WO2017155042A1 - Dithienophosphorine compound and fluorescent dye produced using same - Google Patents
Dithienophosphorine compound and fluorescent dye produced using same Download PDFInfo
- Publication number
- WO2017155042A1 WO2017155042A1 PCT/JP2017/009490 JP2017009490W WO2017155042A1 WO 2017155042 A1 WO2017155042 A1 WO 2017155042A1 JP 2017009490 W JP2017009490 W JP 2017009490W WO 2017155042 A1 WO2017155042 A1 WO 2017155042A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- optionally substituted
- general formula
- dithienophosphorine
- Prior art date
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 title claims description 170
- 238000010521 absorption reaction Methods 0.000 claims abstract description 27
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 150000001450 anions Chemical class 0.000 claims description 11
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 11
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 229960002017 echothiophate Drugs 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- HKNRNTYTYUWGLN-UHFFFAOYSA-N dithieno[3,2-a:2',3'-d]thiophene Chemical compound C1=CSC2=C1SC1=C2C=CS1 HKNRNTYTYUWGLN-UHFFFAOYSA-N 0.000 claims 1
- BJOLKYGKSZKIGU-UHFFFAOYSA-N ecothiopate Chemical compound CCOP(=O)(OCC)SCC[N+](C)(C)C BJOLKYGKSZKIGU-UHFFFAOYSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 27
- 238000006862 quantum yield reaction Methods 0.000 abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 17
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 10
- 239000001022 rhodamine dye Substances 0.000 abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 4
- 239000011574 phosphorus Substances 0.000 abstract description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 166
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- -1 Dithienothiophene phospholine compound Chemical class 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 29
- 239000013256 coordination polymer Substances 0.000 description 28
- 239000003480 eluent Substances 0.000 description 28
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000002835 absorbance Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 20
- 239000012298 atmosphere Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 16
- 238000000862 absorption spectrum Methods 0.000 description 15
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical group CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 14
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- 239000012445 acidic reagent Substances 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 125000000304 alkynyl group Chemical group 0.000 description 12
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 12
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- 230000008859 change Effects 0.000 description 11
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- 238000004007 reversed phase HPLC Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
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- 150000002170 ethers Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 125000003368 amide group Chemical group 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 125000004185 ester group Chemical group 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 238000002189 fluorescence spectrum Methods 0.000 description 8
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 7
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- MNKYQPOFRKPUAE-UHFFFAOYSA-N chloro(triphenyl)silane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 MNKYQPOFRKPUAE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- OSXYHAQZDCICNX-UHFFFAOYSA-N dichloro(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](Cl)(Cl)C1=CC=CC=C1 OSXYHAQZDCICNX-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004770 highest occupied molecular orbital Methods 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
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- YAMQOOCGNXAQGW-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=CC=[C-]1 YAMQOOCGNXAQGW-UHFFFAOYSA-M 0.000 description 1
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- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- DHWBYAACHDUFAT-UHFFFAOYSA-N tricyclopentylphosphane Chemical compound C1CCCC1P(C1CCCC1)C1CCCC1 DHWBYAACHDUFAT-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- IGNTWNVBGLNYDV-UHFFFAOYSA-N triisopropylphosphine Chemical compound CC(C)P(C(C)C)C(C)C IGNTWNVBGLNYDV-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Images
Classifications
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6578—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and sulfur atoms with or without oxygen atoms, as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
Definitions
- the present invention relates to a dithienophosphorine compound and a fluorescent dye using the same.
- organic molecules having absorption and fluorescence maximum wavelengths in this region (620 nm or more) are attracting attention in deep observation of living tissue.
- Organic molecules that exhibit fluorescence in the near-infrared region have high importance beyond the framework of applications such as bioimaging fluorescent probes and fluorescent materials for organic EL devices. So far, many near-infrared fluorescent organic molecules are known based on the skeletons of classic fluorescent dyes such as cyanine dyes, squalin dyes, porphyrin dyes, and phthalocyanine dyes.
- indocyanine green is one of the most widely used near-infrared fluorescent dyes from the viewpoint of a fluorescent probe.
- ICG indocyanine green
- a fluorescein dye has an absorption maximum wavelength of 491 nm, a fluorescence maximum wavelength of 510 nm, and a quantum yield of 0.85 (Non-Patent Document 1), but for bioimaging, it has a wavelength in the deep red to near infrared region.
- Non-Patent Document 1 Non-Patent Document 1
- it since it is necessary to show absorption and fluorescence, it is required to further increase the absorption maximum wavelength and the fluorescence maximum wavelength.
- the present invention provides a fluorescent dye having an absorption maximum and a fluorescence maximum at a high wavelength, a high fluorescence quantum yield, high stability to light, and capable of introducing various substituents. With the goal.
- the present inventors have replaced the benzene ring portion of the rhodamine dye with a thiophene skeleton, and also replaced the oxygen atom in the skeleton with a phosphorus-containing group, thereby achieving an absorption maximum and a fluorescence maximum at a high wavelength. And having high fluorescence quantum yield, high stability to light, and found that various substituents can be introduced.
- the present invention has been completed by further research based on such knowledge. That is, the present invention includes the following configurations.
- R 1 represents the general formula (2A) or (2B):
- R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group;
- Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.
- R 2 is the general formula (3A), (3B) or (3C):
- R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group.
- R 9 represents a hydrogen atom or an optionally substituted alkyl group
- Y represents an oxygen atom or a sulfur atom.
- R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group.
- R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
- X represents an anion.
- n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B).
- Item 2 The dithienophosphorine compound according to Item 1, wherein R 1 in the general formula (1) is a group represented by the general formula (2A).
- Item 3 The dithienophosphorine according to Item 2, wherein in the general formula (1), R 7 is an aryl group which may be substituted.
- Item 4 The dithienophosphorine compound according to any one of Items 1 to 3, wherein, in the general formula (1), R 2 is a group represented by the general formula (3A), and n is 1.
- Item 5 The dithienophosphorine compound according to Item 4, wherein Y in the general formula (1) is an oxygen atom.
- Item 6 The dithienophosphorine compound according to Item 4 or 5, wherein, in the general formula (1), R 8 is an optionally substituted aryl group.
- Item 7. The dithienophosphorine compound according to any one of Items 1 to 6, wherein in the general formula (1), R 3 and R 4 are both hydrogen atoms.
- Item 8 The dithienophosphorine compound according to any one of Items 1 to 7, wherein, in the general formula (1), R 5 and R 6 are the same or different and each is a hydrogen atom or an optionally substituted alkyl group.
- Item 9 The dithienophosphorine compound according to any one of Items 1 to 8, which has an absorption maximum wavelength at 650 to 850 nm.
- Item 10 The dithienophosphorine compound according to any one of Items 1 to 9, which has a fluorescence maximum wavelength at 750 to 1000 nm.
- Item 11 A fluorescent dye containing the dithienophosphorine compound according to any one of Items 1 to 10.
- the thiophene-containing compound of the present invention has an absorption maximum and a fluorescence maximum at a high wavelength by replacing the benzene ring portion of the rhodamine dye with a thiophene skeleton and replacing the oxygen atom in the skeleton with a phosphorus-containing group, and has a high fluorescence. Has quantum yield and high stability to light.
- various groups can be introduced according to the required characteristics.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 1 (compound 1 + .TFA ⁇ ) at pH 4.0.
- FIG. 4 is an ultraviolet-visible near-infrared absorption spectrum of the dithienophosphorine compound of Example 2 (compound 6 + .TFA ⁇ ) at pH 4.0.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 3 (compound 8a + .TFA ⁇ ) at pH 7.4.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 1 (compound 1 + .TFA ⁇ ) at pH 4.0.
- FIG. 4 is an ultraviolet-visible near-infrared absorption spectrum of the dithienophosphorine compound of Example 2 (compound 6 + .TF
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 3 (compound 8b + .TFA ⁇ ) at pH 7.4.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 3 (compound 8c + .TFA ⁇ ) at pH 7.4.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 3 (compound 8d + .TFA ⁇ ) at pH 7.4.
- FIG. 4 shows an ultraviolet-visible near-infrared absorption spectrum and a fluorescence spectrum of the dithienophosphorine compound of Example 3 (compound 8d + .TFA ⁇ ) at pH 7.4.
- Example 4 is an ultraviolet-visible near-infrared absorption spectrum of the dithienophosphorine compound of Example 4 (compound 11 + .TFA ⁇ ) at pH 4.0.
- 2 is a graph showing the transition of relative absorbance with the irradiation time of ICG and the dithienophosphorine compound of Example 1 (compound 1 + .TFA ⁇ ).
- Dithienothiophene phospholine compound of Example 3 (Compound 8a + ⁇ TFA -, 8b + ⁇ TFA -, 8c + ⁇ TFA -, and 8d + ⁇ TFA -) and a graph showing a change in the relative absorbance due to the irradiation time of ICG It is.
- FIG. 2 is a graph showing the change in absorbance of the dithienophosphorine compound of Example 1 (compound 1 + .TFA ⁇ ) with pH.
- (A) shows the change in absorption spectrum with pH
- (b) shows the change in absorbance with pH.
- 2 is a graph showing the change in absorbance of the dithienophosphorine compound of Example 2 (compound 6 + .TFA ⁇ ) with pH.
- (A) shows the change in absorption spectrum with pH
- (b) shows the change in absorbance with pH.
- 4 is a graph showing the change in absorbance of the dithienophosphorine compound of Example 3 (compound 8a + .TFA ⁇ ) with pH.
- (A) shows the change in absorption spectrum with pH
- (b) shows the change in absorbance with pH
- 4 is a graph showing the change in absorbance of the dithienophosphorine compound of Example 4 (compound 11 + .TFA ⁇ ) with pH.
- (A) shows changes in absorption spectrum with pH
- (b) and (c) show changes in absorbance with pH.
- the thiophene compound of the present invention has the general formula (1):
- R 1 represents the general formula (2A) or (2B):
- R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group;
- Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.
- R 2 is the general formula (3A), (3B) or (3C):
- R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group.
- R 9 represents a hydrogen atom or an optionally substituted alkyl group
- Y represents an oxygen atom or a sulfur atom.
- R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group.
- R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
- X represents an anion.
- n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B).
- It is a dithienophosphorine compound represented by these.
- the dithienophosphorine compound represented by the general formula (1) is a novel compound not described in any literature.
- R 1 represents the general formula (2A) or (2B):
- R 7 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group;
- the heteroaryl group which may be sufficient is shown.
- Ar represents an aromatic hydrocarbon ring which may be substituted or a heteroaromatic ring which may be substituted. ] It is group represented by these.
- alkyl group represented by R 7 either a linear alkyl group or a branched alkyl group can be employed.
- a linear alkyl group having 1 to 6 carbon atoms (particularly 1 to 4) is preferable.
- a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, n -A hexyl group etc. are mentioned.
- branched alkyl group a branched alkyl group having 3 to 6 carbon atoms (particularly 3 to 5) is preferable.
- Examples of the substituent that the alkyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, an alkoxy group described later, an alkenyl group described later, an alkynyl group described later, an aryl group described later, Heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- the alkenyl group represented by R 7 is preferably an alkenyl group having 2 to 6 (particularly 2 to 4) carbon atoms, and examples thereof include a vinyl group, an allyl group, a 1-butenyl group, and a 2-butenyl group.
- alkenyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described below, the above alkyl group, an alkoxy group described below, an alkenyl group described below, an alkynyl group described below, and an aryl described below. Groups, heteroaryl groups described later, carboxy groups, amide groups (dimethylamide groups, diethylamide groups, acetamide groups, etc.), ester groups (methoxycarbonyl groups, ethoxycarbonyl groups, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- the alkynyl group represented by R 7 is preferably an alkynyl group having 2 to 6 carbon atoms (particularly 2 to 4 carbon atoms), such as ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 2-butynyl group and the like. Is mentioned.
- alkynyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described below, the above alkyl group, an alkoxy group described below, the alkenyl group, the alkynyl group, and an aryl group described below. And a later-described heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamide group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- any of a monocyclic aryl (phenyl group) group and a polycyclic aryl group can be employed.
- Examples of the substituent that the aryl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, the aryl group, Examples thereof include a heteroaryl group, a carboxy group, an amide group (dimethylamide group, diethylamide group, acetamide group, etc.), an ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like described later.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- heteroaryl group represented by R 7 examples include a thienyl group, a furyl group, a pyridyl group, and the like.
- Examples of the substituent that the heteroaryl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, and the aryl group. And the above heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamide group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- an aryl group which may be substituted is preferable from the viewpoint of having a higher fluorescence quantum yield and facilitating recognition during bioimaging, and an optionally substituted monocyclic aryl Group (optionally substituted phenyl group) is more preferable, monocyclic aryl group having a substituent at ortho position (phenyl group having a substituent at ortho position) is more preferable, o-tolyl group, 2,6- A dimethoxyphenyl group and the like are particularly preferable.
- any of a monocyclic aromatic hydrocarbon ring (benzene ring) and a polycyclic aromatic hydrocarbon ring can be adopted.
- Examples of the substituent that the aromatic hydrocarbon ring represented by Ar may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, and the aryl.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- heteroaromatic ring represented by Ar examples include a thiophene ring, a furan ring, and a pyridine ring.
- Examples of the substituent that the heteroaromatic ring represented by Ar may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, the aryl group, Examples include the heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- Ar is preferably an aromatic hydrocarbon ring which may be substituted from the viewpoint of having a higher fluorescence quantum yield and making it easier to recognize during bioimaging.
- a ring aromatic hydrocarbon ring (an optionally substituted benzene ring) is more preferable.
- R 1 is preferably a group represented by the general formula (2A) from the viewpoint of easier synthesis.
- R 1 is a group represented by the general formula (2B) it is expected that a function of switching fluorescence properties (on / off) by ring opening and ring closing will appear.
- R 2 represents the general formula (3A), (3B) or (3C):
- R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group.
- R 9 represents a hydrogen atom or an optionally substituted alkyl group.
- Y represents an oxygen atom or a sulfur atom.
- alkyl group alkenyl group, alkynyl group, aryl group and heteroaryl group represented by R 8 , those described above can be adopted.
- the kind and number of substituents are the same.
- an alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms is preferable.
- a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an n-pentoxy group, and n-hexoxy group is preferable.
- Examples of the substituent that the alkoxy group represented by R 8 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the aryl group, and the above. Examples include heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like.
- the number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
- an optionally substituted aryl group is preferable, an optionally substituted monocyclic aryl group (an optionally substituted phenyl group) is more preferable, and an unsubstituted phenyl group is further preferable.
- alkyl group represented by R 9 those described above can be adopted.
- the kind and number of substituents are the same.
- Y may be either an oxygen atom or a sulfur atom, but an oxygen atom is preferred from the viewpoint of higher water solubility and ease of use during bioimaging.
- the absorption maximum wavelength and the fluorescence maximum wavelength can be made longer, and furthermore, the electron withdrawing property is higher, and the HOMO level (the energy level of the highest occupied orbit)
- the group represented by the general formula (3A) or (3B) is preferable from the viewpoint of easily improving the stability to light because the LUMO level (the energy level of the lowest orbital orbit) is more easily reduced.
- a group represented by the formula (3A) is more preferable.
- examples of the halogen atom represented by R 3 and R 4 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom is preferable from the viewpoint of further improving light resistance.
- the sulfonyl group represented by R 3 and R 4 includes not only a sulfo group (a group represented by —SO 3 H) but also a methanesulfonyl group, an ethanesulfonyl group, a phenylsulfonyl group, p -Toluenesulfonyl group, trifluoromethanesulfonyl group, etc. are also mentioned.
- R 3 and R 4 a hydrogen atom is preferable from the viewpoint of easier synthesis.
- alkyl group alkenyl group and aryl group represented by R 5 and R 6 , those described above can be adopted.
- the kind and number of substituents are the same.
- R 5 and R 6 are easy to synthesize, easily cationized, and can acquire high stability in a wider pH range, and have longer absorption maximum wavelengths and fluorescence maximum wavelengths.
- a hydrogen atom or an alkyl group is more preferable.
- R 5 and R 6 are alkyl groups, even when R 5 and R 6 are hydrogen atoms, the absorption maximum wavelength and the fluorescence maximum wavelength can be further increased, and a wider range High stability without decomposition in the pH range.
- R 5 and R 6 are alkyl groups, they have high stability without being decomposed even in the neutral region (about pH 6 to 8) that is usually used for bioimaging. Can be maintained. Therefore, in the dithienophosphorine compound of the present invention, compounds in which R 5 and R 6 are alkyl groups are particularly useful for bioimaging applications.
- examples of the anion represented by X include halogen ions (fluoride ions, chloride ions, bromide ions, iodide ions, etc.), cyanide ions, acetate ions, trifluoroacetate ions, and the like.
- N the number of moles of the anion is a 2 for group R 2 is in the case of the group represented by the general formula (3A) or (3C) of 1, R 2 is represented by the general formula (3B) is there.
- the dithienophospholine compound of the present invention that satisfies such conditions is easier to synthesize, has higher light resistance and water solubility, has a higher fluorescence quantum yield, and has a wider range of pH values. From the viewpoint of achieving high stability, making it easier to increase the absorption maximum wavelength and the fluorescence maximum wavelength, and making it easier to recognize during bioimaging, the general formula (1A):
- R 2 , R 3 , R 4 , R 7 , X and n are the same as defined above.
- R 5a and R 6a are the same or different and each represents an optionally substituted alkyl group.
- the dithienophosphorine compound represented by these is more preferable.
- dithienophosphorine compound of the present invention examples include, for example,
- a dithienophosphorine compound represented by the above formula is more preferred.
- the dithienophosphorine compound of the present invention can have an absorption maximum wavelength of preferably 650 to 850 nm, more preferably 700 to 800 nm, and a fluorescence maximum wavelength of 750 to 1000 nm, more preferably 800 to 950 nm.
- the light resistance can be drastically improved over conventional fluorescent dyes in the pH range of about 3-12. Therefore, it is possible to dramatically improve the light resistance compared to the ICG while making the absorption maximum wavelength and the fluorescence maximum wavelength as long as the conventional ICG. For this reason, it is possible to increase the absorption maximum wavelength and the fluorescence maximum wavelength even compared with conventional fluorescent dyes, and it is useful for applications such as a fluorescent probe for bioimaging and a fluorescent material for organic EL elements.
- R 5 and R 6 are alkyl groups
- the absorption maximum wavelength and the fluorescence maximum wavelength can be further increased even when R 5 and R 6 are hydrogen atoms. Furthermore, it has high stability without decomposition over a wide pH range. For this reason, when R 5 and R 6 are alkyl groups, they have high stability without being decomposed even in the neutral region (about pH 6 to 8) that is usually used for bioimaging. Can be maintained. Therefore, in the dithienophosphorine compound of the present invention, compounds in which R 5 and R 6 are alkyl groups are particularly useful for bioimaging applications.
- the dithienophosphorine compound of the present invention may exist as a hydrate or a solvate, and any of these substances is included in the scope of the present invention.
- the dithienophospholine compound of the present invention is not particularly limited, and can be synthesized by various methods.
- the dithienophospholine compounds (1A) of the present invention in which R 1 is a group represented by the general formula (2A) is a group represented by the general formula (2A)
- the dithienophospholine compound (1A2) in which R 5 and R 6 are hydrogen atoms is The following reaction formula 1:
- R 2 , R 7 , X and n are the same as defined above.
- X 1 is the same or different and represents a halogen atom.
- R 10 is the same or different and represents an optionally substituted aryl group.
- examples of the halogen atom represented by X 1 include a chlorine atom, a bromine atom, and an iodine atom, and a bromine atom is preferable from the viewpoint of yield.
- dithienophosphorine compound (1A1) of the present invention in which R 1 is a group represented by the general formula (2A) and R 5 and R 6 are optionally substituted alkyl groups has the following reaction Formula 2:
- compound (4) can be obtained by reacting compound (4) with an organolithium compound, then reacting with an electrophilic halogenating agent, and then adding an acid.
- Compound (4) can be synthesized, for example, according to a report (Angew. Chem. Int. Ed. 2013, 52, 8990-8994.).
- Examples of the organic lithium compound include alkyllithium such as ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, pentyllithium, and hexyllithium; and cycloalkyl such as cyclohexyllithium.
- Lithium One or two or more kinds of aryllithium such as phenyllithium may be used. Among these, in this step, alkyllithium is preferable and sec-butyllithium is more preferable from the viewpoint of yield.
- the amount of the organic lithium compound used is usually preferably from 1 to 10 mol, more preferably from 2 to 5 mol, based on 1 mol of the compound (4), from the viewpoint of ease of synthesis, yield, and the like.
- electrophilic halogenating agent examples include iodine (I 2 ), bromine (Br 2 ), iodine monochloride (ICl), N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), 1,2- One such as diiodoethane (ICH 2 CH 2 I), 1,2-dibromoethane (BrCH 2 CH 2 Br), 1,2-dibromo-1,1,2,2-tetrachloroethane (BrCl 2 CCCl 2 Br) Or 2 or more types are mentioned.
