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WO2021177343A1 - Procédé de libération d'un composé - Google Patents

Procédé de libération d'un composé Download PDF

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Publication number
WO2021177343A1
WO2021177343A1 PCT/JP2021/008120 JP2021008120W WO2021177343A1 WO 2021177343 A1 WO2021177343 A1 WO 2021177343A1 JP 2021008120 W JP2021008120 W JP 2021008120W WO 2021177343 A1 WO2021177343 A1 WO 2021177343A1
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formula
alkyl
compound
compound represented
general formula
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Japanese (ja)
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渡邊賢司
丹羽節
細谷孝充
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RIKEN
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RIKEN
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
    • C07C33/22—Benzylalcohol; phenethyl alcohol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/04—Phenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 releasing a compound.
  • a caged compound is known as a compound that protects a physiologically active substance with a protecting group that can be deprotected with light and temporarily loses its activity.
  • a protecting group that can be deprotected with light and temporarily loses its activity.
  • the original bioactive substance can be instantly made to appear at a desired location, so it is used for molecular biology experiments by administration to cells, etc. There is.
  • Non-Patent Document 1 reports a compound having an indolizine moiety.
  • This document discloses that a compound having an indolizine moiety is irradiated with 500 W of light having a wavelength of 500 nm or more in the presence of rose bengal or methylene blue as a photosensitizer to perform photooxidation.
  • 500 W of light having a wavelength of 500 nm or more in the presence of rose bengal or methylene blue as a photosensitizer to perform photooxidation.
  • this photooxidation has a long reaction time of 9 to 20 hours, and it is not practical to use a compound having this indolizine moiety as a caged compound.
  • an object of the present invention is to provide a method capable of releasing a compound by light irradiation for a short time.
  • the present invention This is a method of releasing the compound represented by the general formula (II) by irradiating the caged compound represented by the general formula (I) with light in the presence of a photosensitizer.
  • the compound represented by the general formula (II) is a compound represented by the general formula (IIA).
  • the compound represented by the general formula (II) is a compound represented by the general formula (IIB).
  • X is a bond
  • the compound represented by the general formula (II) is a compound represented by the general formula (IIC).
  • R 1 , R 2 , R 3 , R 4 and R 5 are independent of each other. Hydrogen atom, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH (C 1-6 alkyl) 2 , -O- (CH 2 ) n- C ⁇ CH [In the formula, n is an integer of 1 to 6] -(CH 2 ) m- NH 2 [in the formula, m is an integer from 1 to 6], -CN, -NO 2 , -NH 2 , -Br, -Cl, -C 6-12 aryl, -C 2-6 alkenyl, -C 2-6 alkynyl, The group represented by the formula (a),
  • R 21 is C 1-6 alkyl] Or a group represented by the formula (b).
  • l is an integer from 1 to 12
  • R is -C 1-6 alkyl-C 6-12 aryl, -C 6-12 aryl, substituted with CN or NO 2 -C 1-6 alkyl C 6-12 aryl, -(CH 2 CH 2 O) q (CH 2 ) t- Y
  • q is an integer of 1 to 12
  • t is an integer of 1 to 6, and Y is a halogen atom.
  • the method of the present invention has an advantage that the compound can be released by light irradiation for a short time.
  • the present inventors have found that when a compound having a specific substituent at the indolizine site is irradiated with light for a short time in the presence of a specific photosensitizer, the compound is released with high efficiency. completed.
  • the compound having a specific substituent at the indolizine site is a caged compound represented by the general formula (I) (hereinafter, may be referred to as “compound of formula (I)” or “compound (I)”). be.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independent of each other. Hydrogen atom, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH (C 1-6 alkyl) 2 , -O- (CH 2 ) n- C ⁇ CH [In the equation, n is an integer of 1 to 6, preferably an integer of 1 to 3] -(CH 2 ) m- NH 2 [In the formula, m is an integer of 1 to 6, preferably an integer of 1 to 3], -CN, -NO 2 , -NH 2 , -Br, -Cl, -C 6-12 aryl, -C 2-6 alkenyl, -C 2-6 alkynyl, The group represented by the formula (a),
  • R 21 is C 1-6 alkyl] Or a group represented by the formula (b).
