 ml (3.0 eq) of cyclopropanecarbonyl chloride was added dropwise. After reacting at ⁇ 10 ° C. for 4 hours, 4.0 ml (1.0 eq) of cyclopropanecarbonyl chloride was further added dropwise. Then, after reacting at ⁇ 10 ° C.
- reaction solution was poured into 200 ml of ethyl acetate and 180 ml of 8% aqueous sodium bicarbonate at 5 ° C. or lower, neutralized by adding 20 ml of 8% aqueous sodium bicarbonate, and then 20 ml of 15% brine was added.
- the mixture was separated after stirring at 10 ° C. The organic layer was washed three times with 60 ml of water, concentrated to 60 ml under reduced pressure, added with 100 ml of ethyl acetate, and further concentrated to 80 ml under reduced pressure.
- Example 20 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 50.0 g of 1,7,11-trideacetylpyripyropene A to 200 ml of N-methyl-2-pyrrolidinone The suspension was cooled to ⁇ 10 ° C., and 15.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise. Thereafter, 15.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise at ⁇ 10 ° C. after 3 hours and 10.0 ml (1.0 eq) after 5 hours. After reacting at ⁇ 10 ° C.
- reaction solution was poured into 500 ml of ethyl acetate and 500 ml of 8% aqueous sodium bicarbonate at 5 ° C. or lower, neutralized with a small amount of 8% aqueous sodium bicarbonate, and 15% sodium chloride at 10 ° C. or higher. 300 ml of water was added for liquid separation. The organic layer was washed three times with 100 ml of water, concentrated to 150 ml under reduced pressure, added with 250 ml of ethyl acetate, concentrated again to 200 ml under reduced pressure, added with 50 ml of ethyl acetate, and stirred overnight at room temperature.
- the precipitated crystals were filtered and washed with 80 ml of ethyl acetate.
- the obtained crystals were dried under reduced pressure at 50 ° C. for 2 hours to obtain 44.90 g of crystals containing 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A.
- the obtained crystals were analyzed by a method according to Example 17, and as a result, 0.99 ethyl acetate was added to 1.0 mol of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A. (weight yield: 60.2% (as ethyl acetate solvate)) (purity 87.5%).
- Example 21 Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 50.0 g of 1,7,11-trideacetylpyripyropene A to 200 ml of N-methyl-2-pyrrolidinone The suspension was cooled to ⁇ 10 ° C., and 15.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise. Thereafter, 15.0 ml (1.5 eq) of cyclopropanecarbonyl chloride was added dropwise at ⁇ 10 ° C. after 3 hours and 10.0 ml (1.0 eq) after 5 hours. After reacting at ⁇ 10 ° C.
- reaction solution was poured into a mixture of 500 ml of ethyl acetate, 500 ml of ice water and 40.0 g of sodium bicarbonate at 5 ° C. or less, neutralized with a small amount of 8% sodium bicarbonate solution, and then 10 ° C. or more.
- the solution was separated by adding 300 ml of 15% saline.
- the organic layer was washed three times with 150 ml of water, concentrated to 100 ml under reduced pressure, then added with 200 ml of ethyl acetate, concentrated again to 150 ml under reduced pressure, added with 50 ml of ethyl acetate, and stirred overnight at room temperature.
- the precipitated crystals were filtered and washed with 60 ml of ethyl acetate.
- the obtained crystals were dried under reduced pressure at 40 ° C. for 1 hour and at room temperature for 2 hours to obtain 49.10 g of crystals containing 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A. (Weight yield: 65.8% (as ethyl acetate solvate)) (purity 84.7%).
- the obtained crystals contained 1.00 mol of ethyl acetate with respect to 1.0 mol of 1,11-di-O-cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A.
- Example 22 From 1,7,11-O-tricyclopropanecarbonyl-1,7,11-trideacetyl pyripyropen A synthesized in Example 8, 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyri Pyropen A was synthesized under the reagents, solvents, time and temperature conditions described in Table 3 below. The reaction solution obtained after completion of the reaction was subjected to high performance liquid chromatography under the analysis conditions shown below, and 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A produced in the reaction solution The amount was confirmed and shown in Table 3.