- the amount of the electrophilic halogenating agent to be used is generally preferably 1 to 10 mol, more preferably 2 to 5 mol, per 1 mol of compound (4).
- the acid examples include hydrogen chloride (hydrochloric acid), sulfuric acid, hydrogen peroxide, formic acid, acetic acid, trifluoroacetic acid (TFA), trifluoroacetic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid and the like. Or 2 or more types are mentioned.
- the amount of the acid to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol with respect to 1 mol of the compound (4), from the viewpoint of ease of synthesis, yield and the like.
- an excess amount for example, a solvent amount can be used.
- reaction solvents include, for example, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and tetrahydrofuran is more preferable from the viewpoint of ease of synthesis and yield. These reaction solvents can be used alone or in combination of two or more.
- the reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.).
- the reaction temperature can be any of heating, normal temperature, and cooling.
- the reaction with the organolithium compound and the electrophilic halogenating agent is ⁇ 150 to 0 ° C. (particularly ⁇ 100 to ⁇ 50 ° C.).
- the reaction with the acid is preferably carried out at -50 to 100 ° C (especially 0 to 50 ° C).
- the reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
- purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement
- the compound (6) or the compound (11) can be obtained by reacting the compound represented by the formula (1) with a Suzuki-Miyaura coupling reaction.
- the compound (8) is preferably used in an amount of 1.5 to 5.0 mol (particularly 2.0 to 3.0 mol) per mol of the compound (5) or the compound (10).
- a palladium catalyst usually used for Suzuki-Miyaura coupling is used. Specifically, palladium acetate (Pd (OAc) 2 ), tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ), palladium trifluoroacetate, palladium chloride, palladium bromide, palladium iodide, Tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3 ) and the like.
- palladium acetate (Pd (OAc) 2 ) is used from the viewpoint of ease of synthesis and yield. preferable.
- the amount of the palladium catalyst used is usually preferably 0.02 to 0.50 mol, more preferably 0.05 to 0.20 mol with respect to 1 mol of the compound (5) or compound (10), from the viewpoint of ease of synthesis, yield, and the like. .
- a ligand compound can be used as necessary.
- ligand compounds that can be used include triphenylphosphine, trimethoxyphosphine, triethylphosphine, triisopropylphosphine, tri (tert-butyl) phosphine, tri (n-butyl) phosphine, triisopropoxyphosphine, and tricyclopentylphosphine.
- Tricyclohexylphosphine 2,2'-bipyridyl, diphenylphosphinomethane, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,5-bis (diphenylphosphino) ) Pentane, 1,5-cyclooctadiene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) and the like.
- 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl is preferable in this step from the viewpoint of yield and ease of synthesis.
- the amount of the ligand compound used is usually preferably from 0.5 to 5.0 mol, more preferably from 1.0 to 3.0 mol, based on 1 mol of the palladium catalyst, from the viewpoint of ease of synthesis, yield, and the like.
- a base can be used as necessary.
- the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate and the like.
- cesium carbonate is used from the viewpoint of yield and ease of synthesis. preferable.
- the amount used is preferably 1 to 5 mol, more preferably 1.5 to 3 mol with respect to 1 mol of compound (5) or compound (10) from the viewpoint of ease of synthesis, yield and the like. preferable.
- the reaction can usually be performed in the presence of a reaction solvent.
- the reaction solvent that can be used include diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene and xylene; nitrile solvents such as acetonitrile; amide solvents such as dimethylformamide, etc., from the viewpoint of ease of synthesis, yield, etc. Aromatic hydrocarbons are preferred, and toluene is more preferred. These reaction solvents can be used alone or in combination of two or more.
- the reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.).
- the reaction temperature can be any of heating, room temperature and cooling, and it is usually preferably 0 to 150 ° C. (especially 50 to 100 ° C.).
- the reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
- purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement
- compound (9) or compound (10) can be obtained by reacting compound (5) with a dialkylamine compound.
- the dialkylamine compound is preferably a dithienophospholine compound (1A1) or dithienophospholine compound (1A3) according to the present invention in which desired R 5a and, if necessary, R 6a can be introduced, dimethylamine, diethylamine , Di (n-propyl) amine, diisopropylamine, di (n-butyl) amine, diisobutylamine, di (sec-butyl) amine, di (tert-butyl) amine, methylethylamine, isopropylethylamine, etc. From the viewpoint of ease of synthesis, diethylamine is preferable.
- the amount of the dialkylamine compound used is preferably an excess amount relative to the compound (5) from the viewpoint of yield and the like, and can also be a solvent amount.
- the reaction can usually be performed in the presence of a reaction solvent.
- the reaction solvent that can be used include ethers such as dibutyl ether, diisopropyl ether, 1,4-dioxane, dimethoxyethane (DME), and diglyme; aromatic hydrocarbons such as toluene and xylene; amide solvents such as dimethylformamide From the viewpoints of ease of synthesis, yield, etc., amide solvents are preferred, and dimethylformamide is more preferred.
- ethers such as dibutyl ether, diisopropyl ether, 1,4-dioxane, dimethoxyethane (DME), and diglyme
- aromatic hydrocarbons such as toluene and xylene
- amide solvents such as dimethylformamide From the viewpoints of ease of synthesis, yield, etc., amide solvents are preferred, and dimethylformamide is more preferred.
- These reaction solvents can be used alone or in combination of two
- the reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.).
- the reaction temperature can be any of heating, room temperature and cooling, and it is usually preferably 50 to 150 ° C. (especially 80 to 130 ° C.). When reacted at a high temperature (100 to 150 ° C., etc.), compound (9) is obtained, and when reacted at a low temperature (50 to 100 ° C., etc.), compound (10) is obtained.
- the reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
- purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement
- Grignard reagent those capable of introducing a desired R 7 in the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention are preferable, and R 7 MgX 2 (R 7 is the same as above) X 2 represents a halogen atom).
- halogen atom represented by X 2 those described above can be adopted. The same applies to preferred embodiments.
- Grignard reagents that satisfy these conditions include:
- organolithium compound those capable of introducing the desired R 7 in the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention are preferable, and R 7 Li (R 7 is the same as above) .) Is preferred.
- organolithium compounds that satisfy these conditions include:
- the amount of the organometallic nucleophile used is preferably 0.2 to 30.0 mol (especially 0.5 to 15.0 mol) with respect to 1 mol of compound (6) or compound (11) from the viewpoint of yield and the like.
- it is preferably used in a large amount (5.0 to 30.0 mol, etc.), and when it is intended to obtain the compound (1A3), it is preferably used in a small amount (0.2 to 5.0 mol, etc.). preferable.
- Examples of the acid reagent that can be used include hydrogen chloride (hydrochloric acid), sulfuric acid, formic acid, acetic acid, trifluoroacetic acid (TFA), trifluoroacetic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid, and the like.
- the amount of the acid reagent to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol, relative to 1 mol of compound (6), from the viewpoint of ease of synthesis, yield and the like.
- the acid reagent is a liquid, it may be in an excess amount, for example, a solvent amount.
- reaction can usually be performed in the presence of a reaction solvent.
- reaction solvents include diethyl ether, dibutyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and tetrahydrofuran is more preferable from the viewpoint of ease of synthesis and yield. These reaction solvents can be used alone or in combination of two or more.
- the reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.).
- the reaction temperature can be any of heating, room temperature, and cooling, and it is usually preferably -50 to 150 ° C (particularly 0 to 100 ° C).
- the reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
- the dithienophosphorine compound (1A2) or dithienophospholine compound (1A3) of the present invention can be obtained by purifying according to a conventional method if necessary.
- this process is not limited only to the above, but the compound (6) or the compound (11) is reacted with a first acid reagent (hydrochloric acid, etc.) to give a general formula (7) or (12):
- R 2 , R 3 , R 4 and R 5a are the same as defined above.
- the compound represented by formula (1) the compound (7) or the compound (12) is reacted with a Grignard reagent, and then reacted with a second acid reagent (hydrochloric acid, trifluoroacetic acid, etc.). It is also possible to obtain a dithienophosphorine compound (1A2) or a dithienophospholine compound (1A3).
- the anion contained in the second acid reagent constitutes the anion X of the dithienophosphorine compound (1A2) or dithienophospholine compound (1A3) of the present invention.
- organic halogen compound examples include one or more halogenated silanes such as trichlorosilane, diphenyldichlorosilane, and triphenylchlorosilane.
- the amount of the organic halogen compound used is preferably from 2.0 to 20.0 mol, more preferably from 3.0 to 10.0 mol, based on 1 mol of the compound (9), from the viewpoint of ease of synthesis, yield and the like.
- the amount of the acid reagent to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol, per 1 mol of compound (9), from the viewpoints of ease of synthesis, yield and the like.
- the acid reagent is a liquid, it may be in an excess amount, for example, a solvent amount.
- reaction can usually be performed in the presence of a reaction solvent.
- reaction solvents include diethyl ether, dibutyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and cyclopentylmethyl ether (CPME) is more preferable from the viewpoint of ease of synthesis and yield.
- reaction solvents can be used alone or in combination of two or more.
- the reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.).
- the reaction temperature can be any of heating, room temperature, and cooling, and it is usually preferably -50 to 150 ° C (particularly 0 to 100 ° C).
- the reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
- the dithienophosphorine compound (1A1) of the present invention can be obtained by purifying according to a conventional method if necessary.
- the dithienophospholine compound (1A) of the present invention is not limited to the above method, and may be produced by various methods. Can do.
- the dithienophospholine compound of the present invention in which R 1 is a group represented by the general formula (2B) is, for example, a Grignard derived from an o-halogenated alkyl benzoate (such as methyl o-bromobenzoate).
- a Grignard derived from an o-halogenated alkyl benzoate such as methyl o-bromobenzoate.
- Fluorescent dye contains the above-described dithienophosphorine compound of the present invention.
- the fluorescent dye of the present invention has an absorption maximum wavelength of preferably 650 to 850 nm, more preferably 700 to 800 nm because the benzene ring portion of the rhodamine dye is replaced with a thiophene skeleton and the oxygen atom in the skeleton is replaced with a phosphorus-containing group. It can have a fluorescence maximum wavelength in the range of 750 to 1000 nm, more preferably 800 to 950 nm, and dramatically improve the light resistance over conventional fluorescent dyes in the pH range of about 3 to 12. Is possible.
- the fluorescent dye of the present invention is particularly useful for uses such as a fluorescent probe for bioimaging and a fluorescent material for organic EL elements.
- the dithienophosphorine compound of the present invention has a high absorption wavelength and a fluorescence maximum wavelength that are not found in conventional fluorescent dyes having an absorption maximum wavelength and a fluorescence maximum wavelength in a high wavelength region.
- the fluorescent dye of the present invention When used for bioimaging applications, it is preferably dissolved in an organic solvent to form a solution.
- the content of the dithienophosphorine compound of the present invention is 1 ⁇ 10 ⁇ 8 to 1 ⁇ 10 ⁇ 4 mol / L is preferable, and 1 ⁇ 10 ⁇ 7 to 1 ⁇ 10 ⁇ 5 mol / L is more preferable.
- content of a dithienophosphorin compound can be restrained low.
- the organic solvent that can be used is not particularly limited, and either a polar solvent or a nonpolar solvent can be used.
- polar solvents examples include ether compounds (tetrahydrofuran, anisole, 1,4-dioxane, cyclopentyl methyl ether, etc.), alcohols (methanol, ethanol, allyl alcohol, etc.), ester compounds (ethyl acetate, etc.), ketones (acetone, etc.) , Halogenated hydrocarbons (dichloromethane, chloroform), dimethyl sulfoxide, amide solvents (N, N-dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc.) .
- nonpolar solvent examples include aliphatic organic solvents such as pentane, hexane, cyclohexane and heptane; aromatic solvents such as benzene, toluene, xylene and mesitylene.
- Buffers Hepes buffer, Tris buffer, tricine-sodium hydroxide buffer, phosphate buffer, phosphate buffered saline, etc. are used to adjust the pH of the cell detection agent of the present invention. You can also
- LC-Forte / R (YMC Technos Co., Ltd.) or Nippon Analytical Industry Co., Ltd. LC-9201 was used for preparative recycling HPLC.
- a UV-visible near-infrared spectrophotometer UV-3150 (Shimadzu Corporation) was used for the measurement of the UV-visible absorption spectrum.
- the fluorescence spectrum was measured using a fluorometer Fluorolog-3 (HORIBA).
- the absolute fluorescence quantum yield was measured using an absolute PL quantum yield measuring apparatus (Hamamatsu Photonics Co., Ltd.) equipped with a multichannel spectrometer PMA-12. Unless otherwise specified, the reaction was carried out under a nitrogen atmosphere using a commercially available dehydrated solvent (Kanto Chemical Co., Ltd.) purified with a Glass Contour organic solvent purifier (Nikko Hansen Co., Ltd.).
- n-BuLi n-butyllithium.
- THF represents tetrahydrofuran.
- Et 2 O represents diethyl ether.
- PhPCl 2 represents phenyldichlorophosphine.
- sec-BuLi represents sec-butyllithium.
- Ph 2 C ⁇ NH represents benzophenone imine.
- Pd (OAc) 2 represents palladium acetate.
- BINAP represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. Ph represents a phenyl group. The same applies hereinafter. ]
- a tetrahydrofuran (THF) solution (0.27M, 2.10 mL) of 2,6-dimethoxyphenyllithium prepared from 2,6-dimethoxybromobenzene was added, and the temperature was slowly returned to room temperature.
- 0.2% aqueous trifluoroacetic acid (TFA) solution (10 mL) was added, and the mixture was stirred for 1 hour.
- n-BuLi n-butyllithium.
- THF represents tetrahydrofuran.
- Et 2 O represents diethyl ether.
- PhPCl 2 represents phenyldichlorophosphine. Ph represents a phenyl group.
- sec-BuLi represents sec-butyllithium.
- Et 2 NH represents diethylamine.
- DMF represents dimethylformamide.
- CPME represents cyclopentyl methyl ether.
- iPr represents an isopropyl group. The same applies hereinafter.
- the reaction mixture was heated to 70 ° C. and stirred for 18 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.05 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure.
- the reaction mixture was heated to 70 ° C. and stirred for 13 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.1 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure.
- the resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure.
- the resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent).
- the eluent was extracted with CHCl 3 .
- the solvent was removed from the combined solution under reduced pressure.
- the resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 8d + ⁇ TFA - was obtained as a green solid. Obtained (25.5 mg, 34.3 ⁇ mol, 39%).
- Ph represents a phenyl group.
- Et 2 NH represents diethylamine.
- DMF represents dimethylformamide.
- Ph 2 C ⁇ NH represents benzophenone imine.
- Pd (OAc) 2 represents palladium acetate.
- BINAP represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl.
- THF represents tetrahydrofuran. The same applies hereinafter.
- the resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure.
- the resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent).
- the eluent was extracted with CHCl 3 .
- the solvent was removed from the combined solution under reduced pressure.
- the resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 11 + • TFA - was obtained as a green solid. Obtained (11.3 mg, 19.2 ⁇ mol, 21%).
- the dithienophosphorine compound of the present invention can increase the absorption maximum wavelength and the fluorescence maximum wavelength to the same extent as ICG, which is a typical near-infrared fluorescent dye, and the fluorescence quantum yield. Can be understood to be sufficiently high.
- the measurement was carried out by measuring the absorbance immediately after irradiation (A 0 ) and the absorbance after a certain period of time (A), and evaluating A / A 0 as the maintenance rate.
- DMSO dimethyl sulfoxide
- water Na 2 HPO 4 / NaH 2 PO 4
- DMSO / water 1/99% by volume
- ICG which is a representative near-infrared fluorescent dye
- the dithienophosphorine compound of the present invention is high stability to light
- compound 1 + ⁇ TFA - is the relative absorbance of about 0.95 hardly decreased absorbance even after the elapse 8 hours or more from the start of irradiation dramatically the stability under acidic conditions It can be understood that it was able to be improved.
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Abstract
Provided is a fluorescent dye which has an absorption maximum and a fluorescent maximum at higher wavelengths, has a high fluorescence quantum yield and has high stability to light, and into which various substituents can be introduced. In a rhodamine dye, the benzene ring moiety is substituted by a thiophene structure and an oxygen atom in the backbone is substituted by a phosphorus-containing group, as shown in general formula (1) [wherein R2 represents a group represented by general formula (3A), (3B) or (3C)].
Description
本発明は、ジチエノホスホリン化合物及びそれを用いた蛍光色素に関する。
The present invention relates to a dithienophosphorine compound and a fluorescent dye using the same.
赤色から近赤外領域の光は高い組織浸透性があるため、この領域(620nm以上)に吸収及び蛍光極大波長を有する有機分子(色素)が、生体組織の深部観察において注目されている。この近赤外領域に蛍光を示す有機分子は、バイオイメージング用蛍光プローブ、有機EL素子用蛍光材料等、応用の枠組みを超えて高い重要性を有する。これまでにシアニン色素、スクアリン色素、ポルフィリン色素、フタロシアニン色素等の古典的な蛍光色素の骨格をもとに、多くの近赤外蛍光性の有機分子が知られている。特に、蛍光プローブという観点で現在最も広く用いられている近赤外蛍光色素として、インドシアニングリーン(ICG)が挙げられる。また、近年では、ローダミン色素の骨格内酸素原子をケイ素原子等に置き換えることで、従来は可視領域に位置するローダミン色素の蛍光を近赤外領域にまで高くすることができることが示されている。
Since light in the red to near-infrared region has high tissue permeability, organic molecules (pigments) having absorption and fluorescence maximum wavelengths in this region (620 nm or more) are attracting attention in deep observation of living tissue. Organic molecules that exhibit fluorescence in the near-infrared region have high importance beyond the framework of applications such as bioimaging fluorescent probes and fluorescent materials for organic EL devices. So far, many near-infrared fluorescent organic molecules are known based on the skeletons of classic fluorescent dyes such as cyanine dyes, squalin dyes, porphyrin dyes, and phthalocyanine dyes. In particular, indocyanine green (ICG) is one of the most widely used near-infrared fluorescent dyes from the viewpoint of a fluorescent probe. In recent years, it has been shown that the fluorescence of the rhodamine dye located in the visible region can be increased to the near infrared region by replacing the oxygen atom in the skeleton of the rhodamine dye with a silicon atom or the like.
例えば、フルオレセイン系色素は、吸収極大波長は491nm、蛍光極大波長は510nm、量子収率は0.85である(非特許文献1)が、バイオイメージングのためは、深赤色~近赤外領域の波長に対して吸収及び蛍光を示す必要があることから、吸収極大波長及び蛍光極大波長をさらに高くすることが求められている。
For example, a fluorescein dye has an absorption maximum wavelength of 491 nm, a fluorescence maximum wavelength of 510 nm, and a quantum yield of 0.85 (Non-Patent Document 1), but for bioimaging, it has a wavelength in the deep red to near infrared region. On the other hand, since it is necessary to show absorption and fluorescence, it is required to further increase the absorption maximum wavelength and the fluorescence maximum wavelength.
このフルオレセイン系色素のキサンテン骨格の酸素原子をケイ素原子に置換すると、吸収極大波長は582nm、蛍光極大波長は598nm、量子収率0.42と、長波長側にシフトさせることができることが知られている(非特許文献2)。しかしながら、その効果は不十分であり、さらなる長波長シフトが必要である。
It is known that when the oxygen atom of the xanthene skeleton of this fluorescein dye is replaced with a silicon atom, the absorption maximum wavelength is 582 nm, the fluorescence maximum wavelength is 598 nm, and the quantum yield is 0.42, which can be shifted to the longer wavelength side ( Non-patent document 2). However, the effect is insufficient and further long wavelength shifts are necessary.
しかしながら、依然として、近赤外領域において高効率での蛍光は困難である。このため、さらに長波長領域に吸収極大及び蛍光極大を有し、高い蛍光量子収率を有する色素が求められている。さらに、近赤外蛍光プローブの代表格であるインドシアニングリーン(ICG)は光照射に対する安定性に乏しく、機能性を付与するために様々な置換基を導入することが困難である。そこで、本発明は、高い波長に吸収極愛及び蛍光極大を有し、且つ、高い蛍光量子収率を有し、光に対する安定性が高く、様々な置換基を導入できる蛍光色素を提供することを目的とする。
However, fluorescence with high efficiency is still difficult in the near infrared region. For this reason, there is a demand for a dye having an absorption maximum and a fluorescence maximum in a longer wavelength region and having a high fluorescence quantum yield. Furthermore, indocyanine green (ICG), which is a representative near-infrared fluorescent probe, has poor stability against light irradiation, and it is difficult to introduce various substituents to impart functionality. Accordingly, the present invention provides a fluorescent dye having an absorption maximum and a fluorescence maximum at a high wavelength, a high fluorescence quantum yield, high stability to light, and capable of introducing various substituents. With the goal.