  • l is an integer of 1 to 12, preferably an integer of 1 to 6
  • R is -C 1-6 alkyl-C 6-12 aryl, -C 6-12 aryl, substituted with CN or NO 2 -C 1-6 alkyl C 6-12 aryl, -(CH 2 CH 2 O) q (CH 2 ) t- Y
  • q is an integer of 1 to 12, preferably an integer of 2 to 4, and t is an integer of 1 to 6. It is preferably 5, and Y is a halogen atom.
  • p is an integer of 1 to 12, preferably an integer of 3 to 6, and R 22 is a C 1-6 alkyl].
  • X is O, NH, or a bond.
  • the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, preferably a fluorine atom, a chlorine atom, and a bromine atom.
  • C 1-6 alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like, and methyl and ethyl are preferable.
  • Examples of OC 1-6 alkyl include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, and methoxy is preferable. , Ethoxy.
  • SC 1-6 alkyl examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentilthio, tert-pentylthio, hexylthio and the like, preferably methylthio and ethylthio. be.
  • NH (C 1-6 alkyl) 2 examples include NH (methyl) 2 , NH (ethyl) 2 , NH (propyl) 2 , NH (butyl) 2 , NH (hexyl) 2, and the like, preferably. NH (methyl) 2 and NH (ethyl) 2 .
  • C 6-12 aryl examples include phenyl, naphthyl and the like, and phenyl is preferable.
  • -C 6-12 aryl substituted with CN or NO 2 is, for example, an arbitrary position of phenyl, naphthyl substituted with CN or NO 2.
  • C 1-6 alkyl C 6-12 aryl examples include, for example, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl, naphthylethyl and the like, preferably phenylmethyl (phenylmethyl).
  • benzyl phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl, naphthylethyl and the like, preferably phenylmethyl (phenylmethyl).
  • Examples of the C 2-6 alkenyl include vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl and the like, and allyl is preferable.
  • C 2-6 alkynyl examples include ethylenyl, propyrenyl, butylene, pentylene, hexylene and the like, and pentylene is preferable.
  • the compound of formula (I) is used when X is O.
  • R 1 is -OC 1-6 alkyl
  • R 2 is a hydrogen atom or -OC 1-6 alkyl
  • R 3 is a hydrogen atom or -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 6-12 aryl, -C 1-6 alkyl C 6-12 aryl, It is preferably -C 6-12 aryl substituted with -CN or NO 2 , or a group represented by the formula (c).
  • the compound of the formula (I) is used when X is O.
  • R 1 is -C 1-6 alkyl
  • R 2 , R 3 , R 4 and R 5 are hydrogen atoms
  • R is preferably -C 6-12 aryl, preferably
  • the compound of the following formula (20) is more preferable.
  • R 1 is a hydrogen atom, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2
  • R 2 is -OC 1-6 alkyl
  • R 3 is a hydrogen atom
  • R 4 is-(CH 2 ) m- NH 2 [in the formula, m is an integer from 1 to 6], -CN, -NO 2 , -NH 2 , or a group represented by the formula (a).
  • R 5 is a hydrogen atom
  • R is preferably -C 1-6 alkyl, preferably
  • R 21 is C 1-6 alkyl
  • the compound of the formula (I) is used when X is O.
  • R 1 is -OC 1-6 alkyl
  • R 2 is a hydrogen atom
  • R 3 is ⁇ O ⁇ (CH 2 ) n ⁇ C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 6-12 aryl, or preferably from been -C 6-12 aryl substituted with -CN or NO 2,
  • the compound of the following formula (15) and the compound of the formula (16) are more preferable.
  • the compound of the formula (I) is used when X is O.
  • R 1 is -SC 1-6 alkyl, or -NH (C 1-6 alkyl) 2
  • R 2 is -OC 1-6 alkyl
  • R 3 is a hydrogen atom
  • R 4 is -NO 2
  • R 5 is a hydrogen atom
  • R is preferably -C 1-6 alkyl, preferably
  • the compound of the following formula (28) and the compound of the formula (31) are more preferable.