Abstract
Description
本発明は、害虫防除剤として有用なピリピロペン誘導体の製造法に関するものであり、より詳細には、1位および11位にアシルオキシ基を有し、7位に水酸基を有するピリピロペン誘導体の製造法に関するものである。
1位および11位にアシルオキシ基を有し、7位が水酸基であるピリピロペン誘導体は、WO2006/129714に記載されるように、害虫に対して防除効果を示す化合物である。
1.本発明は、次式C:
で表される化合物Cを製造する方法であって、
次式B1:
3.また、本発明によれば、化合物B1の11位の水酸基をアシル化剤を用いて次式B2:
で表される化合物B2を製造する工程および化合物B2の1位水酸基をさらにアシル化する工程からなる、2つの工程数でアシル化することを特徴とする、前記1.に記載の方法が提供される。すなわち、この実施態様では、前記1.に記載の方法において、化合物B1の11位の水酸基を、アシル化剤を用いてアシル化することにより、化合物B2を製造する工程、および化合物B2の1位の水酸基をさらにアシル化する工程からなる2つの工程でアシル化することにより化合物Cを得る。
4.別の本発明の態様によれば、化合物B1の11位水酸基をアシル化することによって前記化合物B2を製造する工程、化合物B2の11位のアシル基を1位の水酸基に転移させることによって次式B3:
で表される化合物B3を製造する工程、および化合物B3の11位の水酸基をアシル化する工程からなる、3つの工程数でアシル化することを特徴とする、前記1.に記載の方法が提供される。すなわち、この実施態様では、前記1.に記載の方法において、化合物B1の11位の水酸基をアシル化することによって化合物B2を製造する工程、化合物B2の11位のアシル基を1位の水酸基に転移させることによって化合物B3を製造する工程、および化合物B3の11位の水酸基をアシル化する工程からなる3つの工程でアシル化することにより化合物Cを得る。
5.さらに本発明によれば、式B1の化合物を製造する工程として次式A1:
で表される化合物A1の1位、7位および11位のアシル基を、塩基を用いて加水分解する工程を含む、前記1.~4.に記載の方法が提供される。すなわち、この実施態様では、前記1.~4.に記載の方法において、式B1の化合物を製造する工程として、化合物A1の1位、7位および11位のアシル基を、塩基を用いて加水分解する工程がさらに含まれる。
で表される化合物B4を得た後、7位水酸基を選択的に脱アシル化する工程を含む、方法が提供される。
(a)化合物Cを含有する反応液を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフランおよびジオキサンからなる群から選択される有機溶媒で抽出処理し、得られた抽出液を乾燥した後または乾燥せずに濃縮する工程、
(b)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、メタノール、およびエタノールからなる群から選択される有機溶媒に室温または加温下で溶解する工程、または
(c)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、メタノール、およびエタノールからなる群から選択される有機溶媒に室温または加温下で溶解し、得られた溶解液に、ヘプタン、ヘキサン、およびシクロヘキサンからなる群から選択される貧溶媒を加える工程
を含んでなる。本発明の好ましい実施態様によれば、前記工程(a)は、(a’)化合物Cを含有する反応液を、酢酸エチルで抽出処理し、得られた抽出液を乾燥した後または乾燥せずに濃縮する工程とされる。本発明の他の好ましい実施態様によれば、前記工程(b)は、(b’)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸エチルに室温または加温下で溶解する工程とされる。本発明の他の好ましい実施態様によれば、前記工程(c)は、(c’)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸エチルに室温または加温下で溶解し、得られた溶解液にヘキサンを加える工程とされる。
本明細書において、置換基または置換基の一部としての「アルキル」という用語はそれぞれ、特に定義されていない限り、直鎖状、分岐鎖状、環状またはそれらの組み合わせのアルキルを意味する。
化合物A1は、例えば、Pure Appl. Chem., vol.71, No6, pp.1059-1064, 1999.;特開平8-239385号公報、特開平6-184158号公報、WO2004/060065、特開平8-259569号公報、またはBioorganic Medicinal Chemistry Letter 5巻22号2683頁に記載の方法で得ることができる。
(1)化合物B1から化合物Cを直接製造する工程
前記2.の化合物B1から化合物Cを製造する方法において使用可能な溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N,N-ジメチルアセトアミド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノン、N,N-ジメチル-2-イミダゾリジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、トルエンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられ、好ましくは非プロトン性極性有機溶媒が挙げられる。より好ましくは、N-メチル-2-ピロリジノン、N,N-ジメチル-2-イミダゾリジノンであり、特に好ましくはN-メチル-2-ピロリジノンである。