上記目的を鑑み、鋭意検討した結果、本発明者らは、ローダミン色素のベンゼン環部位をチオフェン骨格に置き換えるとともに、骨格内酸素原子をリン含有基に置き換えることで、高い波長に吸収極大及び蛍光極大を有し、且つ、高い蛍光量子収率を有し、光に対する安定性が高く、様々な置換基を導入できることを見出した。本発明は、このような知見に基づきさらに研究を重ね、完成させたものである。すなわち、本発明は以下の構成を包含する。
As a result of diligent investigations in view of the above object, the present inventors have replaced the benzene ring portion of the rhodamine dye with a thiophene skeleton, and also replaced the oxygen atom in the skeleton with a phosphorus-containing group, thereby achieving an absorption maximum and a fluorescence maximum at a high wavelength. And having high fluorescence quantum yield, high stability to light, and found that various substituents can be introduced. The present invention has been completed by further research based on such knowledge. That is, the present invention includes the following configurations.
項1.一般式(1):
Item 1. General formula (1):
[式中、R1は一般式(2A)又は(2B):
[In the formula, R 1 represents the general formula (2A) or (2B):
(式中、R7は水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。Arは置換されていてもよい芳香族炭化水素環又は置換されていてもよい複素芳香環を示す。)
で表される基を示す。R2は一般式(3A)、(3B)又は(3C): (Wherein R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; And Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.)
The group represented by these is shown. R 2 is the general formula (3A), (3B) or (3C):
で表される基を示す。R2は一般式(3A)、(3B)又は(3C): (Wherein R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; And Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.)
The group represented by these is shown. R 2 is the general formula (3A), (3B) or (3C):
(式中、R8は同一又は異なって、ヒドロキシ基、置換されていてもよいアルキル基、置換されていてもよいアルコキシ基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。R9は水素原子又は置換されていてもよいアルキル基を示す。Yは酸素原子又は硫黄原子を示す。)
で表される基を示す。R3及びR4は同一又は異なって、水素原子、ハロゲン原子、スルホニル基、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R5及びR6は同一又は異なって、水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。Xはアニオンを示す。nは1又は2を示し、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。]
で表される、ジチエノホスホリン化合物。 Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, R 9 represents a hydrogen atom or an optionally substituted alkyl group, and Y represents an oxygen atom or a sulfur atom. )
The group represented by these is shown. R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. X represents an anion. n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B). ]
A dithienophosphorine compound represented by:
で表される基を示す。R3及びR4は同一又は異なって、水素原子、ハロゲン原子、スルホニル基、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R5及びR6は同一又は異なって、水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。Xはアニオンを示す。nは1又は2を示し、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。]
で表される、ジチエノホスホリン化合物。 Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, R 9 represents a hydrogen atom or an optionally substituted alkyl group, and Y represents an oxygen atom or a sulfur atom. )
The group represented by these is shown. R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. X represents an anion. n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B). ]
A dithienophosphorine compound represented by:
項2.前記一般式(1)において、R1が一般式(2A)で表される基である、項1に記載のジチエノホスホリン化合物。
Item 2. Item 2. The dithienophosphorine compound according to Item 1, wherein R 1 in the general formula (1) is a group represented by the general formula (2A).
項3.前記一般式(1)において、R7が置換されていてもよいアリール基である、項2に記載のジチエノホスホリン。
Item 3. Item 3. The dithienophosphorine according to Item 2, wherein in the general formula (1), R 7 is an aryl group which may be substituted.
項4.前記一般式(1)において、R2が一般式(3A)で表される基であり、nが1である、項1~3のいずれかに記載のジチエノホスホリン化合物。
Item 4. Item 4. The dithienophosphorine compound according to any one of Items 1 to 3, wherein, in the general formula (1), R 2 is a group represented by the general formula (3A), and n is 1.
項5.前記一般式(1)において、Yが酸素原子である、項4に記載のジチエノホスホリン化合物。
Item 5. Item 5. The dithienophosphorine compound according to Item 4, wherein Y in the general formula (1) is an oxygen atom.
項6.前記一般式(1)において、R8が置換されていてもよいアリール基である、項4又は5に記載のジチエノホスホリン化合物。
Item 6. Item 6. The dithienophosphorine compound according to Item 4 or 5, wherein, in the general formula (1), R 8 is an optionally substituted aryl group.
項7.前記一般式(1)において、R3及びR4がいずれも水素原子である、項1~6のいずれかに記載のジチエノホスホリン化合物。
Item 7. Item 7. The dithienophosphorine compound according to any one of Items 1 to 6, wherein in the general formula (1), R 3 and R 4 are both hydrogen atoms.
項8.前記一般式(1)において、R5及びR6が同一又は異なって、水素原子又は置換されていてもよいアルキル基である、項1~7のいずれかに記載のジチエノホスホリン化合物。
Item 8. Item 8. The dithienophosphorine compound according to any one of Items 1 to 7, wherein, in the general formula (1), R 5 and R 6 are the same or different and each is a hydrogen atom or an optionally substituted alkyl group.
項9.650~850nmに吸収極大波長を有する、項1~8のいずれかに記載のジチエノホスホリン化合物。
Item 9. The dithienophosphorine compound according to any one of Items 1 to 8, which has an absorption maximum wavelength at 650 to 850 nm.
項10.750~1000nmに蛍光極大波長を有する、項1~9のいずれかに記載のジチエノホスホリン化合物。
Item 10. The dithienophosphorine compound according to any one of Items 1 to 9, which has a fluorescence maximum wavelength at 750 to 1000 nm.
項11.項1~10のいずれかに記載のジチエノホスホリン化合物を含有する蛍光色素。
Item 11. Item 11. A fluorescent dye containing the dithienophosphorine compound according to any one of Items 1 to 10.
本発明の含チオフェン化合物は、ローダミン色素のベンゼン環部位をチオフェン骨格に置き換えるとともに、骨格内酸素原子をリン含有基に置き換えることで、高い波長に吸収極大及び蛍光極大を有し、且つ、高い蛍光量子収率を有し、光に対する安定性が高い。しかも、要求特性に応じて、様々な基を導入することが可能である。
The thiophene-containing compound of the present invention has an absorption maximum and a fluorescence maximum at a high wavelength by replacing the benzene ring portion of the rhodamine dye with a thiophene skeleton and replacing the oxygen atom in the skeleton with a phosphorus-containing group, and has a high fluorescence. Has quantum yield and high stability to light. In addition, various groups can be introduced according to the required characteristics.
1.含チオフェン化合物
本発明の含チオフェン化合物は、一般式(1): 1. Thiophene-containing compound The thiophene compound of the present invention has the general formula (1):
本発明の含チオフェン化合物は、一般式(1): 1. Thiophene-containing compound The thiophene compound of the present invention has the general formula (1):
[式中、R1は一般式(2A)又は(2B):
[In the formula, R 1 represents the general formula (2A) or (2B):
(式中、R7は水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。Arは置換されていてもよい芳香族炭化水素環又は置換されていてもよい複素芳香環を示す。)
で表される基を示す。R2は一般式(3A)、(3B)又は(3C): (Wherein R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; And Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.)
The group represented by these is shown. R 2 is the general formula (3A), (3B) or (3C):
で表される基を示す。R2は一般式(3A)、(3B)又は(3C): (Wherein R 7 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; And Ar represents an optionally substituted aromatic hydrocarbon ring or an optionally substituted heteroaromatic ring.)
The group represented by these is shown. R 2 is the general formula (3A), (3B) or (3C):
(式中、R8は同一又は異なって、ヒドロキシ基、置換されていてもよいアルキル基、置換されていてもよいアルコキシ基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。R9は水素原子又は置換されていてもよいアルキル基を示す。Yは酸素原子又は硫黄原子を示す。)
で表される基を示す。R3及びR4は同一又は異なって、水素原子、ハロゲン原子、スルホニル基、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R5及びR6は同一又は異なって、水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。Xはアニオンを示す。nは1又は2を示し、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。]
で表されるジチエノホスホリン化合物である。この一般式(1)で表されるジチエノホスホリン化合物は、文献未記載の新規化合物である。 Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, R 9 represents a hydrogen atom or an optionally substituted alkyl group, and Y represents an oxygen atom or a sulfur atom. )
The group represented by these is shown. R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. X represents an anion. n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B). ]
It is a dithienophosphorine compound represented by these. The dithienophosphorine compound represented by the general formula (1) is a novel compound not described in any literature.
で表される基を示す。R3及びR4は同一又は異なって、水素原子、ハロゲン原子、スルホニル基、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R5及びR6は同一又は異なって、水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。Xはアニオンを示す。nは1又は2を示し、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。]
で表されるジチエノホスホリン化合物である。この一般式(1)で表されるジチエノホスホリン化合物は、文献未記載の新規化合物である。 Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. Represents an optionally substituted aryl group, or an optionally substituted heteroaryl group, R 9 represents a hydrogen atom or an optionally substituted alkyl group, and Y represents an oxygen atom or a sulfur atom. )
The group represented by these is shown. R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. X represents an anion. n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B). ]
It is a dithienophosphorine compound represented by these. The dithienophosphorine compound represented by the general formula (1) is a novel compound not described in any literature.
一般式(1)において、R1は、一般式(2A)又は(2B):
In the general formula (1), R 1 represents the general formula (2A) or (2B):
[式中、R7は水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。Arは置換されていてもよい芳香族炭化水素環又は置換されていてもよい複素芳香環を示す。]
で表される基である。 [Wherein R 7 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; The heteroaryl group which may be sufficient is shown. Ar represents an aromatic hydrocarbon ring which may be substituted or a heteroaromatic ring which may be substituted. ]
It is group represented by these.
で表される基である。 [Wherein R 7 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, or a substituted group; The heteroaryl group which may be sufficient is shown. Ar represents an aromatic hydrocarbon ring which may be substituted or a heteroaromatic ring which may be substituted. ]
It is group represented by these.
R7で示されるアルキル基としては、直鎖アルキル基及び分岐鎖アルキル基のいずれも採用できる。直鎖アルキル基としては、炭素数1~6(特に1~4)の直鎖アルキル基が好ましく、例えば、メチル基、エチル基、n-プロピル基、n-ブチル基、n-ペンチル基、n-ヘキシル基等が挙げられる。分岐鎖アルキル基としては、炭素数3~6(特に3~5)の分岐鎖アルキル基が好ましく、例えば、イソプロピル基、イソブチル基、tert-ブチル基、sec-ブチル基、ネオペンチル基、イソヘキシル基、3-メチルペンチル基等が挙げられる。
As the alkyl group represented by R 7 , either a linear alkyl group or a branched alkyl group can be employed. As the linear alkyl group, a linear alkyl group having 1 to 6 carbon atoms (particularly 1 to 4) is preferable. For example, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, n -A hexyl group etc. are mentioned. As the branched alkyl group, a branched alkyl group having 3 to 6 carbon atoms (particularly 3 to 5) is preferable. For example, isopropyl group, isobutyl group, tert-butyl group, sec-butyl group, neopentyl group, isohexyl group, Examples include 3-methylpentyl group.
R7で示されるアルキル基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、後述のアルコキシ基、後述のアルケニル基、後述のアルキニル基、後述のアリール基、後述のヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the alkyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, an alkoxy group described later, an alkenyl group described later, an alkynyl group described later, an aryl group described later, Heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
R7で示されるアルケニル基としては、炭素数2~6(特に2~4)のアルケニル基が好ましく、例えば、ビニル基、アリル基、1-ブテニル基、2-ブテニル基等が挙げられる。
The alkenyl group represented by R 7 is preferably an alkenyl group having 2 to 6 (particularly 2 to 4) carbon atoms, and examples thereof include a vinyl group, an allyl group, a 1-butenyl group, and a 2-butenyl group.
R7で示されるアルケニル基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、後述のアルキニル基、後述のアリール基、後述のヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the alkenyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described below, the above alkyl group, an alkoxy group described below, an alkenyl group described below, an alkynyl group described below, and an aryl described below. Groups, heteroaryl groups described later, carboxy groups, amide groups (dimethylamide groups, diethylamide groups, acetamide groups, etc.), ester groups (methoxycarbonyl groups, ethoxycarbonyl groups, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
R7で示されるアルキニル基としては、炭素数2~6(特に2~4)のアルキニル基が好ましく、例えば、エチニル基、1-プロピニル基、プロパルギル基、1-ブチニル基、2-ブチニル基等が挙げられる。
The alkynyl group represented by R 7 is preferably an alkynyl group having 2 to 6 carbon atoms (particularly 2 to 4 carbon atoms), such as ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 2-butynyl group and the like. Is mentioned.
R7で示されるアルキニル基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、上記アルキニル基、後述のアリール基、後述のヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the alkynyl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described below, the above alkyl group, an alkoxy group described below, the alkenyl group, the alkynyl group, and an aryl group described below. And a later-described heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamide group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
R7で示されるアリール基としては、単環アリール(フェニル基)基及び多環アリール基のいずれも採用することができ、例えば、フェニル基、オリゴアリール基(ナフチル基、アントリル基等)、フェナンスレニル基、フルオレニル基、ピレニル基、トリフェニレニル基、ビフェニル基等が挙げられる。
As the aryl group represented by R 7 , any of a monocyclic aryl (phenyl group) group and a polycyclic aryl group can be employed. For example, a phenyl group, an oligoaryl group (naphthyl group, anthryl group, etc.), phenanthrenyl Group, fluorenyl group, pyrenyl group, triphenylenyl group, biphenyl group and the like.
R7で示されるアリール基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、上記アルキニル基、上記アリール基、後述のヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the aryl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, the aryl group, Examples thereof include a heteroaryl group, a carboxy group, an amide group (dimethylamide group, diethylamide group, acetamide group, etc.), an ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like described later. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
R7で示されるヘテロアリール基としては、例えば、チエニル基、フリル基、ピリジル基等が挙げられる。
Examples of the heteroaryl group represented by R 7 include a thienyl group, a furyl group, a pyridyl group, and the like.
R7で示されるヘテロアリール基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、上記アルキニル基、上記アリール基、上記ヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the heteroaryl group represented by R 7 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, and the aryl group. And the above heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamide group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
なかでも、R7としては、より高い蛍光量子収率を有し、バイオイメージングの際により認識しやすくする観点から、置換されていてもよいアリール基が好ましく、置換されていてもよい単環アリール基(置換されていてもよいフェニル基)がより好ましく、オルト位に置換基を有する単環アリール基(オルト位に置換基を有するフェニル基)がさらに好ましく、o-トリル基、2,6-ジメトキシフェニル基等が特に好ましい。なお、中性領域における水に対する安定性の観点からは、より嵩高い基とすることが好ましい。
Among these, as R 7 , an aryl group which may be substituted is preferable from the viewpoint of having a higher fluorescence quantum yield and facilitating recognition during bioimaging, and an optionally substituted monocyclic aryl Group (optionally substituted phenyl group) is more preferable, monocyclic aryl group having a substituent at ortho position (phenyl group having a substituent at ortho position) is more preferable, o-tolyl group, 2,6- A dimethoxyphenyl group and the like are particularly preferable. In addition, from a viewpoint of the stability with respect to the water in a neutral area | region, it is preferable to set it as a bulkier group.
Arで示される芳香族炭化水素環としては、単環芳香族炭化水素環(ベンゼン環)及び多環芳香族炭化水素環のいずれも採用でき、例えば、ベンゼン環、ナフタレン環、アントラセン環、フェナントレン環、フルオレン環、ピレン環、トリフェニレン環等が挙げられる。
As the aromatic hydrocarbon ring represented by Ar, any of a monocyclic aromatic hydrocarbon ring (benzene ring) and a polycyclic aromatic hydrocarbon ring can be adopted. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring Fluorene ring, pyrene ring, triphenylene ring and the like.
Arで示される芳香族炭化水素環が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、上記アルキニル基、上記アリール基、上記ヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the aromatic hydrocarbon ring represented by Ar may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, and the aryl. Group, the above heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamide group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
Arで示される複素芳香環としては、例えば、チオフェン環、フラン環、ピリジン環等が挙げられる。
Examples of the heteroaromatic ring represented by Ar include a thiophene ring, a furan ring, and a pyridine ring.
Arで示される複素芳香環が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、後述のアルコキシ基、上記アルケニル基、上記アルキニル基、上記アリール基、上記ヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the heteroaromatic ring represented by Ar may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, an alkoxy group described later, the alkenyl group, the alkynyl group, the aryl group, Examples include the heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
なかでも、Arとしては、より高い蛍光量子収率を有し、バイオイメージングの際により認識しやすくする観点から、置換されていてもよい芳香族炭化水素環が好ましく、置換されていてもよい単環芳香族炭化水素環(置換されていてもよいベンゼン環)がより好ましい。
Among them, Ar is preferably an aromatic hydrocarbon ring which may be substituted from the viewpoint of having a higher fluorescence quantum yield and making it easier to recognize during bioimaging. A ring aromatic hydrocarbon ring (an optionally substituted benzene ring) is more preferable.
これらのなかでも、R1としては、合成がより容易である観点から、一般式(2A)で表される基が好ましい。なお、R1が一般式(2B)で表される基である場合には、開環及び閉環による蛍光特性のスイッチング(on/off)機能が現れることが期待される。
Among these, R 1 is preferably a group represented by the general formula (2A) from the viewpoint of easier synthesis. In addition, when R 1 is a group represented by the general formula (2B), it is expected that a function of switching fluorescence properties (on / off) by ring opening and ring closing will appear.
一般式(1)において、R2は、一般式(3A)、(3B)又は(3C):
In the general formula (1), R 2 represents the general formula (3A), (3B) or (3C):
[式中、R8は同一又は異なって、ヒドロキシ基、置換されていてもよいアルキル基、置換されていてもよいアルコキシ基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示す。R9は水素原子又は置換されていてもよいアルキル基を示す。Yは酸素原子又は硫黄原子を示す。]
で表される基である。 [Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. , An optionally substituted aryl group, or an optionally substituted heteroaryl group; R 9 represents a hydrogen atom or an optionally substituted alkyl group. Y represents an oxygen atom or a sulfur atom. ]
It is group represented by these.
で表される基である。 [Wherein R 8 is the same or different and is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. , An optionally substituted aryl group, or an optionally substituted heteroaryl group; R 9 represents a hydrogen atom or an optionally substituted alkyl group. Y represents an oxygen atom or a sulfur atom. ]
It is group represented by these.
R8で示されるアルキル基、アルケニル基、アルキニル基、アリール基及びヘテロアリール基としては、上記したものを採用できる。置換基の種類及び数も同様である。
As the alkyl group, alkenyl group, alkynyl group, aryl group and heteroaryl group represented by R 8 , those described above can be adopted. The kind and number of substituents are the same.
R8で示されるアルコキシ基としては、炭素数1~6(特に1~4)のアルコキシ基が好ましく、例えば、メトキシ基、エトキシ基、n-プロポキシ基、n-ブトキシ基、n-ペントキシ基、n-ヘキトキシ基等が挙げられる。
As the alkoxy group represented by R 8 , an alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms is preferable. For example, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an n-pentoxy group, and n-hexoxy group.
R8で示されるアルコキシ基が有していてもよい置換基としては、例えば、ヒドロキシ基、後述のハロゲン原子、上記アルキル基、上記アルコキシ基、上記アルケニル基、上記アルキニル基、上記アリール基、上記ヘテロアリール基、カルボキシ基、アミド基(ジメチルアミド基、ジエチルアミド基、アセトアミド基等)、エステル基(メトキシカルボニル基、エトキシカルボニル基等)等が挙げられる。置換基を有する場合の数は、特に制限されず、1~6個が好ましく、1~3個がより好ましい。
Examples of the substituent that the alkoxy group represented by R 8 may have include, for example, a hydroxy group, a halogen atom described later, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the aryl group, and the above. Examples include heteroaryl group, carboxy group, amide group (dimethylamide group, diethylamide group, acetamido group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, etc.) and the like. The number in the case of having a substituent is not particularly limited and is preferably 1 to 6, more preferably 1 to 3.
このR8の種類によっては、電子構造の微調整や物理特性(溶解性、細胞透過性等)の調整を行うことも可能である。特に、合成上の観点から、置換されていてもよいアリール基が好ましく、置換されていてもよい単環アリール基(置換されていてもよいフェニル基)がより好ましく、非置換フェニル基がさらに好ましい。
Depending on the type of R 8 , fine adjustment of the electronic structure and adjustment of physical properties (solubility, cell permeability, etc.) can be performed. In particular, from the viewpoint of synthesis, an optionally substituted aryl group is preferable, an optionally substituted monocyclic aryl group (an optionally substituted phenyl group) is more preferable, and an unsubstituted phenyl group is further preferable. .
R9で示されるアルキル基としては、上記したものを採用できる。置換基の種類及び数も同様である。
As the alkyl group represented by R 9 , those described above can be adopted. The kind and number of substituents are the same.