  • the compound of the formula (I) is used when X is NH.
  • R 1 is -OC 1-6 alkyl
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom or -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 1-6 alkyl C 6-12 aryl, or-(CH 2 CH 2 O) q (CH 2 ) t- Y
  • q is an integer of 1 to 12 and t is an integer of 1 to 6.
  • Y is a halogen atom.
  • Is preferable The compound of the following formula (7) is more preferable.
  • R 1 is ⁇ OC 1-6 alkyl.
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom, -O- (CH 2 ) n- C ⁇ CH [in the formula, n is an integer of 1 to 6], or a group represented by the formula (b).
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 6-12 aryl, -C 6-12 aryl, substituted with CN or NO 2 -C 1-6 alkyl C 6-12 aryl, A group represented by the formula (d), or
  • the compound of formula (I) When the compound of formula (I) is irradiated with light in the presence of a photosensitizer, it is referred to as a compound represented by the general formula (II) (hereinafter, referred to as "compound of formula (II)" or “compound (II)". There is) is obtained.
  • X is an oxygen atom, that is, "O” in the formula
  • the compound of the formula (II) is further decomposed to release CO 2 to become a compound of the general formula (IIA).
  • X When X is NH in the formula, the compound of the formula (II) is further decomposed to release CO 2 to become a compound of the general formula (IIB).
  • the compound of the formula (II) is represented by the general formula (IIC) when X is a bond, that is, "-" in the formula.
  • the photosensitizers used in the present invention include, for example, methylene blue, phthalocyanine and its derivatives, fluorescein, 5-carboxyfluorescein, rhodamine B, rose bengal, 9-mesityl-10-methylacrydinium perchlorate, 6-bromo. -4-Hydroxycoumarin, as well as tris (bipyridine) ruthenium dichloride (Ru (II) (bpy) 2 Cl 2 ) and derivatives thereof.
  • irradiating light having a wavelength of 660 nm it is preferable to use methylene blue, phthalocyanine tetrasulfonic acid, and phthalocyanine silicon (IV) dichloride as the photosensitizer.
  • irradiating light having a wavelength of 442 nm it is preferable to use tris (bipyridine) ruthenium dichloride and its derivatives, fluorescein, rose bengal, and phthalocyanine as a photosensitizer.
  • the photosensitizer is used, for example, 0.1 mol% to 10 mol%, preferably 0.5 mol% to 5 mol%, and more preferably 1 mol% to 2 mol% with respect to the compound of the formula (I).
  • the compound of formula (I) and the photosensitizer may be in the form of a solution dissolved in a solvent.
  • a solvent alcohols such as methanol and ethanol, acetonitrile, dimethyl sulfoxide, water, serum and the like can be used.
  • the concentration of the caged compound of formula (I) is, for example, 0.01 mM to 100 mM, preferably 0.1 mM to 10 mM, more preferably 1 mM to 2 mM.
  • the light irradiation is performed at, for example, 0 ° C to 80 ° C, preferably 10 ° C to 50 ° C, and more preferably 25 ° C to 37 ° C.
  • a light source having a maximum wavelength of 660 nm When irradiating light at 660 nm, a light source having a maximum wavelength of 660 nm may be used. Specifically, H160 Tuna Flora (manufactured by Kessil) can be used when irradiating light at 660 nm. When irradiating light at 442 nm, a light source having a maximum wavelength of 442 nm may be used. Specifically, PR160-440 (manufactured by Kessil) can be used when irradiating light at 442 nm.
  • light irradiation is performed, for example, for 15 seconds to 60 minutes, preferably 20 seconds to 10 minutes, and more preferably 30 seconds to 180 seconds. That is, according to the method for releasing a compound of the present invention, the compound can be released by light irradiation for a short time. Furthermore, according to the method for emitting a compound of the present invention, it is possible to release the compound by irradiating with long wavelength light.
  • the present invention also comprises a compound represented by the general formula (III) (hereinafter, may be referred to as a "compound of the formula (III)” or a “compound (III)”) and a compound represented by the general formula (II).