前記3.または4.の化合物B1から化合物B2を製造する方法において使用可能な溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N,N-ジメチルアセトアミド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノン、N,N-ジメチル-2-イミダゾリジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、トルエンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられ、好ましくは非プロトン性極性有機溶媒が挙げられる。特に好ましくは、N-メチル-2-ピロリジノンである。
前記3.の化合物B2から化合物Cを製造する方法において使用可能な溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N,N-ジメチルアセトアミド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノン、N,N-ジメチル-2-イミダゾリジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、トルエンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられ、好ましくは非プロトン性極性有機溶媒が挙げられる。特に好ましくは、N-メチル-2-ピロリジノンである。
前記4.の化合物B2から化合物B3を製造する方法において使用可能な溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N,N-ジメチルアセトアミド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノン、N,N-ジメチル-2-イミダゾリジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、トルエン、クロロベンゼン、ジクロロベンゼンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられ、好ましくは非プロトン性極性有機溶媒が挙げられる。
前記4.の化合物B3から化合物Cを製造する方法において使用可能な溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、ジメチルスルホキシド、N,N-ジメチルアセトアミド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノン、N,N-ジメチル-2-イミダゾリジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、トルエンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられ、好ましくは非プロトン性極性有機溶媒が挙げられる。特に好ましくは、N-メチル-2-ピロリジノンである。
前記の(1)、(3)、(5)の方法で得られる化合物Cの反応液または粗生成物から化合物Cを精製単離する方法としては、好ましくは、結晶化によって化合物Cを得る方法が挙げられる。該結晶は、溶媒を結晶格子内に取込んだ溶媒和結晶として得てもよく、得られた溶媒和結晶を乾燥することによって、あるいは得られた溶媒和結晶をメタノールに溶解して水を加えること等によって生じた析出物をろ取し、これを加温、減圧下乾燥することにより、溶媒あるいは水を含まない化合物Cを得ることができる。
前記6.の方法における化合物B1から化合物B4を製造する工程は、無溶媒で実施することもできるが、使用可能な溶媒としては、アセトン、ジエチルケトンなどのケトン系溶媒、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフランなどのエーテル系溶媒、酢酸エチル、酢酸ブチルなどのエステル系溶媒、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメチルスルホキシド、アセトニトリル、N-メチル-2-ピロリジノン、N-メチル-2-ピペラジノンなどの非プロトン性極性有機溶媒、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、トルエンなどの芳香族炭化水素系溶媒、およびこれらの混合溶媒が挙げられる。
カラム: Inertsil ODS-2または4 (5μm) 4.6φ×150 mm
(実施例1~13ではODS-2を使用し、実施例14~20ではODS-4を使用した。)
カラム温度 : 30℃
移動相 : 水-アセトニトリル
移動相の条件:下表1に示したとおり
検出波長 : UV 320 nm
11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