Yとしては、酸素原子及び硫黄原子のいずれでもよいが、水溶性がより高く、バイオイメージングの際により利用しやすくする観点から、酸素原子が好ましい。
Y may be either an oxygen atom or a sulfur atom, but an oxygen atom is preferred from the viewpoint of higher water solubility and ease of use during bioimaging.
これらのなかでも、R2としては、吸収極大波長及び蛍光極大波長をより長波長にすることができ、さらに、より電子求引性が高く、HOMO準位(最高被占有軌道のエネルギー準位)及びLUMO準位(最低空軌道のエネルギー準位)をより低減させやすいために光に対する安定性をより向上させやすい観点から、一般式(3A)又は(3B)で表される基が好ましく、一般式(3A)で表される基がより好ましい。
Among these, as R 2 , the absorption maximum wavelength and the fluorescence maximum wavelength can be made longer, and furthermore, the electron withdrawing property is higher, and the HOMO level (the energy level of the highest occupied orbit) And the group represented by the general formula (3A) or (3B) is preferable from the viewpoint of easily improving the stability to light because the LUMO level (the energy level of the lowest orbital orbit) is more easily reduced. A group represented by the formula (3A) is more preferable.
上記一般式(1)において、R3及びR4で示されるハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられ、耐光性をより高くする観点から、フッ素原子が好ましい。
In the general formula (1), examples of the halogen atom represented by R 3 and R 4 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom is preferable from the viewpoint of further improving light resistance.
一般式(1)において、R3及びR4で示されるスルホニル基としては、スルホ基(-SO3Hで表される基)のみならず、メタンスルホニル基、エタンスルホニル基、フェニルスルホニル基、p-トルエンスルホニル基、トリフルオロメタンスルホニル基等も挙げられる。
In the general formula (1), the sulfonyl group represented by R 3 and R 4 includes not only a sulfo group (a group represented by —SO 3 H) but also a methanesulfonyl group, an ethanesulfonyl group, a phenylsulfonyl group, p -Toluenesulfonyl group, trifluoromethanesulfonyl group, etc. are also mentioned.
一般式(1)において、R3及びR4で示されるアルキル基及びアリール基としては、上記したものを採用できる。置換基の種類及び数も同様である。
In the general formula (1), as the alkyl group and aryl group represented by R 3 and R 4 , those described above can be adopted. The kind and number of substituents are the same.
これらのなかでも、R3及びR4としては、合成がより容易である観点から、水素原子が好ましい。
Among these, as R 3 and R 4 , a hydrogen atom is preferable from the viewpoint of easier synthesis.
一般式(1)において、R5及びR6で示されるアルキル基、アルケニル基及びアリール基としては、上記したものを採用できる。置換基の種類及び数も同様である。
In the general formula (1), as the alkyl group, alkenyl group and aryl group represented by R 5 and R 6 , those described above can be adopted. The kind and number of substituents are the same.
これらのなかでも、R5及びR6としては、合成しやすいとともに、カチオン化させやすく、より幅広い pH の範囲で高い安定性を獲得することができ、吸収極大波長及び蛍光極大波長をより長波長にしやすい観点から、水素原子又はアルキル基がより好ましい。特に、R5及びR6をアルキル基とした場合、R5及びR6が水素原子の場合と比較しても、吸収極大波長及び蛍光極大波長をさらに長波長とすることができ、さらに、幅広いpHの範囲で分解せずに高い安定性を有する。このため、R5及びR6をアルキル基とした場合には、バイオイメージングに通常採用される中性領域(pH6~8程度)であっても分解せずに高い安定性を有するため、高い吸光度を維持することができる。したがって、本発明のジチエノホスホリン化合物において、R5及びR6をアルキル基とした化合物は、バイオイメージング用途に特に有用である。
Among these, R 5 and R 6 are easy to synthesize, easily cationized, and can acquire high stability in a wider pH range, and have longer absorption maximum wavelengths and fluorescence maximum wavelengths. From the viewpoint of easy formation, a hydrogen atom or an alkyl group is more preferable. In particular, when R 5 and R 6 are alkyl groups, even when R 5 and R 6 are hydrogen atoms, the absorption maximum wavelength and the fluorescence maximum wavelength can be further increased, and a wider range High stability without decomposition in the pH range. For this reason, when R 5 and R 6 are alkyl groups, they have high stability without being decomposed even in the neutral region (about pH 6 to 8) that is usually used for bioimaging. Can be maintained. Therefore, in the dithienophosphorine compound of the present invention, compounds in which R 5 and R 6 are alkyl groups are particularly useful for bioimaging applications.
一般式(1)において、Xで示されるアニオンとしては、例えば、ハロゲンイオン(フッ化物イオン、塩化物イオン、臭化物イオン、ヨウ化物イオン等)、シアン化物イオン、酢酸イオン、トリフルオロ酢酸イオン等が挙げられる。このアニオンのモル数であるnは、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。
In the general formula (1), examples of the anion represented by X include halogen ions (fluoride ions, chloride ions, bromide ions, iodide ions, etc.), cyanide ions, acetate ions, trifluoroacetate ions, and the like. Can be mentioned. N the number of moles of the anion is a 2 for group R 2 is in the case of the group represented by the general formula (3A) or (3C) of 1, R 2 is represented by the general formula (3B) is there.
このような条件を満たす本発明のジチエノホスホリン化合物としては、合成がより容易であるとともに、耐光性及び水溶性がより高く、より高い蛍光量子収率を有し、より幅広い pH の範囲で高い安定性を獲得することができ、吸収極大波長及び蛍光極大波長をより高くしやすく、バイオイメージングの際により認識しやすくする観点から、一般式(1A):
The dithienophospholine compound of the present invention that satisfies such conditions is easier to synthesize, has higher light resistance and water solubility, has a higher fluorescence quantum yield, and has a wider range of pH values. From the viewpoint of achieving high stability, making it easier to increase the absorption maximum wavelength and the fluorescence maximum wavelength, and making it easier to recognize during bioimaging, the general formula (1A):
[式中、R2、R3、R4、R5、R6、R7、X及びnは前記に同じである。]
で表されるジチエノホスホリン化合物が好ましく、一般式(1A1): [Wherein, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and n are the same as defined above. ]
A dithienophosphorine compound represented by general formula (1A1):
で表されるジチエノホスホリン化合物が好ましく、一般式(1A1): [Wherein, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and n are the same as defined above. ]
A dithienophosphorine compound represented by general formula (1A1):
[式中、R2、R3、R4、R7、X及びnは前記に同じである。R5a及びR6aは同一又は異なって、置換されていてもよいアルキル基を示す。]
で表されるジチエノホスホリン化合物がより好ましい。 [Wherein R 2 , R 3 , R 4 , R 7 , X and n are the same as defined above. R 5a and R 6a are the same or different and each represents an optionally substituted alkyl group. ]
The dithienophosphorine compound represented by these is more preferable.
で表されるジチエノホスホリン化合物がより好ましい。 [Wherein R 2 , R 3 , R 4 , R 7 , X and n are the same as defined above. R 5a and R 6a are the same or different and each represents an optionally substituted alkyl group. ]
The dithienophosphorine compound represented by these is more preferable.
このような本発明のジチエノホスホリン化合物としては、例えば、
Examples of the dithienophosphorine compound of the present invention include, for example,
[式中、Phはフェニル基を示す。Etはエチル基を示す。以下同様である。]
等で表されるジチエノホスホリン化合物等が挙げられ、 [Wherein, Ph represents a phenyl group. Et represents an ethyl group. The same applies hereinafter. ]
Dithienophosphorine compounds represented by
等で表されるジチエノホスホリン化合物等が挙げられ、 [Wherein, Ph represents a phenyl group. Et represents an ethyl group. The same applies hereinafter. ]
Dithienophosphorine compounds represented by
等で表されるジチエノホスホリン化合物が好ましく、
A dithienophosphorine compound represented by
等で表されるジチエノホスホリン化合物がより好ましい。
A dithienophosphorine compound represented by the above formula is more preferred.
なお、本発明のジチエノホスホリン化合物は、吸収極大波長が好ましくは650~850nm、より好ましくは700~800nmに有することができ、蛍光極大波長を750~1000nm、より好ましくは800~950nmに有することができるとともに、pHが3~12程度の範囲において、従来の蛍光色素よりも耐光性を飛躍的に向上させることが可能である。このため、吸収極大波長及び蛍光極大波長を、従来のICGと同程度にまで長くしつつ、耐光性をICGよりも飛躍的に向上させることが可能である。このため、従来の蛍光色素と比較しても、より吸収極大波長及び蛍光極大波長を高くすることが可能であり、バイオイメージング用蛍光プローブ、有機EL素子用蛍光材料等の用途に有用である。特に、上記のとおり、R5及びR6をアルキル基とした場合、R5及びR6が水素原子の場合と比較しても、吸収極大波長及び蛍光極大波長をさらに長波長とすることができ、さらに、幅広いpHの範囲で分解せずに高い安定性を有する。このため、R5及びR6をアルキル基とした場合には、バイオイメージングに通常採用される中性領域(pH6~8程度)であっても分解せずに高い安定性を有するため、高い吸光度を維持することができる。したがって、本発明のジチエノホスホリン化合物において、R5及びR6をアルキル基とした化合物は、バイオイメージング用途に特に有用である。
The dithienophosphorine compound of the present invention can have an absorption maximum wavelength of preferably 650 to 850 nm, more preferably 700 to 800 nm, and a fluorescence maximum wavelength of 750 to 1000 nm, more preferably 800 to 950 nm. In addition, the light resistance can be drastically improved over conventional fluorescent dyes in the pH range of about 3-12. Therefore, it is possible to dramatically improve the light resistance compared to the ICG while making the absorption maximum wavelength and the fluorescence maximum wavelength as long as the conventional ICG. For this reason, it is possible to increase the absorption maximum wavelength and the fluorescence maximum wavelength even compared with conventional fluorescent dyes, and it is useful for applications such as a fluorescent probe for bioimaging and a fluorescent material for organic EL elements. In particular, as described above, when R 5 and R 6 are alkyl groups, the absorption maximum wavelength and the fluorescence maximum wavelength can be further increased even when R 5 and R 6 are hydrogen atoms. Furthermore, it has high stability without decomposition over a wide pH range. For this reason, when R 5 and R 6 are alkyl groups, they have high stability without being decomposed even in the neutral region (about pH 6 to 8) that is usually used for bioimaging. Can be maintained. Therefore, in the dithienophosphorine compound of the present invention, compounds in which R 5 and R 6 are alkyl groups are particularly useful for bioimaging applications.
なお、本発明のジチエノホスホリン化合物は、水和物又は溶媒和物として存在する場合もあるが、これらの物質はいずれも本発明の範囲に包含される。
The dithienophosphorine compound of the present invention may exist as a hydrate or a solvate, and any of these substances is included in the scope of the present invention.
2.ジチエノホスホリン化合物の製造方法
本発明のジチエノホスホリン化合物は、特に制限されず、様々な方法で合成することが可能である。例えば、R1が一般式(2A)で表される基である本発明のジチエノホスホリン化合物(1A)のうち、R5及びR6が水素原子であるジチエノホスホリン化合物(1A2)は、以下の反応式1: 2. Method for Producing Dithienophosphorine Compound The dithienophospholine compound of the present invention is not particularly limited, and can be synthesized by various methods. For example, among the dithienophospholine compounds (1A) of the present invention in which R 1 is a group represented by the general formula (2A), the dithienophospholine compound (1A2) in which R 5 and R 6 are hydrogen atoms is The following reaction formula 1:
本発明のジチエノホスホリン化合物は、特に制限されず、様々な方法で合成することが可能である。例えば、R1が一般式(2A)で表される基である本発明のジチエノホスホリン化合物(1A)のうち、R5及びR6が水素原子であるジチエノホスホリン化合物(1A2)は、以下の反応式1: 2. Method for Producing Dithienophosphorine Compound The dithienophospholine compound of the present invention is not particularly limited, and can be synthesized by various methods. For example, among the dithienophospholine compounds (1A) of the present invention in which R 1 is a group represented by the general formula (2A), the dithienophospholine compound (1A2) in which R 5 and R 6 are hydrogen atoms is The following reaction formula 1:
[式中、R2、R7、X及びnは前記に同じである。X1は同一又は異なって、ハロゲン原子を示す。R10は同一又は異なって、置換されていてもよいアリール基を示す。]
にしたがって合成することができる。 [Wherein R 2 , R 7 , X and n are the same as defined above. X 1 is the same or different and represents a halogen atom. R 10 is the same or different and represents an optionally substituted aryl group. ]
Can be synthesized according to
にしたがって合成することができる。 [Wherein R 2 , R 7 , X and n are the same as defined above. X 1 is the same or different and represents a halogen atom. R 10 is the same or different and represents an optionally substituted aryl group. ]
Can be synthesized according to
反応式1において、X1で示されるハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子等が挙げられ、収率の観点から、臭素原子が好ましい。
In the reaction formula 1, examples of the halogen atom represented by X 1 include a chlorine atom, a bromine atom, and an iodine atom, and a bromine atom is preferable from the viewpoint of yield.
反応式1において、R10で示されるアリール基としては、上記したものを採用できる。置換基の種類及び数も同様である。
In Reaction Scheme 1, as the aryl group represented by R 10 , those described above can be employed. The kind and number of substituents are the same.
また、R1が一般式(2A)で表される基であり、R5及びR6が置換されていてもよいアルキル基である本発明のジチエノホスホリン化合物(1A1)は、以下の反応式2:
In addition, the dithienophosphorine compound (1A1) of the present invention in which R 1 is a group represented by the general formula (2A) and R 5 and R 6 are optionally substituted alkyl groups has the following reaction Formula 2:
[式中、R2、R3、R4、R5a、R6a、R7、X、X1及びnは前記に同じである。]
にしたがって合成することができる。 [Wherein R 2 , R 3 , R 4 , R 5a , R 6a , R 7 , X, X 1 and n are the same as defined above. ]
Can be synthesized according to
にしたがって合成することができる。 [Wherein R 2 , R 3 , R 4 , R 5a , R 6a , R 7 , X, X 1 and n are the same as defined above. ]
Can be synthesized according to
なお、R1が一般式(2A)で表される基であり、R5が置換されていてもよいアルキル基、R6が水素原子である本発明のジチエノホスホリン化合物(1A3)は、以下の反応式3:
In addition, the dithienophospholine compound (1A3) of the present invention in which R 1 is a group represented by the general formula (2A), R 5 is an optionally substituted alkyl group, and R 6 is a hydrogen atom, Scheme 3 below:
[式中、R2、R3、R4、R5a、R7、R10、X、X1及びnは前記に同じである。]
にしたがって合成することができる。 [Wherein R 2 , R 3 , R 4 , R 5a , R 7 , R 10 , X, X 1 and n are the same as defined above. ]
Can be synthesized according to
にしたがって合成することができる。 [Wherein R 2 , R 3 , R 4 , R 5a , R 7 , R 10 , X, X 1 and n are the same as defined above. ]
Can be synthesized according to
(2-1)化合物(4)→化合物(5)
本工程では、化合物(4)を有機リチウム化合物と反応させた後に、求電子性ハロゲン化剤と反応させ、次いで酸を添加することで、化合物(5)を得ることができる。 (2-1) Compound (4) → Compound (5)
In this step, compound (4) can be obtained by reacting compound (4) with an organolithium compound, then reacting with an electrophilic halogenating agent, and then adding an acid.
本工程では、化合物(4)を有機リチウム化合物と反応させた後に、求電子性ハロゲン化剤と反応させ、次いで酸を添加することで、化合物(5)を得ることができる。 (2-1) Compound (4) → Compound (5)
In this step, compound (4) can be obtained by reacting compound (4) with an organolithium compound, then reacting with an electrophilic halogenating agent, and then adding an acid.
化合物(4)は、例えば、既報(Angew. Chem. Int. Ed. 2013, 52, 8990-8994.)にしたがって合成することができる。
Compound (4) can be synthesized, for example, according to a report (Angew. Chem. Int. Ed. 2013, 52, 8990-8994.).
有機リチウム化合物としては、例えば、エチルリチウム、n-プロピルリチウム、イソプロピルリチウム、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、ペンチルリチウム、ヘキシルリチウム等のアルキルリチウム;シクロヘキシルリチウム等のシクロアルキルリチウム;フェニルリチウム等のアリールリチウム等の1種又は2種以上が挙げられる。これらのうち、本工程では、収率の観点から、アルキルリチウムが好ましく、sec-ブチルリチウムがより好ましい。有機リチウム化合物の使用量は、合成の容易さ、収率等の観点から、通常、化合物(4)1モルに対して、1~10モルが好ましく、2~5モルがより好ましい。
Examples of the organic lithium compound include alkyllithium such as ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, pentyllithium, and hexyllithium; and cycloalkyl such as cyclohexyllithium. Lithium: One or two or more kinds of aryllithium such as phenyllithium may be used. Among these, in this step, alkyllithium is preferable and sec-butyllithium is more preferable from the viewpoint of yield. The amount of the organic lithium compound used is usually preferably from 1 to 10 mol, more preferably from 2 to 5 mol, based on 1 mol of the compound (4), from the viewpoint of ease of synthesis, yield, and the like.
求電子性ハロゲン化剤としては、例えば、ヨウ素(I2)、臭素(Br2)、一塩化ヨウ素(ICl)、N-ヨードスクシンイミド(NIS)、N-ブロモスクシンイミド(NBS)、1,2-ジヨードエタン(ICH2CH2I)、1,2-ジブロモエタン(BrCH2CH2Br)、1,2-ジブロモ-1,1,2,2-テトラクロロエタン(BrCl2CCCl2Br)等の1種又は2種以上が挙げられる。求電子性ハロゲン化剤の使用量は、通常、化合物(4)1モルに対して、1~10モルが好ましく、2~5モルがより好ましい。
Examples of the electrophilic halogenating agent include iodine (I 2 ), bromine (Br 2 ), iodine monochloride (ICl), N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), 1,2- One such as diiodoethane (ICH 2 CH 2 I), 1,2-dibromoethane (BrCH 2 CH 2 Br), 1,2-dibromo-1,1,2,2-tetrachloroethane (BrCl 2 CCCl 2 Br) Or 2 or more types are mentioned. The amount of the electrophilic halogenating agent to be used is generally preferably 1 to 10 mol, more preferably 2 to 5 mol, per 1 mol of compound (4).
酸としては、例えば、塩化水素(塩酸)、硫酸、過酸化水素、ギ酸、酢酸、トリフルオロ酢酸(TFA)、無水トリフルオロ酢酸、三フッ化ホウ素ジエチルエーテル錯体、トリフルオロメタンスルホン酸等の1種又は2種以上が挙げられる。酸の使用量は、合成の容易さ、収率等の観点から、化合物(4)1モルに対して、0.2~3.0モルが好ましく、0.5~1.5モルがより好ましい。酸が液体である場合は過剰量、例えば溶媒量とすることも可能である。
Examples of the acid include hydrogen chloride (hydrochloric acid), sulfuric acid, hydrogen peroxide, formic acid, acetic acid, trifluoroacetic acid (TFA), trifluoroacetic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid and the like. Or 2 or more types are mentioned. The amount of the acid to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol with respect to 1 mol of the compound (4), from the viewpoint of ease of synthesis, yield and the like. When the acid is a liquid, an excess amount, for example, a solvent amount can be used.
反応は通常反応溶媒の存在下で行うことができる。使用できる反応溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ジブチルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、ジメトキシエタン(DME)、ジグライム、シクロペンチルメチルエーテル(CPME)、tert-ブチルメチルエーテル(TBME)、アニソール等のエーテル;ベンゼン、トルエン、キシレン等の芳香族炭化水素等が挙げられ、合成の容易さ、収率等の観点から、エーテルが好ましく、テトラヒドロフランがより好ましい。これらの反応溶媒は単独で用いることもでき、2種以上を組合せて用いることもできる。
The reaction can usually be performed in the presence of a reaction solvent. Usable reaction solvents include, for example, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and tetrahydrofuran is more preferable from the viewpoint of ease of synthesis and yield. These reaction solvents can be used alone or in combination of two or more.
反応雰囲気は、通常、不活性ガス雰囲気(アルゴンガス雰囲気、窒素ガス雰囲気等)を採用し得る。反応温度は、加熱下、常温下及び冷却下のいずれでも行うことができ、通常、有機リチウム化合物及び求電子性ハロゲン化剤との反応は-150~0℃(特に-100~-50℃)で行い、酸との反応は-50~100℃(特に0~50℃)で行うことが好ましい。反応時間は特に制限されず、反応が十分に進行する時間とすることが好ましい。
The reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.). The reaction temperature can be any of heating, normal temperature, and cooling. Usually, the reaction with the organolithium compound and the electrophilic halogenating agent is −150 to 0 ° C. (particularly −100 to −50 ° C.). The reaction with the acid is preferably carried out at -50 to 100 ° C (especially 0 to 50 ° C). The reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
反応終了後は、必要に応じて常法にしたがって精製処理をすることもできる。また、精製処理を施さずに次の工程を行うこともできる。
After completion of the reaction, purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement | purification process.
