Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
  • C07F1/08—Copper compounds
• • 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 an organic copper compound and a method for producing an organic copper compound.
• Non-Patent Document 1 discloses an organic zinc iodide compound protected with a 9-fluorenylmethyloxycarbonyl protecting group (Fmoc).
• Patent Document 1 discloses an organic zinc iodide compound protected with a tert-butoxycarbonyl protecting group (Boc) and an organic zinc bromine compound protected with Boc.
• Patent Document 2 discloses an organic zinc iodide compound protected with Boc and an organic zinc iodide compound protected with a benzyloxycarbonyl protecting group (Cbz).
• the purpose of the present invention is to newly provide an organocopper compound that is useful in the synthesis of special amino acids.
• the present inventor conducted extensive research, and as a result, was able to newly produce a useful organocopper compound in the synthesis of special amino acids by using a copper agent.
• the present invention includes the following organocopper compounds and methods for producing the organocopper compounds.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• the copper agent when producing a compound in which X is a chlorine atom or a bromine atom, the copper agent includes copper (I) chloride, copper (I) bromide, and copper (I) iodide. ) is at least one compound selected from the group consisting of In the general formula (1), when producing a compound in which X is a cyano group, the copper agent is copper (I) cyanide. 3. The production method according to item 2 above.
• the copper agent when producing a compound in which X is a chlorine atom or a bromine atom, is preferably copper (I) chloride, copper (I) bromide, and copper iodide.
• the reaction is carried out in the presence (combination) of at least one compound selected from the group consisting of (I) and at least one compound selected from the group consisting of lithium chloride, lithium bromide, and lithium iodide. .
• the copper agent when producing a compound in which X is a cyano group, is preferably copper (I) cyanide, and the reaction is carried out in the presence (combination) of lithium chloride. conduct.
• the organic solvent is at least one organic solvent selected from the group consisting of aprotic polar solvents, halogen solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents.
• aprotic polar solvents halogen solvents
• ether solvents ether solvents
• ester solvents hydrocarbon solvents
• aromatic solvents aromatic solvents.
• the organocopper compound has excellent stability and is useful in synthesizing special amino acids, particularly in derivatization to aryl-type special amino acids.
• the present invention can newly provide an organocopper compound useful in the synthesis of special amino acids.
• X is a chlorine atom, a bromine atom , a cyano group (-C ⁇ N, CN), or a trifluoromethanesulfonate group ( CF3SO3- , TfO group);
• Prot is a protection selected from a 9-fluorenylmethyloxycarbonyl protecting group (Fmoc), a tert-butoxycarbonyl protecting group (Boc), an allyloxycarbonyl protecting group (Alloc), or a benzyloxycarbonyl protecting group (Cbz) is the basis,
• R 1 is a hydroxyl group or a carboxylic acid-protecting group;
• R2 is a hydrogen atom or an alkyl group.
• the copper agent is preferably copper (I) chloride (CuCl), copper (I) bromide (CuBr), and copper (I) iodide (CuI).
• the copper agent is preferably copper (I) chloride (CuCl), copper (I) bromide (CuBr), and at least one compound selected from the group consisting of copper (I) iodide (CuI), lithium chloride (LiCl), lithium bromide (LiBr) , and lithium iodide (LiI) in the presence (combination) of at least one compound.
• the copper agent is preferably copper (I) cyanide (CuCN) is.
• the copper agent is preferably copper cyanide (I) (CuCN) and the reaction is carried out in the presence (combination) of lithium chloride (LiCl).
• the organic solvent is preferably a group consisting of aprotic polar solvents, halogen solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents. is at least one organic solvent selected from
• the organocopper compound has excellent stability and is useful in synthesizing special amino acids, particularly in derivatization to aryl-type special amino acids.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group.
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group.
• R 1 is a hydroxyl group or a protective group for carboxylic acid.
• R 1 is preferably a carboxylic acid-protecting group, and the carboxylic acid-protecting group may be a commonly known one, for example, "Protective Groups in Organic Synthesis” by Theodora W. Greene , 1981 by John Wiley & Sons. Inc.”, Chapter 5.
• R 1 more preferably has a number of carbon atoms such as methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butoxy, tert-butoxy, 1-ethylpropyloxy, etc.
• n-pentyloxy isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, n-heptyloxy, n- octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 5-propylnonyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy, hexadecyloxy, Linear or branched alkoxy groups with 1 to 18 carbon atoms including heptadecyloxy, octadecyloxy, etc.; 3 to 8 cyclic alkoxy groups with substituents such as phenoxy, 2,6-dimethylphenoxy, 2,6-di-tert-
• R 1 is more preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, a phenoxy group which may have a substituent, a substituent benzyloxy group.
• R 1 is particularly preferably methoxy, tert-butoxy or the like.
• R2 is a hydrogen atom or an alkyl group.
• R 2 is preferably a hydrogen atom or a linear, branched or cyclic alkyl group, specifically, for example, a hydrogen atom, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, linear or branched alkyl groups having 1 to 4 carbon atoms; n-pentyl, isopentyl, neopentyl, n- hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl
• R 2 is more preferably a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or the like. In general formula (2), R 2 is more preferably a hydrogen atom, methyl or the like.