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
  • EDC / HCl 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride
  • DMT-MM 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride
  • DMT-MM O- [ (Ethoxycarbonyl) Cyamethyleneamino] -N, N, N', N'-Tetramethyluronium Hexafluorophosphate (HOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) Dimethylaminomorpholino Presence of condensing agents such as carbenium hexafluorophosphate (COMU) or O- (benzyltriazol-1-yl) -N,
  • the condensation step can be carried out by mixing the compound of formula (II) with an amine compound and a condensing agent such as HATU, and then adding the compound of formula (III) and stirring.
  • amine for example, isopropylamine, triethylamine, N, N-diisopropylethylamine can be used.
  • the amine is used, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the compound of formula (II).
  • the condensing agent such as HATU is used, for example, 1 to 10 equivalents, preferably 1 to 1.5 equivalents, relative to the compound of the formula (II).
  • the compound of formula (III) is used, for example, 1 to 10 equivalents, preferably 1 to 1.2 equivalents, relative to the compound of formula (II).
  • the reaction is carried out, for example, at room temperature to 60 ° C., and is preferably carried out at room temperature. The room temperature is 23 to 27 ° C.
  • X is a bond
  • R 1 is -OC 1-6 alkyl
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom or -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is a group represented by the formula (d) or
  • p is an integer from 1 to 12 and R 22 is C 1-6 alkyl
  • composition for producing a caged compound of formula (I) relates to a compound of formula (III), a compound of formula (II), and O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexa.
  • HATU Fluorophosphate
  • EDC / HCl 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) ) -4-Methylmorpholinium chloride
  • DMT-MM O-[(ethoxycarbonyl) cyanomethyleneamino] -N, N, N', N'-tetramethyluronium hexafluorophosphate
  • HOTU 1-Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), or O- (benzyltriazol-1-yl) -N, N, N', N'-
  • a composition for producing a caged compound of the formula (I) of the present invention which comprises a condensing agent such as
  • This composition is a composition containing a raw material for the method for producing a caged compound of the formula (I) of the present invention, and therefore, a compound of the formula (III), a compound of the formula (II), and a condensing agent such as HATU.
  • a compound of the formula (III), a compound of the formula (II), and a condensing agent such as HATU.
  • the present invention also provides a method for producing a caged compound of the formula (I) of the present invention, which comprises a step of condensing a compound represented by the general formula (III) and a compound represented by the general formula (IV). ..
  • R 1 , R 2 , R 3 , R 4 , R 5 , R, and X are the same as those in formula (I), where Y is a halogen atom or N-hydroxysuccinimide ester. Is. ]
  • the condensation step can be carried out by mixing the compound of formula (III) and the compound of formula (IV).
  • the compound of formula (IV) is used, for example, 1 to 10 equivalents, preferably 1 to 1.2 equivalents, relative to the compound of formula (III).
  • the reaction is carried out, for example, at room temperature to 60 ° C., and is preferably carried out at room temperature.
  • the room temperature is 23 to 27 ° C.
  • X is O or a bond
  • R 1 is -C 1-6 alkyl, or -OC 1-6 alkyl
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom or -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 6-12 aryl, It is preferably -C 6-12 aryl substituted with -CN or NO 2 , or -C 1-6 alkyl C 6-12 aryl.
  • the present invention also provides a composition for producing a caged compound of the formula (I) of the present invention, which comprises a compound of the formula (III) and a compound of the formula (IV).
  • This composition is a composition containing a raw material for the method for producing a caged compound of the formula (I) of the present invention. Therefore, regarding the type and amount of the compound of the formula (III) and the compound of the formula (IV), It is preferable to follow the types and amounts described in the production method.
  • R 1 is ⁇ OCH 3 and R 4 is a hydrogen atom.
  • R 4 is a hydrogen atom.
  • the present invention also comprises a compound represented by the general formula (V) (hereinafter, may be referred to as a "compound of the formula (V)”) and a compound represented by the general formula (VI) (hereinafter, "formula (VI)".