(2-2)化合物(5)→化合物(6)、化合物(10)→化合物(11)
本工程では、化合物(5)又は化合物(10)と、一般式(8): (2-2) Compound (5) → Compound (6), Compound (10) → Compound (11)
In this step, compound (5) or compound (10) and general formula (8):
本工程では、化合物(5)又は化合物(10)と、一般式(8): (2-2) Compound (5) → Compound (6), Compound (10) → Compound (11)
In this step, compound (5) or compound (10) and general formula (8):
[式中、R10は前記に同じである。]
で表される化合物とを、鈴木-宮浦カップリング反応により反応させることで、化合物(6)又は化合物(11)を得ることができる。 [Wherein, R 10 is the same as defined above. ]
The compound (6) or the compound (11) can be obtained by reacting the compound represented by the formula (1) with a Suzuki-Miyaura coupling reaction.
で表される化合物とを、鈴木-宮浦カップリング反応により反応させることで、化合物(6)又は化合物(11)を得ることができる。 [Wherein, R 10 is the same as defined above. ]
The compound (6) or the compound (11) can be obtained by reacting the compound represented by the formula (1) with a Suzuki-Miyaura coupling reaction.
化合物(8)の使用量は、通常、化合物(5)又は化合物(10)1モルに対して、1.5~5.0モル(特に2.0~3.0モル)使用することが好ましい。
In general, the compound (8) is preferably used in an amount of 1.5 to 5.0 mol (particularly 2.0 to 3.0 mol) per mol of the compound (5) or the compound (10).
本工程では、鈴木-宮浦カップリングに通常使用されるパラジウム触媒が使用される。具体的には、酢酸パラジウム(Pd(OAc)2)、テトラキス(トリフェニルホスフィン)パラジウム(0)(Pd(PPh3)4)、トリフルオロ酢酸パラジウム、塩化パラジウム、臭化パラジウム、ヨウ化パラジウム、トリス(ジベンジリデンアセトン)ジパラジウム(0)(Pd2(dba)3)等が挙げられ、本工程では、合成の容易さ、収率等の観点から、酢酸パラジウム(Pd(OAc)2)が好ましい。パラジウム触媒の使用量は、合成の容易さ、収率等の観点から、通常、化合物(5)又は化合物(10)1モルに対して、0.02~0.50モルが好ましく、0.05~0.20モルがより好ましい。
In this step, a palladium catalyst usually used for Suzuki-Miyaura coupling is used. Specifically, palladium acetate (Pd (OAc) 2 ), tetrakis (triphenylphosphine) palladium (0) (Pd (PPh 3 ) 4 ), palladium trifluoroacetate, palladium chloride, palladium bromide, palladium iodide, Tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3 ) and the like. In this step, palladium acetate (Pd (OAc) 2 ) is used from the viewpoint of ease of synthesis and yield. preferable. The amount of the palladium catalyst used is usually preferably 0.02 to 0.50 mol, more preferably 0.05 to 0.20 mol with respect to 1 mol of the compound (5) or compound (10), from the viewpoint of ease of synthesis, yield, and the like. .
本工程では、必要に応じて配位子化合物を使用することもできる。使用できる配位子化合物としては、例えば、トリフェニルホスフィン、トリメトキシホスフィン、トリエチルホスフィン、トリイソプロピルホスフィン、トリ(tert-ブチル)ホスフィン、トリ(n-ブチル)ホスフィン、トリイソプロポキシホスフィン、トリシクロペンチルホスフィン、トリシクロヘキシルホスフィン、2,2’-ビピリジル、ジフェニルホスフィノメタン、1,2-ビス(ジフェニルホスフィノ)エタン、1,3-ビス(ジフェニルホスフィノ)プロパン、1,5-ビス(ジフェニルホスフィノ)ペンタン、1,5-シクロオクタジエン、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)等の1種又は2種以上が挙げられる。なかでも、本工程では、収率及び合成の容易さの観点から、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)が好ましい。配位子化合物の使用量は、合成の容易さ、収率等の観点から、通常、パラジウム触媒1モルに対して、0.5~5.0モルが好ましく、1.0~3.0モルがより好ましい。
In this step, a ligand compound can be used as necessary. Examples of ligand compounds that can be used include triphenylphosphine, trimethoxyphosphine, triethylphosphine, triisopropylphosphine, tri (tert-butyl) phosphine, tri (n-butyl) phosphine, triisopropoxyphosphine, and tricyclopentylphosphine. , Tricyclohexylphosphine, 2,2'-bipyridyl, diphenylphosphinomethane, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,5-bis (diphenylphosphino) ) Pentane, 1,5-cyclooctadiene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) and the like. Among these, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) is preferable in this step from the viewpoint of yield and ease of synthesis. The amount of the ligand compound used is usually preferably from 0.5 to 5.0 mol, more preferably from 1.0 to 3.0 mol, based on 1 mol of the palladium catalyst, from the viewpoint of ease of synthesis, yield, and the like.
本工程では、必要に応じて、塩基を使用することもできる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム、酢酸ナトリウム等が挙げられ、本工程では、収率及び合成の容易さの観点から、炭酸セシウムが好ましい。塩基を使用する場合の使用量は、合成の容易さ、収率等の観点から、化合物(5)又は化合物(10)1モルに対して、1~5モルが好ましく、1.5~3モルがより好ましい。
In this step, a base can be used as necessary. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate and the like. In this step, cesium carbonate is used from the viewpoint of yield and ease of synthesis. preferable. In the case of using a base, the amount used is preferably 1 to 5 mol, more preferably 1.5 to 3 mol with respect to 1 mol of compound (5) or compound (10) from the viewpoint of ease of synthesis, yield and the like. preferable.
反応は通常反応溶媒の存在下で行うことができる。使用できる反応溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ジブチルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、ジメトキシエタン(DME)、ジグライム、シクロペンチルメチルエーテル(CPME)、tert-ブチルメチルエーテル(TBME)、アニソール等のエーテル;ベンゼン、トルエン、キシレン等の芳香族炭化水素;アセトニトリル等のニトリル系溶媒;ジメチルホルムアミド等のアミド系溶媒等が挙げられ、合成の容易さ、収率等の観点から、芳香族炭化水素が好ましく、トルエンがより好ましい。これらの反応溶媒は単独で用いることもでき、2種以上を組合せて用いることもできる。
The reaction can usually be performed in the presence of a reaction solvent. Examples of the reaction solvent that can be used include diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene and xylene; nitrile solvents such as acetonitrile; amide solvents such as dimethylformamide, etc., from the viewpoint of ease of synthesis, yield, etc. Aromatic hydrocarbons are preferred, and toluene is more preferred. These reaction solvents can be used alone or in combination of two or more.
反応雰囲気は、通常、不活性ガス雰囲気(アルゴンガス雰囲気、窒素ガス雰囲気等)を採用し得る。反応温度は、加熱下、常温下及び冷却下のいずれでも行うことができ、通常、0~150℃(特に50~100℃)で行うことが好ましい。反応時間は特に制限されず、反応が十分に進行する時間とすることが好ましい。
The reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.). The reaction temperature can be any of heating, room temperature and cooling, and it is usually preferably 0 to 150 ° C. (especially 50 to 100 ° C.). The reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
反応終了後は、必要に応じて常法にしたがって精製処理をすることもできる。また、精製処理を施さずに次の工程を行うこともできる。
After completion of the reaction, purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement | purification process.
(2-3)化合物(5)→化合物(9)、化合物(10)
本工程では、化合物(5)とジアルキルアミン化合物とを反応させることで、化合物(9)又は化合物(10)を得ることができる。 (2-3) Compound (5) → Compound (9), Compound (10)
In this step, compound (9) or compound (10) can be obtained by reacting compound (5) with a dialkylamine compound.
本工程では、化合物(5)とジアルキルアミン化合物とを反応させることで、化合物(9)又は化合物(10)を得ることができる。 (2-3) Compound (5) → Compound (9), Compound (10)
In this step, compound (9) or compound (10) can be obtained by reacting compound (5) with a dialkylamine compound.
ジアルキルアミン化合物としては、本発明のジチエノホスホリン化合物(1A1)又はジチエノホスホリン化合物(1A3)において、所望のR5a及び必要に応じてR6aを導入できるものが好ましく、ジメチルアミン、ジエチルアミン、ジ(n-プロピル)アミン、ジイソプロピルアミン、ジ(n-ブチル)アミン、ジイソブチルアミン、ジ(sec-ブチル)アミン、ジ(tert-ブチル)アミン、メチルエチルアミン、イソプロピルエチルアミン等の1種又は2種以上が挙げられ、合成の容易さの観点から、ジエチルアミンが好ましい。ジアルキルアミン化合物の使用量は、収率等の観点から、化合物(5)に対して過剰量とすることが好ましく、溶媒量とすることも可能である。
The dialkylamine compound is preferably a dithienophospholine compound (1A1) or dithienophospholine compound (1A3) according to the present invention in which desired R 5a and, if necessary, R 6a can be introduced, dimethylamine, diethylamine , Di (n-propyl) amine, diisopropylamine, di (n-butyl) amine, diisobutylamine, di (sec-butyl) amine, di (tert-butyl) amine, methylethylamine, isopropylethylamine, etc. From the viewpoint of ease of synthesis, diethylamine is preferable. The amount of the dialkylamine compound used is preferably an excess amount relative to the compound (5) from the viewpoint of yield and the like, and can also be a solvent amount.
反応は通常反応溶媒の存在下で行うことができる。使用できる反応溶媒としては、例えば、ジブチルエーテル、ジイソプロピルエーテル、1,4-ジオキサン、ジメトキシエタン(DME)、ジグライム等のエーテル;トルエン、キシレン等の芳香族炭化水素;ジメチルホルムアミド等のアミド系溶媒等が挙げられ、合成の容易さ、収率等の観点から、アミド系溶媒が好ましく、ジメチルホルムアミドがより好ましい。これらの反応溶媒は単独で用いることもでき、2種以上を組合せて用いることもできる。
The reaction can usually be performed in the presence of a reaction solvent. Examples of the reaction solvent that can be used include ethers such as dibutyl ether, diisopropyl ether, 1,4-dioxane, dimethoxyethane (DME), and diglyme; aromatic hydrocarbons such as toluene and xylene; amide solvents such as dimethylformamide From the viewpoints of ease of synthesis, yield, etc., amide solvents are preferred, and dimethylformamide is more preferred. These reaction solvents can be used alone or in combination of two or more.
反応雰囲気は、通常、不活性ガス雰囲気(アルゴンガス雰囲気、窒素ガス雰囲気等)を採用し得る。反応温度は、加熱下、常温下及び冷却下のいずれでも行うことができ、通常、50~150℃(特に80~130℃)で行うことが好ましい。なお、高温(100~150℃等)で反応させた場合は化合物(9)が得られ、低温(50~100℃等)で反応させた場合は化合物(10)が得られる。反応時間は特に制限されず、反応が十分に進行する時間とすることが好ましい。
The reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.). The reaction temperature can be any of heating, room temperature and cooling, and it is usually preferably 50 to 150 ° C. (especially 80 to 130 ° C.). When reacted at a high temperature (100 to 150 ° C., etc.), compound (9) is obtained, and when reacted at a low temperature (50 to 100 ° C., etc.), compound (10) is obtained. The reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
反応終了後は、必要に応じて常法にしたがって精製処理をすることもできる。また、精製処理を施さずに次の工程を行うこともできる。
After completion of the reaction, purification can be performed according to a conventional method if necessary. Moreover, the following process can also be performed without performing a refinement | purification process.
(2-4)化合物(6)→化合物(1A2)、化合物(11)→化合物(1A3)
本工程では、化合物(6)又は化合物(11)と有機金属求核剤(グリニャール試薬、有機リチウム化合物等)及び酸試薬とを反応させることで、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)を得ることができる。この際、酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)のアニオンXを構成する。 (2-4) Compound (6) → Compound (1A2), Compound (11) → Compound (1A3)
In this step, the dithienophosphorine compound (1A2) of the present invention or the compound (6) or the compound (11) is reacted with an organometallic nucleophile (Grignard reagent, organolithium compound, etc.) and an acid reagent. A dithienophosphorine compound (1A3) can be obtained. At this time, the anion contained in the acid reagent constitutes the anion X of the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention.
本工程では、化合物(6)又は化合物(11)と有機金属求核剤(グリニャール試薬、有機リチウム化合物等)及び酸試薬とを反応させることで、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)を得ることができる。この際、酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)のアニオンXを構成する。 (2-4) Compound (6) → Compound (1A2), Compound (11) → Compound (1A3)
In this step, the dithienophosphorine compound (1A2) of the present invention or the compound (6) or the compound (11) is reacted with an organometallic nucleophile (Grignard reagent, organolithium compound, etc.) and an acid reagent. A dithienophosphorine compound (1A3) can be obtained. At this time, the anion contained in the acid reagent constitutes the anion X of the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention.
グリニャール試薬としては、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)において所望のR7を導入できるものが好ましく、R7MgX2(R7は前記に同じである。X2はハロゲン原子を示す。)で表される有機マグネシウム化合物が好ましい。
As the Grignard reagent, those capable of introducing a desired R 7 in the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention are preferable, and R 7 MgX 2 (R 7 is the same as above) X 2 represents a halogen atom).
X2で示されるハロゲン原子としては、上記したものを採用できる。好ましい具体例も同様である。
As the halogen atom represented by X 2 , those described above can be adopted. The same applies to preferred embodiments.
このような条件を満たすグリニャール試薬としては、例えば、
Examples of Grignard reagents that satisfy these conditions include:
等が挙げられる。
Etc.
有機リチウム化合物としては、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)において所望のR7を導入できるものが好ましく、R7Li(R7は前記に同じである。)で表される有機リチウム化合物が好ましい。
As the organolithium compound, those capable of introducing the desired R 7 in the dithienophospholine compound (1A2) or dithienophospholine compound (1A3) of the present invention are preferable, and R 7 Li (R 7 is the same as above) .) Is preferred.
このような条件を満たす有機リチウム化合物としては、例えば、
Examples of organolithium compounds that satisfy these conditions include:
等が挙げられる。
Etc.
有機金属求核剤の使用量は、収率等の観点から、化合物(6)又は化合物(11)1モルに対して、0.2~30.0モル(特に0.5~15.0モル)使用することが好ましい。化合物(1A2)を得ようとする場合は多め(5.0~30.0モル等)に使用することが好ましく、化合物(1A3)を得ようとする場合は少なめ(0.2~5.0モル等)に使用することが好ましい。
The amount of the organometallic nucleophile used is preferably 0.2 to 30.0 mol (especially 0.5 to 15.0 mol) with respect to 1 mol of compound (6) or compound (11) from the viewpoint of yield and the like. When it is intended to obtain the compound (1A2), it is preferably used in a large amount (5.0 to 30.0 mol, etc.), and when it is intended to obtain the compound (1A3), it is preferably used in a small amount (0.2 to 5.0 mol, etc.). preferable.
酸試薬としては、例えば、塩化水素(塩酸)、硫酸、ギ酸、酢酸、トリフルオロ酢酸(TFA)、無水トリフルオロ酢酸、三フッ化ホウ素ジエチルエーテル錯体、トリフルオロメタンスルホン酸等を使用することができる。酸試薬の使用量は、合成の容易さ、収率等の観点から、化合物(6)1モルに対して、0.2~3.0モルが好ましく、0.5~1.5モルがより好ましい。酸試薬が液体である場合は過剰量、例えば溶媒量とすることも可能である。
Examples of the acid reagent that can be used include hydrogen chloride (hydrochloric acid), sulfuric acid, formic acid, acetic acid, trifluoroacetic acid (TFA), trifluoroacetic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid, and the like. . The amount of the acid reagent to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol, relative to 1 mol of compound (6), from the viewpoint of ease of synthesis, yield and the like. When the acid reagent is a liquid, it may be in an excess amount, for example, a solvent amount.
反応は通常反応溶媒の存在下で行うことができる。使用できる反応溶媒としては、例えば、ジエチルエーテル、ジブチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、ジメトキシエタン(DME)、ジグライム、シクロペンチルメチルエーテル(CPME)、tert-ブチルメチルエーテル(TBME)、アニソール等のエーテル;ベンゼン、トルエン、キシレン等の芳香族炭化水素等が挙げられ、合成の容易さ、収率等の観点から、エーテルが好ましく、テトラヒドロフランがより好ましい。これらの反応溶媒は単独で用いることもでき、2種以上を組合せて用いることもできる。
The reaction can usually be performed in the presence of a reaction solvent. Examples of usable reaction solvents include diethyl ether, dibutyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and tetrahydrofuran is more preferable from the viewpoint of ease of synthesis and yield. These reaction solvents can be used alone or in combination of two or more.
反応雰囲気は、通常、不活性ガス雰囲気(アルゴンガス雰囲気、窒素ガス雰囲気等)を採用し得る。反応温度は、加熱下、常温下及び冷却下のいずれでも行うことができ、通常、-50~150℃(特に0~100℃)で行うことが好ましい。反応時間は特に制限されず、反応が十分に進行する時間とすることが好ましい。
The reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.). The reaction temperature can be any of heating, room temperature, and cooling, and it is usually preferably -50 to 150 ° C (particularly 0 to 100 ° C). The reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
反応終了後は、必要に応じて常法にしたがって精製し、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)を得ることができる。
After completion of the reaction, the dithienophosphorine compound (1A2) or dithienophospholine compound (1A3) of the present invention can be obtained by purifying according to a conventional method if necessary.
なお、本工程は、上記のみに限定されず、化合物(6)又は化合物(11)と第一酸試薬(塩酸等)とを反応させて一般式(7)又は(12):
In addition, this process is not limited only to the above, but the compound (6) or the compound (11) is reacted with a first acid reagent (hydrochloric acid, etc.) to give a general formula (7) or (12):
[式中、R2、R3、R4及びR5aは前記に同じである。]
で表される化合物を得た後に、化合物(7)又は化合物(12)とグリニャール試薬とを反応させ、その後、第二酸試薬(塩酸、トリフルオロ酢酸等)と反応させることで、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)を得ることも可能である。この際、第二酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)のアニオンXを構成する。 [Wherein, R 2 , R 3 , R 4 and R 5a are the same as defined above. ]
After obtaining the compound represented by formula (1), the compound (7) or the compound (12) is reacted with a Grignard reagent, and then reacted with a second acid reagent (hydrochloric acid, trifluoroacetic acid, etc.). It is also possible to obtain a dithienophosphorine compound (1A2) or a dithienophospholine compound (1A3). At this time, the anion contained in the second acid reagent constitutes the anion X of the dithienophosphorine compound (1A2) or dithienophospholine compound (1A3) of the present invention.
で表される化合物を得た後に、化合物(7)又は化合物(12)とグリニャール試薬とを反応させ、その後、第二酸試薬(塩酸、トリフルオロ酢酸等)と反応させることで、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)を得ることも可能である。この際、第二酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A2)又はジチエノホスホリン化合物(1A3)のアニオンXを構成する。 [Wherein, R 2 , R 3 , R 4 and R 5a are the same as defined above. ]
After obtaining the compound represented by formula (1), the compound (7) or the compound (12) is reacted with a Grignard reagent, and then reacted with a second acid reagent (hydrochloric acid, trifluoroacetic acid, etc.). It is also possible to obtain a dithienophosphorine compound (1A2) or a dithienophospholine compound (1A3). At this time, the anion contained in the second acid reagent constitutes the anion X of the dithienophosphorine compound (1A2) or dithienophospholine compound (1A3) of the present invention.
(2-5)化合物(9)→化合物(1A1)
本工程では、化合物(9)と有機ハロゲン化合物とを反応させた後に、有機金属求核剤(グリニャール試薬、有機リチウム化合物等)及び酸試薬と反応させることで、本発明のジチエノホスホリン化合物(1A1)を得ることができる。この際、酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A1)のアニオンXを構成する。 (2-5) Compound (9) → Compound (1A1)
In this step, after reacting compound (9) with an organic halogen compound, the dithienophosphorine compound of the present invention is reacted with an organometallic nucleophile (Grignard reagent, organolithium compound, etc.) and an acid reagent. (1A1) can be obtained. At this time, the anion contained in the acid reagent constitutes the anion X of the dithienophosphorine compound (1A1) of the present invention.
本工程では、化合物(9)と有機ハロゲン化合物とを反応させた後に、有機金属求核剤(グリニャール試薬、有機リチウム化合物等)及び酸試薬と反応させることで、本発明のジチエノホスホリン化合物(1A1)を得ることができる。この際、酸試薬中に含まれるアニオンが、本発明のジチエノホスホリン化合物(1A1)のアニオンXを構成する。 (2-5) Compound (9) → Compound (1A1)
In this step, after reacting compound (9) with an organic halogen compound, the dithienophosphorine compound of the present invention is reacted with an organometallic nucleophile (Grignard reagent, organolithium compound, etc.) and an acid reagent. (1A1) can be obtained. At this time, the anion contained in the acid reagent constitutes the anion X of the dithienophosphorine compound (1A1) of the present invention.