WO2006/129714に記載の方法に準じて合成した1,7,11-トリデアセチルピリピロペンA 1.00gをN-メチル-2-ピロリジノン5mlに懸濁し、2,6-ルチジン0.55ml(2.2eq)を加え、室温下、シクロプロパンカルボニルクロライド0.44ml(2.2eq)を滴下した。1時間後、反応液を200mlの水に滴下した。5時間攪拌後析出物をろ過し水洗の後、乾燥し、0.816gの11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を得た。また、ろ液に食塩25gを加え、酢酸エチル20mlで抽出し、酢酸エチル層を水洗後、酢酸エチルを溜去後、乾燥して、0.27gの11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの泡状物質を得た。粉末及び泡状物質を合わせて、シリカゲルクロマト(MERCK社製Silica gel C-60を100ml、酢酸エチル-メタノール(50:1(v/v)、流速10ml/min)を行い、11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを532mg得た(収率:46.3%)(純度95.6%)。
11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 1.00gをN-メチル-2-ピロリジノン5mlに懸濁し、2,6-ルチジン0.50ml(2.0eq)を加え、室温下、シクロプロパンカルボニルクロライド0.33ml(1.7eq)を滴下した。45分後、反応液を100mlの水に滴下した。食塩5gを加え、1晩攪拌後析出物をろ過し水洗の後、乾燥し、1.053gの11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を得た。粉末のうち526mg(半量)を、シリカゲルクロマト(関東化学社Silica gel C-60N(40-50μm)を100ml、酢酸エチル-メタノール(50:1(v/v)、流速5ml/min)を行い、11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを366mg得た(収率:63.7%)(純度95.1%)。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA1.00gをN-メチル-2-ピロリジノン5mlに懸濁し、2,4,6-コリジン0.76ml(2.6eq)を加え、室温下、シクロプロパンカルボニルクロライド0.50ml(2.5eq)に滴下した。8.5時間反応後、反応液を200mlの水に滴下した。1晩攪拌後、析出物をろ過、乾燥し、1.135gの1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を得た。また、ろ液に食塩25gを加え、酢酸エチル20mlで抽出し、酢酸エチル層を水洗後、酢酸エチルを溜去後、乾燥して、0.12gの1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの泡状物質を得た。粉末及び泡状物質を合わせて、シリカゲルクロマト(MERCK社製Silica gel C-60を150ml、酢酸エチルのみ、流速10ml/min)を行い、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを743mg(収率:57.2%)(純度80.8%)で得た。得られた化合物のFAB-MS、1H-NMR測定し、WO2006/129714に記載の化合物261のデータと一致することを確認した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 1.00gをN-メチル-2-ピロリジノン4mlに懸濁し、2,6-ルチジン0.75ml(3.0eq)を加え、室温下、シクロプロパンカルボニルクロライド0.54ml(2.7eq)を滴下した。3時間反応後、反応液を100mlの水に滴下した。2時間攪拌した後、食塩10gを加えた。その後、一晩攪拌し、析出物をろ過し水洗した。得られた粉末を乾燥し、1.276gの1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を得た。この1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを、シリカゲルクロマト(MERCK社製Silica gel C-60を一回目50ml、メインを集めて二回目150ml、酢酸エチルのみ、流速5ml/min)を行い、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを576mg(収率:44.4%)(純度:88.6%)と115mg(収率:8.8%)(純度:74.9%)を得た。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 500mgをN-メチル-2-ピロリジノン2.5mlに懸濁し、室温下、シクロプロパンカルボニルクロライド0.25ml(2.5eq)を滴下した。24時間反応後、反応液を50mlの水に滴下した。8%重曹水でpH7.5に調整後、食塩5gを加え、一晩攪拌した後、析出物をろ過し水洗した。