• the compound represented by the general formula (2) has a three-dimensional structure of L-type (compound represented by the general formula (2a) (L-form)) or D-type (the compound represented by the general formula (2b) compound (D-form)), or a mixture of a compound that is L-form and a compound that is D-form.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• the compound represented by the general formula (2) used in the method for producing the organocopper compound of the present invention is obtained by adding zinc to the compound represented by the general formula (3) by a conventionally known method such as Org. . Chem., 1(23), 4254-4261 (2003).
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• X in the compound represented by the general formula (3) is a chlorine atom or a bromine atom
• the compound represented by the general formula (3) is reacted with zinc in the presence of a halogen compound in an organic solvent.
• a compound represented by general formula (2) can be produced.
• the organic solvent is preferably at least one organic solvent selected from the group consisting of aprotic polar solvents, halogen solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents. .
• the amount of the organic solvent used is such that the concentration (M (mol/L)) of the compound represented by the general formula (3) is preferably 0.01M to 5M, more preferably 0.1M to 2M. It should be adjusted so that the concentration of
• the halogen compound is preferably at least one halogen compound selected from the group consisting of halogen and halogenated alkyl.
• Alkyl halides are organic compounds represented by the general formula R a -X a (R a represents an alkyl group and X a represents a halogen atom).
• R a represents an alkyl group, preferably a linear, branched or cyclic alkyl group, specifically, for example, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, linear or branched alkyl groups having 1 to 4 carbon atoms; n-pentyl, isopentyl, neopentyl, n- hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-penta
• X a represents a halogen atom and is at least one halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, more preferably a chlorine atom or bromine is an atom.
• the amount of the halogen compound used is adjusted so that the concentration (M (mol/L)) in the organic solvent is preferably 0.01M to 5M, more preferably 0.1M to 2M. Just do it.
• the amount of zinc used is adjusted so that the concentration (M (mol/L)) in the organic solvent is preferably 0.01M to 5M, more preferably 0.1M to 2M. Just do it.
• the reaction temperature is preferably 0°C to 100°C, preferably 10°C to 80°C, more preferably 20°C to 60°C. And it is sufficient.
• the reaction time is preferably 0.1 hour to 100 hours, preferably 0.1 hour to 50 hours, more preferably 0.1 hour to 10 hours. And it is sufficient.
• the ⁇ -position configuration of the compound represented by the general formula (2) to be obtained maintains the ⁇ -position configuration of the compound represented by the general formula (3) to be used.
• the compound represented by the general formula (2a), or the compound represented by the general formula (2b), or the mixture of the compound represented by the general formula (2a) and the compound represented by the general formula (2b) It can be produced by selecting the compound represented by the general formula (3) to be used.
• the method for producing an organocopper compound of the present invention includes the step of reacting the compound (substrate) represented by the general formula (2) with a copper agent in an organic solvent.
• the organic solvent is preferably at least one organic solvent selected from the group consisting of aprotic polar solvents, halogen solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents. .
• the aprotic polar solvent is preferably acetone, acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or the like.
• the halogen-based solvent is preferably dichloromethane (CH 2 Cl 2 ), trichloromethane (CHCl 3 ), or the like.
• the ether solvent is preferably tetrahydrofuran (THF), dioxane, diethyl ether (Et 2 O), isopropyl ether (IPE), or the like.
• the ester solvent is preferably ethyl acetate (AcOEt) or the like.
• the hydrocarbon-based solvent is preferably n-hexane or the like.
• the aromatic solvent is preferably toluene or the like.
• the organic solvent is more preferably an aprotic polar solvent such as acetone, acetonitrile, DMF or DMSO, an ether solvent (polar solvent) such as THF, dioxane or diethyl ether, or a halogen solvent such as dichloromethane or trichloromethane.
• an aprotic polar solvent such as acetone, acetonitrile, DMF or DMSO
• an ether solvent such as THF, dioxane or diethyl ether
• a halogen solvent such as dichloromethane or trichloromethane.
• the amount of the organic solvent used is such that the concentration (M (mol/L)) of the compound (substrate) represented by the general formula (2) is preferably 0.01 M to 5 M, more preferably 0.1 Adjust so that the concentration is between M and 2M.
• the method for producing the organocopper compound of the present invention includes the step of reacting the compound represented by the general formula (2) with a copper agent in an organic solvent.
• the copper (Cu) in the organocopper compound represented by the general formula (1) of the product produced by the method for producing an organocopper compound of the present invention is copper derived from a copper agent used as a substrate (raw material compound). be.
• the copper agent is preferably , copper (I) chloride, copper (I) bromide, and copper (I) iodide.
• the copper agent is preferably , at least one compound selected from the group consisting of copper (I) chloride, copper (I) bromide, and copper (I) iodide, and from the group consisting of lithium chloride, lithium bromide, and lithium iodide
• the reaction is carried out in the presence (combination) of at least one selected compound.
• the copper agent is preferably copper (I) cyanide.
• the copper agent is preferably copper cyanide (I) (CuCN) and the reaction is carried out in the presence (in combination) of lithium chloride.