有機ハロゲン化合物としては、例えば、トリクロロシラン、ジフェニルジクロロシラン、トリフェニルクロロシラン等のハロゲン化シランの1種又は2種以上が挙げられる。有機ハロゲン化合物の使用量は、合成の容易さ、収率等の観点から、化合物(9)1モルに対して、2.0~20.0モルが好ましく、3.0~10.0モルがより好ましい。
Examples of the organic halogen compound include one or more halogenated silanes such as trichlorosilane, diphenyldichlorosilane, and triphenylchlorosilane. The amount of the organic halogen compound used is preferably from 2.0 to 20.0 mol, more preferably from 3.0 to 10.0 mol, based on 1 mol of the compound (9), from the viewpoint of ease of synthesis, yield and the like.
グリニャール試薬及び有機リチウム化合物としては、上記したものを採用できる。好ましい具体例も同様である。
As the Grignard reagent and the organic lithium compound, those described above can be adopted. The same applies to preferred embodiments.
有機金属求核剤の使用量は、収率等の観点から、化合物(9)1モルに対して、1.0~30.0モル(特に2.0~15.0モル)使用することが好ましい。
The amount of the organometallic nucleophile used is preferably 1.0 to 30.0 mol (particularly 2.0 to 15.0 mol) per 1 mol of compound (9) from the viewpoint of yield and the like.
酸試薬としては、上記したものを採用できる。好ましい具体例も同様である。酸試薬の使用量は、合成の容易さ、収率等の観点から、化合物(9)1モルに対して、0.2~3.0モルが好ましく、0.5~1.5モルがより好ましい。酸試薬が液体である場合は過剰量、例えば溶媒量とすることも可能である。
As the acid reagent, those described above can be adopted. The same applies to preferred embodiments. The amount of the acid reagent to be used is preferably 0.2 to 3.0 mol, more preferably 0.5 to 1.5 mol, per 1 mol of compound (9), from the viewpoints of ease of synthesis, yield and the like. When the acid reagent is a liquid, it may be in an excess amount, for example, a solvent amount.
反応は通常反応溶媒の存在下で行うことができる。使用できる反応溶媒としては、例えば、ジエチルエーテル、ジブチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、ジメトキシエタン(DME)、ジグライム、シクロペンチルメチルエーテル(CPME)、tert-ブチルメチルエーテル(TBME)、アニソール等のエーテル;ベンゼン、トルエン、キシレン等の芳香族炭化水素等が挙げられ、合成の容易さ、収率等の観点から、エーテルが好ましく、シクロペンチルメチルエーテル(CPME)がより好ましい。これらの反応溶媒は単独で用いることもでき、2種以上を組合せて用いることもできる。
The reaction can usually be performed in the presence of a reaction solvent. Examples of usable reaction solvents include diethyl ether, dibutyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane (DME), diglyme, cyclopentyl methyl ether (CPME), tert-butyl methyl ether ( TBME), ethers such as anisole; aromatic hydrocarbons such as benzene, toluene, and xylene, and the like. Ethers are preferable and cyclopentylmethyl ether (CPME) is more preferable from the viewpoint of ease of synthesis and yield. These reaction solvents can be used alone or in combination of two or more.
反応雰囲気は、通常、不活性ガス雰囲気(アルゴンガス雰囲気、窒素ガス雰囲気等)を採用し得る。反応温度は、加熱下、常温下及び冷却下のいずれでも行うことができ、通常、-50~150℃(特に0~100℃)で行うことが好ましい。反応時間は特に制限されず、反応が十分に進行する時間とすることが好ましい。
The reaction atmosphere can usually be an inert gas atmosphere (argon gas atmosphere, nitrogen gas atmosphere, etc.). The reaction temperature can be any of heating, room temperature, and cooling, and it is usually preferably -50 to 150 ° C (particularly 0 to 100 ° C). The reaction time is not particularly limited, and is preferably a time for which the reaction proceeds sufficiently.
反応終了後は、必要に応じて常法にしたがって精製し、本発明のジチエノホスホリン化合物(1A1)を得ることができる。
After completion of the reaction, the dithienophosphorine compound (1A1) of the present invention can be obtained by purifying according to a conventional method if necessary.
また、上記では、本発明のジチエノホスホリン化合物(1A)の製造方法の一例を示したが、本発明のジチエノホスホリン化合物は、上記方法に限定されず、様々な方法で製造することができる。
Further, in the above, an example of the method for producing the dithienophospholine compound (1A) of the present invention has been shown. However, the dithienophospholine compound of the present invention is not limited to the above method, and may be produced by various methods. Can do.
例えば、R1が一般式(2B)で表される基である本発明のジチエノホスホリン化合物は、例えば、o-ハロゲン化安息香酸アルキル(o-ブロモ安息香酸メチル等)から誘導されるグリニャール試薬を用いること以外は反応式1と同様に処理を行い、安息香酸エステル部位を有するジチエノホスホリン化合物を合成した後、酸性条件又は塩基性条件下にエステル部位を加水分解することで製造することができる。
For example, the dithienophospholine compound of the present invention in which R 1 is a group represented by the general formula (2B) is, for example, a Grignard derived from an o-halogenated alkyl benzoate (such as methyl o-bromobenzoate). Produced by hydrolyzing the ester moiety under acidic or basic conditions after synthesizing a dithienophosphorine compound having a benzoate ester moiety by treating in the same manner as in Reaction Scheme 1 except that a reagent is used. be able to.
3.蛍光色素
本発明の蛍光色素は、上記の本発明のジチエノホスホリン化合物を含有する。 3. Fluorescent dye The fluorescent dye of the present invention contains the above-described dithienophosphorine compound of the present invention.
本発明の蛍光色素は、上記の本発明のジチエノホスホリン化合物を含有する。 3. Fluorescent dye The fluorescent dye of the present invention contains the above-described dithienophosphorine compound of the present invention.
本発明の蛍光色素は、ローダミン色素のベンゼン環部位をチオフェン骨格に置き換えるとともに、骨格内酸素原子をリン含有基に置き換えたため、吸収極大波長が好ましくは650~850nm、より好ましくは700~800nmに有することができ、蛍光極大波長を750~1000nm、より好ましくは800~950nmに有することができるとともに、pHが3~12程度の範囲において、従来の蛍光色素よりも耐光性を飛躍的に向上させることが可能である。このため、吸収極大波長及び蛍光極大波長を、従来のICGと同程度にまで長くし、高い蛍光量子収率を有しつつ、耐光性をICGよりも飛躍的に向上させることが可能である。しかも、要求特性に応じて、R1に所望の基を導入することが可能である。このため、本発明の蛍光色素は、バイオイメージング用蛍光プローブ、有機EL素子用蛍光材料等の用途に特に有用である。特に、本発明のジチエノホスホリン化合物は、吸収極大波長及び蛍光極大波長を高い波長に有しつつも、高波長領域に吸収極大波長及び蛍光極大波長を有する従来の蛍光色素にはなかった高い蛍光量子収率を有し、さらに耐光性を飛躍的に向上させることができるため、バイオイメージングがしやすいとともに、バイオイメージングに必要な蛍光色素濃度を低く抑えることができ、生体へのダメージを大幅に低減でき、生体深部の観測を長時間にわたって行うことが可能である。なかでも、上記のとおり、R5及びR6をアルキル基とした場合、R5及びR6が水素原子の場合と比較しても、吸収極大波長及び蛍光極大波長をさらに長波長とすることができ、さらに、幅広いpHの範囲で分解せずに高い安定性を有する。このため、R5及びR6をアルキル基とした場合には、バイオイメージングに通常採用される中性領域(pH6~8程度)であっても分解せずに高い安定性を有するため、高い吸光度を維持することができる。したがって、本発明のジチエノホスホリン化合物において、R5及びR6をアルキル基とした化合物は、バイオイメージング用蛍光色素として特に有用である。
The fluorescent dye of the present invention has an absorption maximum wavelength of preferably 650 to 850 nm, more preferably 700 to 800 nm because the benzene ring portion of the rhodamine dye is replaced with a thiophene skeleton and the oxygen atom in the skeleton is replaced with a phosphorus-containing group. It can have a fluorescence maximum wavelength in the range of 750 to 1000 nm, more preferably 800 to 950 nm, and dramatically improve the light resistance over conventional fluorescent dyes in the pH range of about 3 to 12. Is possible. For this reason, it is possible to lengthen the absorption maximum wavelength and the fluorescence maximum wavelength to the same extent as those of the conventional ICG, and to greatly improve the light resistance as compared with the ICG while having a high fluorescence quantum yield. Moreover, it is possible to introduce a desired group into R 1 according to the required characteristics. For this reason, the fluorescent dye of the present invention is particularly useful for uses such as a fluorescent probe for bioimaging and a fluorescent material for organic EL elements. In particular, the dithienophosphorine compound of the present invention has a high absorption wavelength and a fluorescence maximum wavelength that are not found in conventional fluorescent dyes having an absorption maximum wavelength and a fluorescence maximum wavelength in a high wavelength region. Because it has a fluorescent quantum yield and can dramatically improve light resistance, it is easy to perform bioimaging, and the fluorescent dye concentration required for bioimaging can be kept low, resulting in significant damage to the living body. The observation of the deep part of the living body can be performed for a long time. In particular, as described above, when R 5 and R 6 are alkyl groups, even when R 5 and R 6 are hydrogen atoms, the absorption maximum wavelength and the fluorescence maximum wavelength can be further increased. In addition, it has high stability without degradation over a wide pH range. For this reason, when R 5 and R 6 are alkyl groups, they have high stability without being decomposed even in the neutral region (about pH 6 to 8) that is usually used for bioimaging. Can be maintained. Therefore, in the dithienophosphorine compound of the present invention, compounds in which R 5 and R 6 are alkyl groups are particularly useful as fluorescent dyes for bioimaging.
本発明の蛍光色素をバイオイメージング用途に使用する場合、有機溶媒中に溶解させて溶液とすることが好ましく、本発明のジチエノホスホリン化合物の含有量は、1×10-8~1×10-4mol/Lが好ましく、1×10-7~1×10-5mol/Lがより好ましい。このように、本発明では、従来の蛍光色素と比較し、ジチエノホスホリン化合物の含有量を低く抑えることができる。
When the fluorescent dye of the present invention is used for bioimaging applications, it is preferably dissolved in an organic solvent to form a solution. The content of the dithienophosphorine compound of the present invention is 1 × 10 −8 to 1 × 10 −4 mol / L is preferable, and 1 × 10 −7 to 1 × 10 −5 mol / L is more preferable. Thus, in this invention, compared with the conventional fluorescent pigment | dye, content of a dithienophosphorin compound can be restrained low.
本発明の蛍光色素(ジチエノホスホリン化合物)を溶液とする場合、使用し得る有機溶媒としては、特に制限はなく、極性溶媒及び非極性溶媒のいずれも使用できる。
When the fluorescent dye (dithienophosphorine compound) of the present invention is used as a solution, the organic solvent that can be used is not particularly limited, and either a polar solvent or a nonpolar solvent can be used.
極性溶媒としては、例えば、エーテル化合物(テトラヒドロフラン、アニソール、1,4-ジオキサン、シクロペンチルメチルエーテル等)、アルコール(メタノール、エタノール、アリルアルコール等)、エステル化合物(酢酸エチル等)、ケトン(アセトン等)、ハロゲン化炭化水素(ジクロロメタン、クロロホルム)、ジメチルスルホキシド、アミド系溶媒(N,N-ジメチルホルムアミド、ジメチルアセトアミド、1,3-ジメチル-2-イミダゾリジノン、N-メチルピロリドン等)等が挙げられる。
Examples of polar solvents include ether compounds (tetrahydrofuran, anisole, 1,4-dioxane, cyclopentyl methyl ether, etc.), alcohols (methanol, ethanol, allyl alcohol, etc.), ester compounds (ethyl acetate, etc.), ketones (acetone, etc.) , Halogenated hydrocarbons (dichloromethane, chloroform), dimethyl sulfoxide, amide solvents (N, N-dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc.) .
非極性溶媒としては、例えば、ペンタン、ヘキサン、シクロヘキサン、ヘプタン等の脂肪族有機溶媒;ベンゼン、トルエン、キシレン、メシチレン等の芳香族溶媒等が挙げられる。
Examples of the nonpolar solvent include aliphatic organic solvents such as pentane, hexane, cyclohexane and heptane; aromatic solvents such as benzene, toluene, xylene and mesitylene.
溶液とする場合、吸収極大波長及び蛍光極大波長を高くしつつも、生理的条件下でもより十分に高い蛍光量子収率としつつ、耐光性にも優れ、細胞中に投入する観点から、pHは3~12程度が好ましい。本発明の細胞検出剤のpHを調整するために、緩衝剤(ヘペス緩衝剤、トリス緩衝剤、トリシン-水酸化ナトリウム緩衝剤、リン酸系緩衝剤、リン酸緩衝生理食塩水等)等を使用することもできる。
In the case of a solution, while increasing the absorption maximum wavelength and the fluorescence maximum wavelength, the fluorescence quantum yield is sufficiently high even under physiological conditions, and the light resistance is excellent. About 3 to 12 is preferable. Buffers (Hepes buffer, Tris buffer, tricine-sodium hydroxide buffer, phosphate buffer, phosphate buffered saline, etc.) are used to adjust the pH of the cell detection agent of the present invention. You can also
実施例に基づいて、本発明を具体的に説明するが、本発明は、これらのみに限定されるものではない。
The present invention will be specifically described based on examples, but the present invention is not limited to these examples.
一般操作
1H NMR、13C NMR及び31P NMRスペクトルは核磁気共鳴装置AL-400(JEOL, 400 MHz for 1H, 162 MHz for 31P)を用いて測定した。1H NMRの化学シフト値は、重クロロホルム又は重メタノールの残留プロトンのシグナル(それぞれδ 7.26ppm, 3.31ppm)を内部標準として決定した。31P NMRの化学シフト値はH3PO4(δ 0.00ppm)を外部標準として決定した。カラムクロマトグラフィーには、シリカゲルPSQ 100B(富士シリシア化学(株))を用いた。分取リサイクルHPLCにはLC-Forte/R(YMCテクノス(株))又は日本分析工業(株)LC-9201を使用した。紫外可視吸収スペクトルの測定には、紫外可視近赤外分光光度計UV-3150((株)島津製作所)を用いた。蛍光スペクトルは、蛍光光度計Fluorolog-3(HORIBA)を用いて測定した。絶対蛍光量子収率は、マルチチャンネル分光器PMA-12を備えた絶対PL量子収率測定装置(浜松ホトニクス(株))を用いて測定した。反応には特に記述のない限り、市販の脱水溶媒(関東化学(株))をGlass Contour有機溶媒精製装置(ニッコー・ハンセン(株))で精製したものを用い、窒素雰囲気下で行った。 General operation 1 H NMR, 13 C NMR and 31 P NMR spectra were measured using a nuclear magnetic resonance apparatus AL-400 (JEOL, 400 MHz for 1 H, 162 MHz for 31 P). The chemical shift value of 1 H NMR was determined using the residual proton signals of deuterated chloroform or deuterated methanol (δ 7.26 ppm and 3.31 ppm, respectively) as an internal standard. The chemical shift value of 31 P NMR was determined using H 3 PO 4 (δ 0.00 ppm) as an external standard. Silica gel PSQ 100B (Fuji Silysia Chemical Co., Ltd.) was used for column chromatography. LC-Forte / R (YMC Technos Co., Ltd.) or Nippon Analytical Industry Co., Ltd. LC-9201 was used for preparative recycling HPLC. A UV-visible near-infrared spectrophotometer UV-3150 (Shimadzu Corporation) was used for the measurement of the UV-visible absorption spectrum. The fluorescence spectrum was measured using a fluorometer Fluorolog-3 (HORIBA). The absolute fluorescence quantum yield was measured using an absolute PL quantum yield measuring apparatus (Hamamatsu Photonics Co., Ltd.) equipped with a multichannel spectrometer PMA-12. Unless otherwise specified, the reaction was carried out under a nitrogen atmosphere using a commercially available dehydrated solvent (Kanto Chemical Co., Ltd.) purified with a Glass Contour organic solvent purifier (Nikko Hansen Co., Ltd.).
1H NMR、13C NMR及び31P NMRスペクトルは核磁気共鳴装置AL-400(JEOL, 400 MHz for 1H, 162 MHz for 31P)を用いて測定した。1H NMRの化学シフト値は、重クロロホルム又は重メタノールの残留プロトンのシグナル(それぞれδ 7.26ppm, 3.31ppm)を内部標準として決定した。31P NMRの化学シフト値はH3PO4(δ 0.00ppm)を外部標準として決定した。カラムクロマトグラフィーには、シリカゲルPSQ 100B(富士シリシア化学(株))を用いた。分取リサイクルHPLCにはLC-Forte/R(YMCテクノス(株))又は日本分析工業(株)LC-9201を使用した。紫外可視吸収スペクトルの測定には、紫外可視近赤外分光光度計UV-3150((株)島津製作所)を用いた。蛍光スペクトルは、蛍光光度計Fluorolog-3(HORIBA)を用いて測定した。絶対蛍光量子収率は、マルチチャンネル分光器PMA-12を備えた絶対PL量子収率測定装置(浜松ホトニクス(株))を用いて測定した。反応には特に記述のない限り、市販の脱水溶媒(関東化学(株))をGlass Contour有機溶媒精製装置(ニッコー・ハンセン(株))で精製したものを用い、窒素雰囲気下で行った。 General operation 1 H NMR, 13 C NMR and 31 P NMR spectra were measured using a nuclear magnetic resonance apparatus AL-400 (JEOL, 400 MHz for 1 H, 162 MHz for 31 P). The chemical shift value of 1 H NMR was determined using the residual proton signals of deuterated chloroform or deuterated methanol (δ 7.26 ppm and 3.31 ppm, respectively) as an internal standard. The chemical shift value of 31 P NMR was determined using H 3 PO 4 (δ 0.00 ppm) as an external standard. Silica gel PSQ 100B (Fuji Silysia Chemical Co., Ltd.) was used for column chromatography. LC-Forte / R (YMC Technos Co., Ltd.) or Nippon Analytical Industry Co., Ltd. LC-9201 was used for preparative recycling HPLC. A UV-visible near-infrared spectrophotometer UV-3150 (Shimadzu Corporation) was used for the measurement of the UV-visible absorption spectrum. The fluorescence spectrum was measured using a fluorometer Fluorolog-3 (HORIBA). The absolute fluorescence quantum yield was measured using an absolute PL quantum yield measuring apparatus (Hamamatsu Photonics Co., Ltd.) equipped with a multichannel spectrometer PMA-12. Unless otherwise specified, the reaction was carried out under a nitrogen atmosphere using a commercially available dehydrated solvent (Kanto Chemical Co., Ltd.) purified with a Glass Contour organic solvent purifier (Nikko Hansen Co., Ltd.).