  • V general formula
  • VI general formula
  • a method for producing a caged compound of the formula (I) of the present invention which comprises a step of condensing with (sometimes referred to as a "compound of)").
  • the reaction step was carried out by Dominik S. et al. Allgauer et al. , Journal of the American Chemical Society, Vol. 139, p. It is carried out with reference to 13318 to 13329. Specifically, the compound of formula (V) and the compound of formula (VI) are mixed in dimethyl sulfoxide (DMSO) at 20 ° C. for 1 hour in the presence of Na 2 CO 3. Then chloranil (2 eq) is added and mixed for an additional hour to give the compound of formula (I).
  • DMSO dimethyl sulfoxide
  • R 2 is -OC 1-6 alkyl
  • R 3 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R is -C 1-6 alkyl
  • X is O
  • R 1 is a hydrogen atom, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2
  • R 4 is preferably -CN or -NO 2.
  • R 11 and R 12 are independent of each other Hydrogen atom, -OC 1-6 alkyl, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2
  • R 13 is -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6, preferably an integer of 1 to 3].
  • R 14 is Hydrogen atom, -(CH 2 ) m- NH 2 [In the formula, m is an integer of 1 to 6, preferably an integer of 1 to 3], -NO 2 or -NH 2
  • R 15 is a hydrogen atom
  • R' is A -C 1-6 alkyl -C 6-12 aryl, or -C 6-12 aryl substituted with -NO 2,
  • X'is O, or R 11 and R 12 are independent of each other.
  • R 13 is It is a hydrogen atom
  • R 14 is -(CH 2 ) m- NH 2 [In the formula, m is an integer of 1 to 6, preferably an integer of 1 to 3], -CN, -NO 2 or -NH 2
  • R 15 is a hydrogen atom R'is -C 1-6 alkyl, X'is O.
  • the compound of formula (X) is X'is O, R 11 is -OC 1-6 alkyl
  • R 12 is a hydrogen atom
  • R 13 is ⁇ O ⁇ (CH 2 ) n ⁇ C ⁇ CH [in the equation, n is an integer of 1 to 6].
  • R 14 is a hydrogen atom
  • R 15 is a hydrogen atom R 'is -C 6-12 aryl, or preferably from been -C 6-12 aryl substituted with -NO 2,
  • the compound of the following formula (15) or the compound of the following formula (16) is more preferable.
  • the compound of the formula (X) is used.
  • X' is O
  • R 11 is a hydrogen atom
  • R 12 is -OC 1-6 alkyl
  • R 13 is a hydrogen atom
  • R 14 is-(CH 2 ) m- NH 2 [in the formula, m is an integer of 1 to 6]
  • R 15 is a hydrogen atom R'preferably ⁇ C 1-6 alkyl
  • the compound of the following formula (24), the compound of the formula (25), the compound of the formula (28), the compound of the formula (29) or the compound of the formula (31) are more preferable.
  • the present invention provides a method for producing a compound of the formula (X) of the present invention, which comprises a step of condensing a compound represented by the general formula (XI) and a compound represented by the general formula (XII).
  • Compound of formula (X) [In the formula, R 11 and R 12 are independent of each other. Hydrogen atom, -OC 1-6 alkyl, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2 R 13 is -O- (CH 2 ) n- C ⁇ CH [in the equation, n is an integer of 1 to 6, preferably an integer of 1 to 3].
  • R 14 is Hydrogen atom, -(CH 2 ) m- NH 2 [In the formula, m is an integer of 1 to 6, preferably an integer of 1 to 3], -NO 2 or -NH 2 R 15 is a hydrogen atom R'is A -C 1-6 alkyl -C 6-12 aryl, or -C 6-12 aryl substituted with -NO 2,, X'is O] can be produced as follows.
  • the condensation step can be carried out by mixing the compound of formula (XI) and the compound of formula (XII).
  • the compound of formula (XII) is used, for example, 1 to 10 equivalents, preferably 1 to 1.2 equivalents, relative to the compound of formula (XI).
  • the reaction is carried out, for example, at room temperature to 60 ° C., and is preferably carried out at room temperature.
  • the room temperature is 23 to 27 ° C.