得られた粉末を乾燥し、604mgの1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を得た。この1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを、シリカゲルクロマト精製(関東化学社Silica gel C-60Nを100ml、酢酸エチルのみ、流速5ml/min)を行い、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを338mg(収率:52.0%)(純度:93.2%)得た。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 500mgをN-メチル-2-ピロリジノン2.5mlに懸濁し、0℃に冷却後、シクロプロパンカルボニルクロライド0.15ml(1.5eq)を滴下した。0℃で20時間攪拌後にシクロプロパンカルボニルクロライド0.1ml(1.0eq)を追加し、さらに66時間攪拌後にシクロプロパンカルボニルクロライド0.1ml(1.0eq)を追加した。95時間攪拌後、氷水50mlに滴下した。8%重曹水でpH7.5に調整後、食塩5gを加え、攪拌した後、析出物をろ過し水洗した。ろ液を酢酸エチルで抽出した後、酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去した。この残渣と析出物をあわせてシリカゲルクロマト精製(関東化学社Silica gel C-60Nを150ml、酢酸エチルのみ、流速5ml/min)を行い、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを396mg(収率:60.9%)(純度:95.3%)得た。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
実施例1で得られた11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA200mg(純度95.6%)をN-メチル-2-ピロリジノン1.0mlに懸濁し、室温下、シクロプロパンカルボニルクロライド0.06ml(1.5eq)を滴下した。21時間30分反応後、反応液に20mlの水に加え、8%重曹水でpH7.5に調整後、酢酸エチル10mlと食塩3gを加え、抽出後水洗した。水層についてさらに酢酸エチル10mlを加え抽出後さらに水洗し、先の酢酸エチル層を合わせて、酢酸エチルを減圧溜去した。得られた295mgの1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAがメインの粉末を、シリカゲルクロマト精製(関東化学社Silica gel C-60Nを100ml、酢酸エチルのみ、流速5ml/min)し、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを119mg(収率:55.0%)(純度:96.5%)得た。
実施例8
1,7,11-トリ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 500mgをN-メチル-2-ピロリジノン2.5mlに懸濁し、ピリジン 0.44ml(5eq)を加え、室温下、シクロプロパンカルボニルクロライド0.45ml(4.5eq)を滴下した。1.5時間反応後、反応液を50mlの水に滴下した。3時間攪拌した後、食塩5gを加えた。その後、1.5時間攪拌し、析出物をろ過し水洗した。得られた粉末を乾燥し、721mg(収率99.4%)(純度 89.6%)の1,7,11-トリ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの粉末を得た。得られた化合物のFAB-MS、1H-NMR測定し、WO2006/129714に記載の化合物218のデータと一致することを確認した。
1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
実施例8で合成した1,7,11-O-トリシクロプロパンカルボニル-1,7,11-トリデアセチル ピリピロペンA(1.0g)を95%メタノール水溶液(30 mL)に溶解し、室温でtert-ブトキシカリウム(85 mg)を加えた。同温で16時間撹拌後、酢酸を加え、減圧下でメタノールを留去してクロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去して、1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの粗生成物(724 mg、純度50%)を得た。これをシリカゲルカラムクロマトグラフィー(Merck シリカゲル60F254 0.5 mm、ヘキサン:アセトン=10:5.5)にて精製して、1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチル ピリピロペンA(370 mg、収率41%)を得た。
1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成(結晶化による手法)