[実施例1]
[Example 1]
[式中、n-BuLiはn-ブチルリチウムを示す。THFはテトラヒドロフランを示す。Et2Oはジエチルエーテルを示す。PhPCl2はフェニルジクロロホスフィンを示す。sec-BuLiはsec-ブチルリチウムを示す。Ph2C=NHはベンゾフェノンイミンを示す。Pd(OAc)2は酢酸パラジウムを示す。BINAPは2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチルを示す。Phはフェニル基を示す。以下同様である。]
[Wherein n-BuLi represents n-butyllithium. THF represents tetrahydrofuran. Et 2 O represents diethyl ether. PhPCl 2 represents phenyldichlorophosphine. sec-BuLi represents sec-butyllithium. Ph 2 C═NH represents benzophenone imine. Pd (OAc) 2 represents palladium acetate. BINAP represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. Ph represents a phenyl group. The same applies hereinafter. ]
ジチエノ[2,3-b;3’,2’-e]-4-(2,5-ジオキソラニル)-1-フェニル-2H-ホスフィン-1-オキシド(化合物3)の合成
無水テトラヒドロフラン/ジエチルエーテル(THF/Et2O; 1: 3, 66mL)中のビス(2-ブロモチエノ)-2,5-ジオキソラン(化合物2; 1.02g, 2.56mmol)の溶液に、n-ブチルリチウム(n-BuLi; 1.60M, 3.48mL, 5.12mmol)を-78℃で添加した。1時間撹拌した後、ジエチルエーテル(Et2O; 1.65mL)中のフェニルジクロロホスフィン(PhPCl2; 0.41mL, 3.07mmol)の溶液を-78℃でゆっくりと添加した。同じ温度でさらに1時間撹拌した後、室温まで昇温し、34.5%H2O2水溶液(2.0mL)を加えた。混合物を1時間撹拌した後、飽和Na2SO3水溶液及び飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(15mL×4)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 5/1, Rf= 0.38)で精製し、白色固体として化合物3を得た(0.640g, 1.77mol, 69%)。
1H NMR (400 MHz, CDCl3): δ 7.80-7.74 (m, 2H), 7.48-7.38 (m, 5H), 7.32 (dd, J = 4.8, 4.8 Hz, 2H), 4.45 (t, J = 6.0 Hz, 3H), 4.35 (t, J = 6.0 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 151.9 (d, JCP = 10.7 Hz), 132.7 (d, JCP = 105.8 Hz), 132.3 (d, JCP = 113.3 Hz), 131.9 (d, JCP = 10.7 Hz), 131.9 (d, JCP = 3.3 Hz), 131.0 (d, JCP = 11.6 Hz), 128.7 (d, JCP = 12.4 Hz), 128.0 (d, JCP = 10.7 Hz), 127.8 (d, JCP = 5.8 Hz), 101.7 (d, JCP = 5.8 Hz), 67.3 (s), 65.3 (s). 31P{1H} NMR(CDCl3, 162 MHz) δ 2.9. HRMS(ESI): m/z calcd. For C17H14O3PS2: 361.0122 ([M+H]+); found. 361.0117。 Synthesis of dithieno [2,3-b; 3 ', 2'-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) anhydrous tetrahydrofuran / diethyl ether ( To a solution of bis (2-bromothieno) -2,5-dioxolane (compound 2; 1.02 g, 2.56 mmol) in THF / Et 2 O; 1: 3, 66 mL) was added n-butyllithium (n-BuLi; 1.60). M, 3.48 mL, 5.12 mmol) was added at -78 ° C. After stirring for 1 hour, a solution of phenyldichlorophosphine (PhPCl 2 ; 0.41 mL, 3.07 mmol) in diethyl ether (Et 2 O; 1.65 mL) was added slowly at −78 ° C. After further stirring at the same temperature for 1 hour, the temperature was raised to room temperature, and 34.5% H 2 O 2 aqueous solution (2.0 mL) was added. The mixture was stirred for 1 hour and then quenched with saturated aqueous Na 2 SO 3 and saturated aqueous NH 4 Cl. The resulting solution was extracted with CHCl 3 (15 mL × 4). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography (CHCl 3 / ethyl acetate = 5/1, R f = 0.38 as eluent) to give compound 3 as a white solid ( 0.640g, 1.77mol, 69%).
1 H NMR (400 MHz, CDCl 3 ): δ 7.80-7.74 (m, 2H), 7.48-7.38 (m, 5H), 7.32 (dd, J = 4.8, 4.8 Hz, 2H), 4.45 (t, J = 6.0 Hz, 3H), 4.35 (t, J = 6.0 Hz, 3H). 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 151.9 (d, J CP = 10.7 Hz), 132.7 (d, J CP = 105.8 Hz), 132.3 (d, J CP = 113.3 Hz), 131.9 (d, J CP = 10.7 Hz), 131.9 (d, J CP = 3.3 Hz), 131.0 (d, J CP = 11.6 Hz), 128.7 (d, J CP = 12.4 Hz), 128.0 (d, J CP = 10.7 Hz), 127.8 (d, J CP = 5.8 Hz), 101.7 (d, J CP = 5.8 Hz), 67.3 (s), 65.3 ( s). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 2.9. HRMS (ESI): m / z calcd. For C 17 H 14 O 3 PS 2 : 361.0122 ([M + H] + ); found. 361.0117.
無水テトラヒドロフラン/ジエチルエーテル(THF/Et2O; 1: 3, 66mL)中のビス(2-ブロモチエノ)-2,5-ジオキソラン(化合物2; 1.02g, 2.56mmol)の溶液に、n-ブチルリチウム(n-BuLi; 1.60M, 3.48mL, 5.12mmol)を-78℃で添加した。1時間撹拌した後、ジエチルエーテル(Et2O; 1.65mL)中のフェニルジクロロホスフィン(PhPCl2; 0.41mL, 3.07mmol)の溶液を-78℃でゆっくりと添加した。同じ温度でさらに1時間撹拌した後、室温まで昇温し、34.5%H2O2水溶液(2.0mL)を加えた。混合物を1時間撹拌した後、飽和Na2SO3水溶液及び飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(15mL×4)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 5/1, Rf= 0.38)で精製し、白色固体として化合物3を得た(0.640g, 1.77mol, 69%)。
1H NMR (400 MHz, CDCl3): δ 7.80-7.74 (m, 2H), 7.48-7.38 (m, 5H), 7.32 (dd, J = 4.8, 4.8 Hz, 2H), 4.45 (t, J = 6.0 Hz, 3H), 4.35 (t, J = 6.0 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 151.9 (d, JCP = 10.7 Hz), 132.7 (d, JCP = 105.8 Hz), 132.3 (d, JCP = 113.3 Hz), 131.9 (d, JCP = 10.7 Hz), 131.9 (d, JCP = 3.3 Hz), 131.0 (d, JCP = 11.6 Hz), 128.7 (d, JCP = 12.4 Hz), 128.0 (d, JCP = 10.7 Hz), 127.8 (d, JCP = 5.8 Hz), 101.7 (d, JCP = 5.8 Hz), 67.3 (s), 65.3 (s). 31P{1H} NMR(CDCl3, 162 MHz) δ 2.9. HRMS(ESI): m/z calcd. For C17H14O3PS2: 361.0122 ([M+H]+); found. 361.0117。 Synthesis of dithieno [2,3-b; 3 ', 2'-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) anhydrous tetrahydrofuran / diethyl ether ( To a solution of bis (2-bromothieno) -2,5-dioxolane (
1 H NMR (400 MHz, CDCl 3 ): δ 7.80-7.74 (m, 2H), 7.48-7.38 (m, 5H), 7.32 (dd, J = 4.8, 4.8 Hz, 2H), 4.45 (t, J = 6.0 Hz, 3H), 4.35 (t, J = 6.0 Hz, 3H). 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 151.9 (d, J CP = 10.7 Hz), 132.7 (d, J CP = 105.8 Hz), 132.3 (d, J CP = 113.3 Hz), 131.9 (d, J CP = 10.7 Hz), 131.9 (d, J CP = 3.3 Hz), 131.0 (d, J CP = 11.6 Hz), 128.7 (d, J CP = 12.4 Hz), 128.0 (d, J CP = 10.7 Hz), 127.8 (d, J CP = 5.8 Hz), 101.7 (d, J CP = 5.8 Hz), 67.3 (s), 65.3 ( s). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 2.9. HRMS (ESI): m / z calcd. For C 17 H 14 O 3 PS 2 : 361.0122 ([M + H] + ); found. 361.0117.
ビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4)の合成
無水テトラヒドロフラン(THF; 20mL)中のジチエノ[2,3-b;3’,2’-e]-4-(2,5-ジオキソラニル)-1-フェニル-2H-ホスフィン-1-オキシド(化合物3; 0.802g, 2.23mmol)の溶液に、シクロヘキサン及びヘキサン中のsec-ブチルリチウム(sec-BuLi; 1.05M, 6.34mL, 6.66mmol)を-78℃で添加した。1時間撹拌した後、1,2-ジブロモ-1,1,2,2-テトラクロロエタン(BrCl2CCCl2Br; 2.34g, 7.19mmol) を加えた。同じ温度でさらに1時間撹拌した後、溶液を室温まで昇温し37%HCl水溶液(16mL)を加えた。混合物を11時間撹拌した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(10mL×4)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3, Rf= 0.23)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3)で精製し、淡黄色固体として化合物4を得た(0.583g, 1.23mol, 55%)。
1H NMR (400 MHz, CDCl3): δ 7.70-7.64 (m, 2H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.36 (d, J = 4.8 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 170.3 (d, JCP = 5.8 Hz), 146.5 (d, JCP = 8.3 Hz), 140.4 (d, JCP = 99.7 Hz), 133.4 (d, JCP = 3.7 Hz), 132.8 (d, JCP = 12.3 Hz), 131.1 (d, JCP = 11.6 Hz), 129.5 (d, JCP = 14.0 Hz), 129.2 (d, JCP = 113.6 Hz), 125.8 (d, JCP = 19.8 Hz). 31P{1H} NMR (CDCl3, 162 MHz) δ -0.5. HRMS(ESI): m/z calcd. For C15H8Br2O2PS2: 472.8070 ([M+H]+); found. 472.8064。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) anhydrous tetrahydrofuran (THF; 20 mL) Dithieno [2,3-b; 3 ', 2'-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3; 0.802g, 2.23mmol) To the solution was added sec-butyllithium (sec-BuLi; 1.05M, 6.34 mL, 6.66 mmol) in cyclohexane and hexane at −78 ° C. After stirring for 1 hour, 1,2-dibromo-1,1,2,2-tetrachloroethane (BrCl 2 CCCl 2 Br; 2.34 g, 7.19 mmol) was added. After further stirring at the same temperature for 1 hour, the solution was warmed to room temperature and 37% aqueous HCl (16 mL) was added. The mixture was stirred for 11 hours and then quenched with saturated aqueous NH 4 Cl. The resulting solution was extracted with CHCl 3 (10 mL × 4). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography (CHCl 3 , R f = 0.23 as eluent) and HPLC (silica gel Wakosil-II 5SIL-Prep, CHCl 3 as eluent). Compound 4 was obtained as a pale yellow solid (0.583 g, 1.23 mol, 55%).
1 H NMR (400 MHz, CDCl 3 ): δ 7.70-7.64 (m, 2H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.36 (d, J = 4.8 Hz, 2H) 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 170.3 (d, J CP = 5.8 Hz), 146.5 (d, J CP = 8.3 Hz), 140.4 (d, J CP = 99.7 Hz), 133.4 (d, J CP = 3.7 Hz), 132.8 (d, J CP = 12.3 Hz), 131.1 (d, J CP = 11.6 Hz), 129.5 (d, J CP = 14.0 Hz), 129.2 (d, J CP = .. 113.6 Hz), 125.8 ( d, J CP = 19.8 Hz) 31 P {1 H} NMR (CDCl 3, 162 MHz) δ -0.5 HRMS (ESI):. m / z calcd For C 15 H 8 Br 2 O 2 PS 2 : 472.8070 ([M + H] + ); found. 472.8064.
無水テトラヒドロフラン(THF; 20mL)中のジチエノ[2,3-b;3’,2’-e]-4-(2,5-ジオキソラニル)-1-フェニル-2H-ホスフィン-1-オキシド(化合物3; 0.802g, 2.23mmol)の溶液に、シクロヘキサン及びヘキサン中のsec-ブチルリチウム(sec-BuLi; 1.05M, 6.34mL, 6.66mmol)を-78℃で添加した。1時間撹拌した後、1,2-ジブロモ-1,1,2,2-テトラクロロエタン(BrCl2CCCl2Br; 2.34g, 7.19mmol) を加えた。同じ温度でさらに1時間撹拌した後、溶液を室温まで昇温し37%HCl水溶液(16mL)を加えた。混合物を11時間撹拌した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(10mL×4)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3, Rf= 0.23)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3)で精製し、淡黄色固体として化合物4を得た(0.583g, 1.23mol, 55%)。
1H NMR (400 MHz, CDCl3): δ 7.70-7.64 (m, 2H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.36 (d, J = 4.8 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 170.3 (d, JCP = 5.8 Hz), 146.5 (d, JCP = 8.3 Hz), 140.4 (d, JCP = 99.7 Hz), 133.4 (d, JCP = 3.7 Hz), 132.8 (d, JCP = 12.3 Hz), 131.1 (d, JCP = 11.6 Hz), 129.5 (d, JCP = 14.0 Hz), 129.2 (d, JCP = 113.6 Hz), 125.8 (d, JCP = 19.8 Hz). 31P{1H} NMR (CDCl3, 162 MHz) δ -0.5. HRMS(ESI): m/z calcd. For C15H8Br2O2PS2: 472.8070 ([M+H]+); found. 472.8064。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) anhydrous tetrahydrofuran (THF; 20 mL) Dithieno [2,3-b; 3 ', 2'-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (
1 H NMR (400 MHz, CDCl 3 ): δ 7.70-7.64 (m, 2H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.36 (d, J = 4.8 Hz, 2H) 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 170.3 (d, J CP = 5.8 Hz), 146.5 (d, J CP = 8.3 Hz), 140.4 (d, J CP = 99.7 Hz), 133.4 (d, J CP = 3.7 Hz), 132.8 (d, J CP = 12.3 Hz), 131.1 (d, J CP = 11.6 Hz), 129.5 (d, J CP = 14.0 Hz), 129.2 (d, J CP = .. 113.6 Hz), 125.8 ( d, J CP = 19.8 Hz) 31 P {1 H} NMR (
ビス{[5-(1,1-ジフェニルメチル)イミノ]チエノ}[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物5)の合成
無水トルエン(16 mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 200mg, 0.422mmol)に、ベンゾフェノンイミン(Ph2C=NH; 192mg, 1.06mmol)、酢酸パラジウム(Pd(OAc)2; 9.5mg, 0.041mmol)、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(rac-BINAP; 39.8mg, 0.064mmol)、及びCs2CO3(342mg, 1.05mmol)を添加し、90℃で撹拌した。同じ温度で21時間加熱した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(4mL×8)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 20/1, Rf= 0.30)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3/酢酸エチル= 20/1)で精製し、橙色固体として化合物5を得た(0.244g, 0.363mmol, 86%)。
1H NMR (400 MHz, CDCl3): δ 7.75-7.33 (d, J = 7.6 Hz, 4H), 7.62-7.37 (m, 17H), 7.19 (d, J = 7.2 Hz, 4H), 7.05 (d, J = 5.6 Hz, 2H). 31P{1H} NMR(CDCl3, 162 MHz) δ 1.0。 Bis {[5- (1,1-diphenylmethyl) imino] thieno} [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 5) Synthesis of bis (5-bromothieno) [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide in anhydrous toluene (16 mL) (Compound 4; 200 mg, 0.422 mmol) to benzophenone imine (Ph 2 C = NH; 192 mg, 1.06 mmol), palladium acetate (Pd (OAc) 2 ; 9.5 mg, 0.041 mmol), 2,2′-bis (diphenylphosphine) Fino) -1,1′-binaphthyl (rac-BINAP; 39.8 mg, 0.064 mmol) and Cs 2 CO 3 (342 mg, 1.05 mmol) were added and stirred at 90 ° C. After heating at the same temperature for 21 hours, it was quenched with saturated aqueous NH 4 Cl. The resulting solution was extracted with CHCl 3 (4 mL × 8). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. Volatiles were removed under reduced pressure, and the resulting solid was subjected to silica gel column chromatography (CHCl 3 / ethyl acetate = 20/1, R f = 0.30 as eluent) and HPLC (silica gel Wakosil-II 5SIL-Prep, elution) The solution was purified by CHCl 3 / ethyl acetate = 20/1) to obtain Compound 5 as an orange solid (0.244 g, 0.363 mmol, 86%).
1 H NMR (400 MHz, CDCl 3 ): δ 7.75-7.33 (d, J = 7.6 Hz, 4H), 7.62-7.37 (m, 17H), 7.19 (d, J = 7.2 Hz, 4H), 7.05 (d , J = 5.6 Hz, 2H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 1.0.
無水トルエン(16 mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 200mg, 0.422mmol)に、ベンゾフェノンイミン(Ph2C=NH; 192mg, 1.06mmol)、酢酸パラジウム(Pd(OAc)2; 9.5mg, 0.041mmol)、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(rac-BINAP; 39.8mg, 0.064mmol)、及びCs2CO3(342mg, 1.05mmol)を添加し、90℃で撹拌した。同じ温度で21時間加熱した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3(4mL×8)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 20/1, Rf= 0.30)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3/酢酸エチル= 20/1)で精製し、橙色固体として化合物5を得た(0.244g, 0.363mmol, 86%)。
1H NMR (400 MHz, CDCl3): δ 7.75-7.33 (d, J = 7.6 Hz, 4H), 7.62-7.37 (m, 17H), 7.19 (d, J = 7.2 Hz, 4H), 7.05 (d, J = 5.6 Hz, 2H). 31P{1H} NMR(CDCl3, 162 MHz) δ 1.0。 Bis {[5- (1,1-diphenylmethyl) imino] thieno} [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 5) Synthesis of bis (5-bromothieno) [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide in anhydrous toluene (16 mL) (
1 H NMR (400 MHz, CDCl 3 ): δ 7.75-7.33 (d, J = 7.6 Hz, 4H), 7.62-7.37 (m, 17H), 7.19 (d, J = 7.2 Hz, 4H), 7.05 (d , J = 5.6 Hz, 2H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 1.0.
ビス(5-アミノチエノ)[2,3-b;3’,2’-e]-4-(o-トリル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物1
+
・TFA
-
)の合成
テトラヒドロフラン(THF; 1.2mL)中のビス{[5-(1,1-ジフェニルメチル)イミノ]チエノ}[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物5; 101mg, 0.150mmol)の溶液に、o-トリルマグネシウムブロミド(1.03M, 1.43mL)を室温で滴下し、60℃で撹拌した。16時間撹拌した後、混合物を室温に冷却し、トリフルオロ酢酸(TFA; 0.83mL)及び蒸留水(1.66mL)を添加した。さらに4時間撹拌した後、飽和NaHCO3水溶液でクエンチした。減圧下で溶媒を除去し、得られた固体をCHCl3及び蒸留水で洗浄した。得られた固体を分取 HPLC(YMC-DispoPack AT, 溶離液として30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、青緑色固体として化合物1+・TFA-を得た(3.5mg, 6.6μmol, 4%)。
1H NMR (400 MHz, CD3OD): δ 7.81-7.71 (m, 3H), 7.66-7.62 (m, 2H), 7.54-7.50 (m, 1H), 7.45-7.40 (m, 3H), 6.98 (d, J = 6.8 Hz, 2H), 2.36 (s, 3H). 31P{1H} NMR(CD3OD, 162 MHz) δ 4.6。 Bis (5-aminothieno) [2,3-b; 3 ' , 2'-e] -4- (o- tolyl) -1-phenyl -2H- Hosufiniumu 1-oxide trifluoroacetate (Compound 1 + · TFA - synthesis of tetrahydrofuran (THF) of; bis in 1.2mL) {[5- (1,1- diphenylmethyl) imino] thieno} [2,3-b; 3 ' , 2'-e] -4- keto To a solution of -1-phenyl-2H-phosphine-1-oxide (Compound 5; 101 mg, 0.150 mmol), o-tolylmagnesium bromide (1.03 M, 1.43 mL) was added dropwise at room temperature and stirred at 60 ° C. After stirring for 16 hours, the mixture was cooled to room temperature and trifluoroacetic acid (TFA; 0.83 mL) and distilled water (1.66 mL) were added. The mixture was further stirred for 4 hours, and then quenched with a saturated aqueous NaHCO 3 solution. The solvent was removed under reduced pressure and the resulting solid was washed with CHCl 3 and distilled water. The resulting solid preparative HPLC purified by (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent) to give compound as a blue-green solid 1 + · TFA - (3.5 mg, 6.6 μmol, 4%) was obtained.
1 H NMR (400 MHz, CD 3 OD): δ 7.81-7.71 (m, 3H), 7.66-7.62 (m, 2H), 7.54-7.50 (m, 1H), 7.45-7.40 (m, 3H), 6.98 (d, J = 6.8 Hz, 2H), 2.36 (s, 3H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 4.6.
テトラヒドロフラン(THF; 1.2mL)中のビス{[5-(1,1-ジフェニルメチル)イミノ]チエノ}[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物5; 101mg, 0.150mmol)の溶液に、o-トリルマグネシウムブロミド(1.03M, 1.43mL)を室温で滴下し、60℃で撹拌した。16時間撹拌した後、混合物を室温に冷却し、トリフルオロ酢酸(TFA; 0.83mL)及び蒸留水(1.66mL)を添加した。さらに4時間撹拌した後、飽和NaHCO3水溶液でクエンチした。減圧下で溶媒を除去し、得られた固体をCHCl3及び蒸留水で洗浄した。得られた固体を分取 HPLC(YMC-DispoPack AT, 溶離液として30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、青緑色固体として化合物1+・TFA-を得た(3.5mg, 6.6μmol, 4%)。
1H NMR (400 MHz, CD3OD): δ 7.81-7.71 (m, 3H), 7.66-7.62 (m, 2H), 7.54-7.50 (m, 1H), 7.45-7.40 (m, 3H), 6.98 (d, J = 6.8 Hz, 2H), 2.36 (s, 3H). 31P{1H} NMR(CD3OD, 162 MHz) δ 4.6。 Bis (5-aminothieno) [2,3-b; 3 ' , 2'-e] -4- (o- tolyl) -1-phenyl -2H- Hosufiniumu 1-oxide trifluoroacetate (
1 H NMR (400 MHz, CD 3 OD): δ 7.81-7.71 (m, 3H), 7.66-7.62 (m, 2H), 7.54-7.50 (m, 1H), 7.45-7.40 (m, 3H), 6.98 (d, J = 6.8 Hz, 2H), 2.36 (s, 3H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 4.6.