  • R 11 and R 12 are independent of each other. Hydrogen atom, -OC 1-6 alkyl, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2 R 13 is a hydrogen atom R 14 is -(CH 2 ) m- NH 2 [In the formula, m is an integer of 1 to 6, preferably an integer of 1 to 3], -CN, -NO 2 or -NH 2 R 15 is a hydrogen atom R'is -C 1-6 alkyl and X'is O] can be produced as follows.
  • a compound represented by the general formula (VII) (hereinafter, may be referred to as a "compound of the formula (VII)") and a compound represented by the general formula (VIII) (hereinafter, a compound of the formula (VIII) ".
  • the compound of formula (X) can be obtained by condensing with (sometimes referred to as).
  • the reaction step was carried out by Dominik S. et al. Allgauer et al. , Journal of the American Chemical Society, Vol. 139, p. It is carried out with reference to 13318 to 13329. Specifically, the compound of formula (VII) and the compound of formula (VIII) are mixed in dimethyl sulfoxide (DMSO) at 20 ° C. for 1 hour in the presence of Na 2 CO 3. Then, chloranil (2 equivalents) is added and mixed for another hour to obtain the compound of formula (X).
  • DMSO dimethyl sulfoxide
  • R 12 is -OC 1-6 alkyl
  • R 13 is a hydrogen atom
  • R 15 is a hydrogen atom
  • R 11 is a hydrogen atom, -SC 1-6 alkyl or -NH (C 1-6 alkyl) 2
  • R 14 is preferably -CN or -NO 2.
  • THF Tetrahydrofuran
  • DMF Dimethylformamide
  • DMSO Dimethyl sulfoxide
  • the room temperature was 23 to 27 ° C. in the following examples, production examples, reactions and the like.
  • Step 1 Production of 1- (2-ethoxy-2-oxoethyl) -2-methyl-1-pyridium bromide (1)
  • 2-methoxyindolizine (2) (44.2 mg, 0.300 mmol, 1.0 equiv) and THF (0.50 mL) were added to a 4 mL vial.
  • the reaction vessel was transferred to an ice bath, a THF solution (1.0 mL) of phenylchloroformate (56.6 mg, 0.362 mmol, 1.2 quiv) was added dropwise, and then the mixture was stirred at room temperature for 4 hours.
  • ethyl acetate (15 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the reaction solution, and extraction was carried out three times.
  • 2-methoxyindolizine (2) (58.9 mg, 0.400 mmol, 1.0 equiv) and THF (0.50 mL) were added to a 4 mL vial.
  • the reaction vessel was transferred to an ice bath, a THF solution (1.0 mL) of benzyl chloroformate (82.6 mg, 0.484 mmol, 1.2 equiv) was added dropwise, and then the mixture was stirred at 40 ° C. for 20 hours.
  • ethyl acetate (15 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the reaction solution, and extraction was carried out three times.
  • 2-methoxyindolizine (2) (44.2 mg, 0.300 mmol, 1.0 equiv) and THF (0.50 mL) were added to a 4 mL vial.
  • the reaction vessel was transferred to an ice bath, a THF solution (1.0 mL) of benzoyl chloride (50.4 mg, 0.359 mmol, 1.2 equiv) was added dropwise, and then the mixture was stirred at room temperature for 1 hour.
  • ethyl acetate (15 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the reaction solution, and extraction was carried out three times.
  • 2-methoxyindolizine (2) (44.2 mg, 0.300 mmol, 1.0 equiv) and THF (0.50 mL) were added to a 4 mL vial.
  • the reaction vessel was transferred to an ice bath, a THF solution (1.0 mL) of 4-nitrophenyl chloroformate (72.6 mg, 0.334 mmol, 1.1 equiv) was added dropwise, and then the mixture was stirred at room temperature for 4 hours.
  • ethyl acetate (15 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the reaction solution, and extraction was carried out three times.
  • Step 2 Production of 1- (2-ethoxy-2-oxoethyl) -2-methyl-5- (2-propynyl-1-oxy) -1-pyridinium bromide (13)
  • 2-Methoxy-6- (2-propynyl-1-oxy) indolizine (14) (30.2 mg, 0.150 mmol, 1.0 equiv) and THF (0.75 mL) were added to a 4 mL vial under an argon atmosphere. ..