実施例8で合成した1,7,11-O-トリシクロプロパンカルボニル-1,7,11-トリデアセチル ピリピロペンA(4 g)をメタノール(100 mL)に加温溶解し、室温で炭酸カリウム(420 mg)を加えた。同温で6時間撹拌後、酢酸(370 mg)と水(100 mL)を加え、23時間放置した。析出した原料を濾取した後、水(50 mL)を加えて20時間放置した。メタノールを減圧下で留去して7時間放置することで、1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAが析出し、濾取によりこれを得た(900 mg、収率25.1%、純度81%)。
11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 4.53gをN-メチル-2-ピロリジノン22.5gに懸濁し、トリエチルアミン1.51g(1.51eq)と無水シクロプロパンカルボン酸2.25(1.47eq)gを60℃で23時間過熱攪拌した。その後、減圧下、バス温70℃で濃縮した。得られた油状物質に水10mlを加え固化した後、水10mlで3回洗浄しろ取した。得られた粉末を水5mlで洗浄し減圧下40℃で一日乾燥し、11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを4.73g(収率91.4%)(純度:76.2%)を得た。
1-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
実施例1と同様にして得た11-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA199.7mg(純度95.6%)をクロロベンゼン2.0mlに懸濁し、DBU0.02ml(ca0.4eq)を加え、80℃で9時間過熱攪拌した。その後徐々に室温とし、2日間室温にて攪拌し、酢酸エチル20ml、水5mlを加えて、有機層を分離し減圧下濃縮した。クロロベンゼンが残った状態で結晶が析出したので、結晶をろ過し、トルエンで洗浄した。得られた結晶を減圧下60℃一晩乾燥し、1-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA153.4mg(収率:76.8%)(純度94.5%)を得た。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA(500mg)をN-メチル-2-ピロリジノン3.0mlに懸濁し、0℃で、シクロプロパンカルボニルクロライド0.10ml(1.0eq)に滴下した。1日反応後、シクロプロパンカルボニルクロライド0.025ml(0.25eq)を、さらに41時間後にN-メチル-2-ピロリジノン1.0mlとシクロプロパンカルボニルクロライド0.025ml(0.25eq)を加え、65時間反応させた後、反応液を30mlの氷水と酢酸エチル50mlに注下した。さらに、8%重曹水で中和し、3gの食塩を加え攪拌後、分液した。有機層を水10mlで2回洗浄し、減圧下溶媒を溜去した。得られた粉末678mgを、シリカゲルクロマト(MERCK社製Silica gel C-60(80ml)、酢酸エチル-メタノール(50:1(v/v))を行い、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを479mg(収率:83.3%)(純度95.2%)で、また、1-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを51mg(10.2%)回収した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 1.00gをN-メチル-2-ピロリジノン7.0mlに懸濁し、0℃に冷却し、シクロプロパンカルボニルクロライド0.4ml(2.0eq)を滴下した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 10.0gをN-メチル-2-ピロリジノン40.0mlに懸濁し、0℃に冷却し、シクロプロパンカルボニルクロライド3.0ml(1.5eq)を滴下した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA 10.0gをN-メチル-2-ピロリジノン40.0mlに懸濁し、0℃に冷却し、シクロプロパンカルボニルクロライド7.0ml(3.5eq)を滴下した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA10.0gをN-メチル-2-ピロリジノン40.0mlに懸濁し、3℃に冷却し、シクロプロパンカルボニルクロライド7.0ml(3.5eq)を滴下した。その後0℃で48時間反応後、反応液を酢酸エチル50mlと氷水80mlに注下し、10℃以下で攪拌後分液した。得られた水層に、酢酸エチル100mlを加え、5N水酸化ナトリウム25mlと少量の8%重曹水で中和し、10~15℃で食塩8gを加え、攪拌溶解し、静置後、分液した。有機層を5%食塩水30mlで一回、水30mlで二回洗浄し、減圧下40mlまで濃縮後、室温下5時間攪拌して結晶を析出させた後、n-ヘキサン20mlを2時間かけて加え、一晩攪拌した。得られた結晶をろ過し、n-ヘキサン-酢酸エチル(1:1(v/v))30mlで洗浄した。得られた結晶を室温減圧下30分乾燥し、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの結晶を7.31gで得た。得られた結晶は、NMRスペクトラム(装置:Lambda-400、溶媒:CDCl3、δ4.12のCH3COOCH 2 CH3の2プロトンの積分値と1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの1プロトンの積分値の比)から、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA1.0molに対して酢酸エチル0.96molを含有していた(重量収率(酢酸エチル和物として):49.1%)(純度88.9%)。