• the copper agent is more preferably copper chloride (I ) with lithium chloride.
• the copper agent when producing a compound in which the X in the general formula (1) is a cyano group, is more preferably copper cyanide (I) and chloride It is a combination with lithium.
• the amount of the copper agent used is such that the concentration (M (mol/L)) in the organic solvent is preferably 0.01 M to 5 M, more preferably 0.1 Adjust so that the concentration is between M and 2M.
• the amount of the copper agent to be used is the concentration relative to the compound (substrate) represented by the general formula (2) (when the substrate is 100 mol%), and the molar ratio is as follows: It is preferably 20 mol % to 10,000 mol %, more preferably 80 mol % to 1,000 mol %, still more preferably 90 mol % to 500 mol %.
• the amount of lithium halide (LiCl, LiBr, LiI, etc.) used in the copper agent is equivalent to the compound (substrate) represented by the general formula (2) (substrate 1 equivalent), the molar ratio is preferably 0.2 equivalent to 200 equivalents, more preferably 0.8 equivalents to 20 equivalents, still more preferably 0.9 equivalents to 10 equivalents.
• the amount of the copper agent to be used is as an equivalent to the compound (substrate) represented by the general formula (2) (when the substrate is taken as 1 equivalent), in terms of molar ratio, especially , 1 equivalent of at least one compound selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide and copper (I) cyanide with 2 equivalents of lithium chloride Therefore, the desired organocopper compound represented by the general formula (1) can be obtained with the maximum yield.
• the organocopper compound of the present invention is useful in synthesizing special amino acids, particularly in derivatization to aryl-type special amino acids.
• a new organic copper compound can be produced by using a copper agent, and this organic copper compound is stable. It is useful in synthesizing special amino acids, particularly in derivatization to aryl-type special amino acids.
• the reaction temperature is preferably 0°C to 100°C, preferably 10°C to 80°C, and more preferably 20°C to 60°C.
• the target organocopper compound can be produced while maintaining the three-dimensional structure of the substrate.
• the organocopper compound (L-form) represented by formula (1a) can be produced.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• the organocopper compound represented by the formula (1) maintaining the ratio of the L- and D-isomers A mixture of the L and D forms of is produced.
• Organic copper compound The organic copper compound of the present invention has the following general formula (1):
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• the organocopper compound of the present invention is produced according to the method for producing the organocopper compound of the present invention by a step of reacting the compound represented by the general formula (2) with a copper agent in an organic solvent. I can do things.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group.
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group.
• R 1 is a hydroxyl group or a protective group for carboxylic acid.
• R 1 is preferably a carboxylic acid-protecting group, and the carboxylic acid-protecting group may be a commonly known one, such as "Protective Groups in Organic Synthesis” by Theodora W. Greene. , 1981 by John Wiley & Sons. Inc.”, Chapter 5.
• R 1 more preferably has a number of carbon atoms such as methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butoxy, tert-butoxy, 1-ethylpropyloxy, etc.
• n-pentyloxy isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, n-heptyloxy, n- octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 5-propylnonyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy, hexadecyloxy, Linear or branched alkoxy groups with 1 to 18 carbon atoms including heptadecyloxy, octadecyloxy, etc.; 3-8 cyclic alkoxy groups with substituents such as phenoxy, 2,6-dimethylphenoxy, 2,6-di-tert-but
• R 1 is more preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, a phenoxy group which may have a substituent, or a substituent. benzyloxy group.
• R 1 is particularly preferably methoxy, tert-butoxy or the like.
• R2 is a hydrogen atom or an alkyl group.
• R 2 is preferably a hydrogen atom or a linear, branched or cyclic alkyl group, specifically, for example, a hydrogen atom, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, linear or branched alkyl groups having 1 to 4 carbon atoms; n-pentyl, isopentyl, neopentyl, n- hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl,
• R 2 is more preferably a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or the like. In general formula (1), R 2 is more preferably a hydrogen atom, methyl or the like.
• the compound represented by the general formula (1) has an L-type (organic copper compound represented by the general formula (1a)) or a D-type (organic copper compound represented by the general formula (1b)). compounds), or mixtures of Forms L and D.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• X is a chlorine atom, a bromine atom, a cyano group, or a trifluoromethanesulfonate group
• Prot is a protecting group selected from a 9-fluorenylmethyloxycarbonyl protecting group, a tert-butoxycarbonyl protecting group, an allyloxycarbonyl protecting group, or a benzyloxycarbonyl protecting group
• R 1 is a hydroxyl group or a carboxylic acid-protecting group
• R2 is a hydrogen atom or an alkyl group.
• the organocopper compound of the present invention has excellent stability and is useful in synthesizing special amino acids, particularly in derivatization to allylic special amino acids.
• the present invention is not limited to these.
• MeO represents a methoxy group
• t-BuO represents a tert-butoxy group
• DMSO dimethyl sulfoxide
• DMSO dimethyl sulfoxide
• DMSO dimethyl sulfoxide
• DMSO dimethyl sulfoxide
• the organocopper compound of the present invention is useful in synthesizing special amino acids, particularly in derivatization to allylic special amino acids.

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