  • the reaction vessel was transferred to an ice bath, a THF solution (0.75 mL) of phenylchloroformate (25.8 mg, 0.165 mmol, 1.1 equiv) was added dropwise, and then the mixture was stirred at room temperature for 4 hours.
  • 2-Methoxy-6- (2-propynyl-1-oxy) indolizine (14) (80.5 mg, 0.400 mmol, 1.0 equiv), THF (2.0 mL) and N, in a 4 mL vial under an argon atmosphere.
  • N-diisopropylethylamine (83.6 ⁇ L, 0.48 mmol, 1.2 equiv) was added.
  • the reaction vessel was transferred to an ice bath, a THF solution (1.0 mL) of 4-nitrophenyl chloroformate (96.7 mg, 0.480 mmol, 1.2 quiv) was added dropwise, and then the mixture was stirred at room temperature for 4 hours.
  • the compound (23) is described in the literature (Wiles, J. A .; Phadke, A. S .; Deshpande, M .; Agarwal, A .; Chen, D .; Gadhachanda, V. R .; Hashimoto, A. ; Pais, G .; Wang, Q .; Wang, X .; Greenlee, W. PCT Int. Appl. 2017 (WO2017 / 035409)).
  • tert-butyl 1- (aminomethyl) -7-methoxyindolizine-3-carboxylate (25) (53.3 mg, 0.193 mmol, 1.0 quiv) was added, and the mixture was stirred at room temperature for 6 hours.
  • ethyl acetate (10 mL) and saturated brine (10 mL) were added to the reaction solution, and extraction was carried out three times.
  • the combined organic layer was dried over sodium sulfate and distilled off under reduced pressure.
  • HRMS (ESI + ) m / z 472.2444 calculated as C 25 H 34 N 3 O 6 + , 472.2442, [M + H] + ).
  • H160 Tuna Flora (maximum wavelength 660 nm) or PR160-440 (maximum wavelength 442 nm) manufactured by Kessil was used as an LED light source.
  • the solution was transferred to an NMR tube and 1 H-NMR measurement was carried out.
  • the reaction yield was determined from the ratio of the integrated values of the phenol and compound (11) produced from the reaction and the internal standard tert-butyl alcohol. The results obtained are shown in Tables 1 and 2 below.
  • reaction yield was determined from the peak area ratio of 2-naphthol of the standard substance to the alcohol, carboxylic acid or amine produced by the reaction.
  • the photocaged compound of the present invention can release the compound in a short time by photooxidation at a long wavelength (see entries 1 to 9).
  • the compound which is not the photo-caged compound of the present invention does not undergo photo-oxidation even when irradiated with light, and as a result, the compound is not released by photo-oxidation (see entry 10).
  • the photocaged compound of the present invention was photooxidized in a short time only under the conditions of a photosensitizer and light irradiation.
  • the k obs of the photooxidation reaction of olefin 55 under the same light irradiation conditions was obtained as 0.0136s -1. It was confirmed that the photooxidation of indolizine was 7.6 times faster than the photooxidation of olefins. Therefore, according to the method for releasing a compound of the present invention, the compound can be released by light irradiation for a short time. Furthermore, according to the method for emitting a compound of the present invention, it is possible to release the compound by irradiating with long wavelength light.
  • the present invention can release a compound by light irradiation for a short time, it can be expected to be applied to release a biologically active substance in a living body.

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé selon lequel un composé encagé représenté par la formule générale (I) est irradié avec de la lumière en présence d'un photosensibilisateur pour ainsi libérer un composé représenté par la formule générale (II).　Dans les cas où X est O, le composé représenté par la formule générale (II) est un composé représenté par la formule générale (IIA). Dans les cas où X est NH, le composé représenté par la formule générale (II) est un composé représenté par la formule générale (IIB). Dans les cas où X est une liaison, le composé représenté par la formule générale (II) est un composé représenté par la formule générale (IIC).
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