粉末X線回折パターン
装置:RINT 2200(理学電気株式会社製)
測定条件:X線:CuKα/40kV/20mA、サンプリング幅:0.020°、スキャンスピード:0.500°/min、走査幅:2θ/θ、走査範囲:3.0~40.0°
以下の回折角[2θ(°)]にその特徴的なピークを示す。
回折角(2θ):7.4±0.1°、12.0±0.1°、17.0±0.1°、18.3±0.1°、19.1±0.1°
図1に得られた粉末X線パターンを示した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA10.0gをN-メチル-2-ピロリジノン40.0mlに懸濁し、0℃に冷却し、シクロプロパンカルボニルクロライド3.0ml(1.5eq)を滴下した。その後、シクロプロパンカルボニルクロライドは4時間後に2.0ml(1.0eq)を0℃で滴下した。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA20.0gをN-メチル-2-ピロリジノン80.0mlに懸濁し、-10℃に冷却し、シクロプロパンカルボニルクロライド12.0ml(3.0eq)を滴下した。-10℃で4時間反応後、さらにシクロプロパンカルボニルクロライド4.0ml(1.0eq)を滴下した。その後、-10℃で72時間反応後、反応液を酢酸エチル200mlと8%重曹水180mlに5℃以下で注下し、8%重曹水20mlを加えて中和後、15%食塩水20mlを加え、10℃で攪拌後分液した。有機層を水60mlで三回洗浄し、減圧下60mlまで濃縮後、酢酸エチル100mlを加えさらに減圧下、80mlまで濃縮した。室温下一晩攪拌し、得られた結晶をろ過し、n-ヘキサン10ml-酢酸エチル20mlの混液で洗浄した。得られた結晶を80℃減圧下一晩乾燥し、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを17.80gで得た。得られた結晶は、実施例17に準じた方法で解析したところ、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA1.0molに対して酢酸エチル0.75molを含有していた(重量収率:61.8%(酢酸エチル和物として))(純度87.5%)。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA50.0gをN-メチル-2-ピロリジノン200mlに懸濁し、-10℃に冷却し、シクロプロパンカルボニルクロライド15.0ml(1.5eq)を滴下した。その後、シクロプロパンカルボニルクロライドは3時間後に15.0ml(1.5eq)と5時間後に10.0ml(1.0eq)を-10℃で滴下した。-10℃で72時間反応させた後に、反応液を酢酸エチル500mlと8%重曹水500mlに5℃以下で注下し、少量の8%重曹水で中和後、10℃以上で15%食塩水300mlを加え分液した。有機層を水100mlで三回洗浄し、減圧下150mlまで濃縮後、酢酸エチル250mlを加え、再度減圧下200mlまで濃縮し、酢酸エチル50mlを加えて、室温下一晩攪拌した。析出した結晶をろ過し、酢酸エチル80mlで洗浄した。得られた結晶を減圧下50℃、2時間乾燥し、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA含有の結晶を44.90g得た。得られた結晶は、実施例17に準じた方法で解析したところ、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA1.0molに対して酢酸エチル0.99molを含有していた(重量収率:60.2%(酢酸エチル和物として))(純度87.5%)。
1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの合成
1,7,11-トリデアセチルピリピロペンA50.0gをN-メチル-2-ピロリジノン200mlに懸濁し、-10℃に冷却し、シクロプロパンカルボニルクロライド15.0ml(1.5eq)を滴下した。その後、シクロプロパンカルボニルクロライドは3時間後に15.0ml(1.5eq)と5時間後に10.0ml(1.0eq)を-10℃で滴下した。-10℃で75時間反応させた後に、反応液を酢酸エチル500mlと氷水500mlと重曹40.0gの混合液に5℃以下で注下し、少量の8%重曹水で中和後、10℃以上で15%食塩水300mlを加え分液した。有機層を水150mlで三回洗浄し、減圧下100mlまで濃縮後、酢酸エチル200mlを加え、再度減圧下150mlまで濃縮し、酢酸エチル50mlを加えて、室温下一晩攪拌した。析出した結晶をろ過し、酢酸エチル60mlで洗浄した。得られた結晶を減圧下40℃で1時間、室温で2時間乾燥し、1,11-ジ-O-シクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンA含有の結晶を49.10g(重量収率:65.8%(酢酸エチル和物として))(純度84.7%)得た。
実施例8で合成した1,7,11-O-トリシクロプロパンカルボニル-1,7,11-トリデアセチル ピリピロペンAから1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAを以下の表3に記載の試薬、溶媒、時間、温度条件で合成した。反応終了後に得られた反応液を以下に示した分析条件で高速液体クロマトグラフィーにかけて反応液中に生成した1,11-O-ジシクロプロパンカルボニル-1,7,11-トリデアセチルピリピロペンAの量を確認し、表3に示した。
検出器:紫外吸光光度計又はフォトダイオードアレイ検出器(測定波長:254 nm) カラム: CAPCELL PAK C18 2.0mm.I.D×150 mm 内径 5μm
カラム温度:40°C
移動相A:水
移動相B:液体クロマトグラフィー用アセトニトリル
移動相の送液:移動相A及び移動相Bの混合比を次のように変えて濃度勾配制御する。
流量:毎分0.2 mL
移動相の条件:下表2に示したとおり
Claims (16)
- 化合物B1の1位および11位の水酸基を1つの工程でアシル化することにより化合物Cを得る、請求項1に記載の方法。
- アシル化を塩基非存在下で行う、請求項1~5のいずれか一項に記載の方法。
- 化合物B1の1位および/または11位の水酸基をアシル化する際に用いる塩基が2,4,6-コリジンまたは2,6-ルチジンである、請求項1~5のいずれか一項に記載の方法。
- 化合物B2を製造する工程において、化合物B1に対して1.0~3.0等量の塩基を使用し、該工程と化合物B2の1位水酸基をさらにアシル化する工程とを併せて合計2.0~4.5等量の塩基を使用する、請求項3に記載の方法。
- 化合物B1に対して2.0~5.0等量のアシル化剤を使用する、請求項1~4のいずれか一項に記載の方法。
- 化合物B2を製造する工程において、化合物B1に対して1.0~3.5等量のアシル化剤を使用し、該工程と化合物B2の1位水酸基をさらにアシル化する工程とを併せて合計2.0~4.5等量のアシル化剤を使用する、請求項3に記載の方法。
- Rがシクロプロパンカルボニル基である、請求項1~10のいずれか一項に記載の方法。
- 化合物B2から化合物B3を製造する工程を塩基の存在下で行う、請求項4に記載の方法。
- 化合物Cを含有する反応液から、化合物Cを結晶化によって単離精製する工程をさらに含んでなる、請求項1~11のいずれか一項に記載の方法。
- [規則91に基づく訂正 15.10.2010]
次式C:
で表される化合物Cの溶媒和物結晶を単離精製する方法であって、
(a)化合物Cを含有する反応液を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフランおよびジオキサンからなる群から選択される有機溶媒で抽出処理し、得られた抽出液を乾燥した後または乾燥せずに濃縮する工程、
(b)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、メタノール、およびエタノールからなる群から選択される有機溶媒に室温または加温下で溶解する工程、または
(c)化合物Cを含有する反応液を乾固することによって粗生成物を得た後に、該粗生成物を、酢酸メチル、酢酸エチル、酢酸ブチル、トルエン、クロロベンゼン、クロロホルム、ジクロルメタン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、メタノール、およびエタノールからなる群から選択される有機溶媒に室温または加温下で溶解し、得られた溶解液に、ヘプタン、ヘキサン、およびシクロヘキサンからなる群から選択される貧溶媒を加える工程
を含んでなる、方法。
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US8263778B2 (en) | 2007-08-13 | 2012-09-11 | Meiji Seika Pharma Co., Ltd. | Process for producing pyripyropene derivatives and intermediates for the production thereof |
JP5206145B2 (ja) | 2007-10-15 | 2013-06-12 | 株式会社リコー | 廃トナー回収容器ユニットおよび画像形成装置 |
KR20100094550A (ko) | 2007-12-21 | 2010-08-26 | 메이지 세이카 가부시키가이샤 | 신규한 침투성 살충제 |
UA111151C2 (uk) | 2010-03-01 | 2016-04-11 | Мейдзі Сейка Фарма Ко., Лтд. | Спосіб одержання похідних пірипіропену |
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