[実施例2]
[Example 2]
[式中、Meはメチル基を示す。Phはフェニル基を示す。以下同様である。]
ビス(5-アミノチエノ)[2,3-b;3’,2’-e]-4-(2,6-ジメトキシ)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物6 + ・TFA - )の合成
テトラヒドロフラン(THF; 2.0mL)中のビス{[5-(1,1-ジフェニルメチル)イミノ]チエノ}[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物5; 95.2mg, 0.141mmol)の溶液に、三フッ化ホウ素ジエチルエーテル錯体(18.6μL, 0.148mmol)を-78℃で添加した。40分撹拌した後、2,6-ジメトキシブロモベンゼンから調製した2,6-ジメトキシフェニルリチウムのテトラヒドロフラン(THF)溶液(0.27M, 2.10mL)を添加し、ゆっくりと室温に戻した。2時間撹拌した後、0.2%トリフルオロ酢酸(TFA)水溶液(10mL)を加え、1時間撹拌した。減圧下で溶媒を留去し、得られた組成生物を分取HPLC(YMC-DispoPack AT(ODS: 12g, 50μm)及び(YMC-Actus Triart C18 ExRS, CH3CN/H2O = 2/8 to 10/0 containing 0.1% TFA)により精製し、青緑色固体として化合物6+・TFA-を得た(6.2mg, 7%)。
1H NMR (400 MHz, CD3OD): δ 7.83-7.78 (m, 2H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.85 (2d, J = 8.4 Hz, 2H), 3.86, 3.85 (2s, 6H). 31P{1H} NMR(CD3OD, 162 MHz) δ 4.8。 [Wherein, Me represents a methyl group. Ph represents a phenyl group. The same applies hereinafter. ]
Bis (5-aminothieno) [2,3-b; 3 ', 2'-e] -4- (2,6-dimethoxy) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (compound 6 + ・ Synthesis of TFA − ) Bis {[5- (1,1-diphenylmethyl) imino] thieno} [2,3-b; 3 ′, 2′-e] -4 in tetrahydrofuran (THF; 2.0 mL) To a solution of -keto-1-phenyl-2H-phosphine-1-oxide (Compound 5; 95.2 mg, 0.141 mmol) was added boron trifluoride diethyl ether complex (18.6 μL, 0.148 mmol) at −78 ° C. After stirring for 40 minutes, a tetrahydrofuran (THF) solution (0.27M, 2.10 mL) of 2,6-dimethoxyphenyllithium prepared from 2,6-dimethoxybromobenzene was added, and the temperature was slowly returned to room temperature. After stirring for 2 hours, 0.2% aqueous trifluoroacetic acid (TFA) solution (10 mL) was added, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and the resulting organism was subjected to preparative HPLC (YMC-DispoPack AT (ODS: 12 g, 50 μm) and (YMC-Actus Triart C18 ExRS, CH 3 CN / H 2 O = 2/8). to 10/0 containing 0.1% TFA) to obtain Compound 6 + · TFA − as a blue-green solid (6.2 mg, 7%).
1 H NMR (400 MHz, CD 3 OD): δ 7.83-7.78 (m, 2H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H ), 6.89 (d, J = 7.2 Hz, 2H), 6.85 (2d, J = 8.4 Hz, 2H), 3.86, 3.85 (2s, 6H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 4.8.
ビス(5-アミノチエノ)[2,3-b;3’,2’-e]-4-(2,6-ジメトキシ)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物6 + ・TFA - )の合成
テトラヒドロフラン(THF; 2.0mL)中のビス{[5-(1,1-ジフェニルメチル)イミノ]チエノ}[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物5; 95.2mg, 0.141mmol)の溶液に、三フッ化ホウ素ジエチルエーテル錯体(18.6μL, 0.148mmol)を-78℃で添加した。40分撹拌した後、2,6-ジメトキシブロモベンゼンから調製した2,6-ジメトキシフェニルリチウムのテトラヒドロフラン(THF)溶液(0.27M, 2.10mL)を添加し、ゆっくりと室温に戻した。2時間撹拌した後、0.2%トリフルオロ酢酸(TFA)水溶液(10mL)を加え、1時間撹拌した。減圧下で溶媒を留去し、得られた組成生物を分取HPLC(YMC-DispoPack AT(ODS: 12g, 50μm)及び(YMC-Actus Triart C18 ExRS, CH3CN/H2O = 2/8 to 10/0 containing 0.1% TFA)により精製し、青緑色固体として化合物6+・TFA-を得た(6.2mg, 7%)。
1H NMR (400 MHz, CD3OD): δ 7.83-7.78 (m, 2H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.85 (2d, J = 8.4 Hz, 2H), 3.86, 3.85 (2s, 6H). 31P{1H} NMR(CD3OD, 162 MHz) δ 4.8。 [Wherein, Me represents a methyl group. Ph represents a phenyl group. The same applies hereinafter. ]
Bis (5-aminothieno) [2,3-b; 3 ', 2'-e] -4- (2,6-dimethoxy) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (
1 H NMR (400 MHz, CD 3 OD): δ 7.83-7.78 (m, 2H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H ), 6.89 (d, J = 7.2 Hz, 2H), 6.85 (2d, J = 8.4 Hz, 2H), 3.86, 3.85 (2s, 6H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 4.8.
[実施例3]
[Example 3]
[式中、n-BuLiはn-ブチルリチウムを示す。THFはテトラヒドロフランを示す。Et2Oはジエチルエーテルを示す。PhPCl2はフェニルジクロロホスフィンを示す。Phはフェニル基を示す。sec-BuLiはsec-ブチルリチウムを示す。Et2NHはジエチルアミンを示す。DMFはジメチルホルムアミドを示す。CPMEはシクロペンチルメチルエーテルを示す。iPrはイソプロピル基を示す。以下同様である。]
[Wherein n-BuLi represents n-butyllithium. THF represents tetrahydrofuran. Et 2 O represents diethyl ether. PhPCl 2 represents phenyldichlorophosphine. Ph represents a phenyl group. sec-BuLi represents sec-butyllithium. Et 2 NH represents diethylamine. DMF represents dimethylformamide. CPME represents cyclopentyl methyl ether. iPr represents an isopropyl group. The same applies hereinafter. ]
ジチエノ[2,3-b;3’,2’-e]-4-(2,5-ジオキソラニル)-1-フェニル-2H-ホスフィン-1-オキシド(化合物3)の合成
実施例1と同様に、化合物3を合成した。 Synthesis of dithieno [2,3-b; 3 ′, 2′-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) As in Example 1.Compound 3 was synthesized.
実施例1と同様に、化合物3を合成した。 Synthesis of dithieno [2,3-b; 3 ′, 2′-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) As in Example 1.
ビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4)の合成
実施例1と同様に、化合物4を合成した。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) As in Example 1,Compound 4 was synthesized.
実施例1と同様に、化合物4を合成した。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) As in Example 1,
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物7)の合成
ジメチルホルムアミド(DMF; 1.25mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 255mg, 0.539mmol)の溶液に、ジエチルアミン(2.75mL, 26.9mmol)を添加し、110℃で撹拌した。同じ温度で3日間撹拌した後、減圧下で溶媒を除去した。得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/ヘキサン= 2/1, Rf= 0.25)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3)で精製し、赤色固体として化合物7を得た(83.2mg, 0.280mmol, 52%)。
1H NMR (600 MHz, CDCl3): δ 7.76-7.73 (m, 2H), 7.52-7.49 (m, 1H), 7.24-7.42 (m, 2H), 6.09 (d, J = 6.0 Hz, 2H), 3.35 (q, J = 7.2 Hz, 8H), 1.20 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 170.1 (d, JCP = 6.6 Hz), 164.3 (d, JCP = 19.0 Hz), 140.0 (d, JCP = 102.1 Hz), 132.5 (d, JCP = 109.5 Hz), 132.2 (d, JCP = 3.3 Hz), 130.8 (d, JCP = 10.7 Hz), 128.9 (d, JCP = 13.2 Hz), 127.3 (d, JCP = 9.9 Hz), 102.9 (d, JCP = 13.2 Hz), 47.3 (s), 12.2 (s). 31P{1H} NMR(CDCl3, 162 MHz) δ 3.2. HRMS(ESI): m/z calcd. For C23H28N2O2PS2: 459.1330 ([M+H]+); found. 459.1326。 Synthesis of bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 7) Dimethylformamide (DMF 1.25 mL) bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4; 255 mg, 0.539 mmol) was added diethylamine (2.75 mL, 26.9 mmol) and stirred at 110 ° C. After stirring at the same temperature for 3 days, the solvent was removed under reduced pressure. The obtained solid was purified by silica gel column chromatography (CHCl 3 / hexane = 2/1, R f = 0.25 as eluent) and HPLC (silica gel Wakosil-II 5SIL-Prep, CHCl 3 as eluent). Compound 7 was obtained as a solid (83.2 mg, 0.280 mmol, 52%).
1 H NMR (600 MHz, CDCl 3 ): δ 7.76-7.73 (m, 2H), 7.52-7.49 (m, 1H), 7.24-7.42 (m, 2H), 6.09 (d, J = 6.0 Hz, 2H) , 3.35 (q, J = 7.2 Hz, 8H), 1.20 (t, J = 7.2 Hz, 3H). 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 170.1 (d, J CP = 6.6 Hz) , 164.3 (d, J CP = 19.0 Hz), 140.0 (d, J CP = 102.1 Hz), 132.5 (d, J CP = 109.5 Hz), 132.2 (d, J CP = 3.3 Hz), 130.8 (d, J CP = 10.7 Hz), 128.9 (d, J CP = 13.2 Hz), 127.3 (d, J CP = 9.9 Hz), 102.9 (d, J CP = 13.2 Hz), 47.3 (s), 12.2 (s). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 3.2.HRMS (ESI): m / z calcd.For C 23 H 28 N 2 O 2 PS 2 : 459.1330 ([M + H] + ); found. 459.1326.
ジメチルホルムアミド(DMF; 1.25mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 255mg, 0.539mmol)の溶液に、ジエチルアミン(2.75mL, 26.9mmol)を添加し、110℃で撹拌した。同じ温度で3日間撹拌した後、減圧下で溶媒を除去した。得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/ヘキサン= 2/1, Rf= 0.25)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3)で精製し、赤色固体として化合物7を得た(83.2mg, 0.280mmol, 52%)。
1H NMR (600 MHz, CDCl3): δ 7.76-7.73 (m, 2H), 7.52-7.49 (m, 1H), 7.24-7.42 (m, 2H), 6.09 (d, J = 6.0 Hz, 2H), 3.35 (q, J = 7.2 Hz, 8H), 1.20 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 170.1 (d, JCP = 6.6 Hz), 164.3 (d, JCP = 19.0 Hz), 140.0 (d, JCP = 102.1 Hz), 132.5 (d, JCP = 109.5 Hz), 132.2 (d, JCP = 3.3 Hz), 130.8 (d, JCP = 10.7 Hz), 128.9 (d, JCP = 13.2 Hz), 127.3 (d, JCP = 9.9 Hz), 102.9 (d, JCP = 13.2 Hz), 47.3 (s), 12.2 (s). 31P{1H} NMR(CDCl3, 162 MHz) δ 3.2. HRMS(ESI): m/z calcd. For C23H28N2O2PS2: 459.1330 ([M+H]+); found. 459.1326。 Synthesis of bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 7) Dimethylformamide (DMF 1.25 mL) bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (
1 H NMR (600 MHz, CDCl 3 ): δ 7.76-7.73 (m, 2H), 7.52-7.49 (m, 1H), 7.24-7.42 (m, 2H), 6.09 (d, J = 6.0 Hz, 2H) , 3.35 (q, J = 7.2 Hz, 8H), 1.20 (t, J = 7.2 Hz, 3H). 13 C { 1 H} NMR (CDCl 3 , 100 MHz) δ 170.1 (d, J CP = 6.6 Hz) , 164.3 (d, J CP = 19.0 Hz), 140.0 (d, J CP = 102.1 Hz), 132.5 (d, J CP = 109.5 Hz), 132.2 (d, J CP = 3.3 Hz), 130.8 (d, J CP = 10.7 Hz), 128.9 (d, J CP = 13.2 Hz), 127.3 (d, J CP = 9.9 Hz), 102.9 (d, J CP = 13.2 Hz), 47.3 (s), 12.2 (s). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 3.2.HRMS (ESI): m / z calcd.For C 23 H 28 N 2 O 2 PS 2 : 459.1330 ([M + H] + ); found. 459.1326.
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-(o-トリル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物8a
+
・TFA
-
)の合成(その1)
テトラヒドロフラン(THF; 6.0 mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 98.2mg, 0.214mmol)の溶液に、三フッ化ホウ素ジエチルエーテル錯体(27.0μL, 0.218mmol)を-78℃で添加した。40分撹拌した後、調製したo-トリルリチウム(0.22M, 2.92mL)を添加し、ゆっくりと室温に戻した。2時間撹拌した後、1N塩酸水溶液(10mL)を加え、10分間撹拌した。水層をCH2Cl2(15mL×4)で抽出し、有機層を無水Na2SO4で乾燥後、ろ過した。得られた粗生成物を分取HPLC(YMC-DispoPack AT (ODS: 12g, 50μm), CH3CN/H2O= 2/8 to 10/0 containing 0.1% TFA)、(YMC-Actus SIL, CHCl3/メタノール= 20/1, Rf= 0.35)及び(YMC-Actus Triart C18 ExRS, CH3CN/H2O= 2/8 to 10/0 containing 0.1% TFA)で精製し、緑色固体として化合物8a+・TFA-を得た(8.4mg, 6%)。
1H NMR (400 MHz, CD2Cl2): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C30H34N2OPS2: 533.1850 ([M-CF3CO2]+); found. 533.1851。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (o-tolyl) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (compound 8a + · TFA -) synthesis of (Part 1)
Bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide in tetrahydrofuran (THF; 6.0 mL) ( To a solution ofCompound 7; 98.2 mg, 0.214 mmol), boron trifluoride diethyl ether complex (27.0 μL, 0.218 mmol) was added at −78 ° C. After stirring for 40 minutes, the prepared o-tolyl lithium (0.22M, 2.92 mL) was added, and the temperature was slowly returned to room temperature. After stirring for 2 hours, 1N hydrochloric acid aqueous solution (10 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with CH 2 Cl 2 (15 mL × 4), and the organic layer was dried over anhydrous Na 2 SO 4 and filtered. The obtained crude product was subjected to preparative HPLC (YMC-DispoPack AT (ODS: 12 g, 50 μm), CH 3 CN / H 2 O = 2/8 to 10/0 containing 0.1% TFA), (YMC-Actus SIL, CHCl 3 / methanol = 20/1, R f = 0.35) and (YMC-Actus Triart C18 ExRS, CH 3 CN / H 2 O = 2/8 to 10/0 containing 0.1% TFA) Compound 8a + · TFA − was obtained (8.4 mg, 6%).
1 H NMR (400 MHz, CD 2 Cl 2 ): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 30 H 34 N 2 OPS 2 : 533.1850 ([M-CF 3 CO 2 ] + ); found. 533.1851 .
テトラヒドロフラン(THF; 6.0 mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 98.2mg, 0.214mmol)の溶液に、三フッ化ホウ素ジエチルエーテル錯体(27.0μL, 0.218mmol)を-78℃で添加した。40分撹拌した後、調製したo-トリルリチウム(0.22M, 2.92mL)を添加し、ゆっくりと室温に戻した。2時間撹拌した後、1N塩酸水溶液(10mL)を加え、10分間撹拌した。水層をCH2Cl2(15mL×4)で抽出し、有機層を無水Na2SO4で乾燥後、ろ過した。得られた粗生成物を分取HPLC(YMC-DispoPack AT (ODS: 12g, 50μm), CH3CN/H2O= 2/8 to 10/0 containing 0.1% TFA)、(YMC-Actus SIL, CHCl3/メタノール= 20/1, Rf= 0.35)及び(YMC-Actus Triart C18 ExRS, CH3CN/H2O= 2/8 to 10/0 containing 0.1% TFA)で精製し、緑色固体として化合物8a+・TFA-を得た(8.4mg, 6%)。
1H NMR (400 MHz, CD2Cl2): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C30H34N2OPS2: 533.1850 ([M-CF3CO2]+); found. 533.1851。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (o-tolyl) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (
Bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide in tetrahydrofuran (THF; 6.0 mL) ( To a solution of
1 H NMR (400 MHz, CD 2 Cl 2 ): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 30 H 34 N 2 OPS 2 : 533.1850 ([M-CF 3 CO 2 ] + ); found. 533.1851 .
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-(o-トリル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物8a
+
・TFA
-
)の合成(その2)
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 40.3mg, 0.0872mmol)の溶液に、トリクロロシラン(44.0μL, 0.436mmol)を加え、室温で撹拌した。6時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、2-ブロモトルエン(63.0μL, 0.523mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 1mL)から調製したo-トリルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、16時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8a+・TFA-を得た(30.8mg, 48.8μmol, 56%)。
1H NMR (400 MHz, CD2Cl2): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR (CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C30H34N2OPS2: 533.1850 ([M-CF3CO2]+); found. 533.1851。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (o-tolyl) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (compound 8a + · TFA -) synthesis of (Part 2)
Bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide in toluene (1 mL) (compound 7; Trichlorosilane (44.0 μL, 0.436 mmol) was added to a solution of 40.3 mg, 0.0872 mmol) and stirred at room temperature. After stirring for 6 hours, the mixture was filtered through a silica gel pad (THF as eluent) under a nitrogen atmosphere. The solvent was removed under reduced pressure followed by the addition of anhydrous cyclopentyl methyl ether (CPME; 5 mL). The mixture was cooled to −78 ° C. and 2-bromotoluene (63.0 μL, 0.523 mmol), tert-butyllithium (t-BuLi; 1.64M, 0.32 mL, 0.523 mmol), and cyclopentyl methyl ether (CPME; 1 mL) The o-tolyllithium solution prepared from was added at -78 ° C. The reaction mixture was heated to 70 ° C. and stirred for 16 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.05 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 8a + · TFA - was obtained as a green solid. Obtained (30.8 mg, 48.8 μmol, 56%).
1 H NMR (400 MHz, CD 2 Cl 2 ): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 30 H 34 N 2 OPS 2 : 533.1850 ([M-CF 3 CO 2 ] + ); found. 533.1851 .
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 40.3mg, 0.0872mmol)の溶液に、トリクロロシラン(44.0μL, 0.436mmol)を加え、室温で撹拌した。6時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、2-ブロモトルエン(63.0μL, 0.523mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 1mL)から調製したo-トリルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、16時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8a+・TFA-を得た(30.8mg, 48.8μmol, 56%)。
1H NMR (400 MHz, CD2Cl2): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR (CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C30H34N2OPS2: 533.1850 ([M-CF3CO2]+); found. 533.1851。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (o-tolyl) -1-phenyl-2H-phosphinium-1-oxide trifluoroacetate (
Bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide in toluene (1 mL) (
1 H NMR (400 MHz, CD 2 Cl 2 ): δ 7.80-7.75 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59-7.51 (m, 3H), 7.45-7.35 (m, 3H), 6.92 (d, J = 5.6 Hz, 2H), 3.51 (q, J = 7.2 Hz, 8H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 30 H 34 N 2 OPS 2 : 533.1850 ([M-CF 3 CO 2 ] + ); found. 533.1851 .
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-(2,6-ジメチルフェニル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物8b
+
・TFA
-
)の合成
トルエン(2mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 80.5mg, 0.174mmol)の溶液に、トリクロロシラン(90.0μL, 0.890mmol)を加え、室温で撹拌した。15時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,6-ジメチルベンゼン(0.140mL, 1.02mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.64mL, 1.04mmol)、及びシクロペンチルメチルエーテル(CPME; 2mL)から調製した2,6-ジメチルフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、18時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8b+・TFA-を得た(40.9mg, 63.4μmol, 36%)。
1H NMR (400 MHz, CD3OD): δ 7.86-7.81 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.41 (t, J = 8.0 Hz 1H), 7.29-7.26 (m, 4H), 3.62 (q, J = 7.2 Hz 8H), 2.34 and 2.33 (double singlet, 6H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.3. HRMS(ESI): m/z calcd. For C31H36N2OPS2: 547.2007 ([M-CF3CO2]+); found. 547.2002。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,6-dimethylphenyl) -1-phenyl-2H-phosphinium-1-oxide trifluoro Synthesis of acetate (compound 8b + .TFA − ) bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-in toluene (2 mL) Trichlorosilane (90.0 μL, 0.890 mmol) was added to a solution of 2H-phosphinium-1-oxide (Compound 7; 80.5 mg, 0.174 mmol), and the mixture was stirred at room temperature. After stirring for 15 hours, the mixture was filtered through a silica gel pad (THF as eluent) under a nitrogen atmosphere. The solvent was removed under reduced pressure followed by the addition of anhydrous cyclopentyl methyl ether (CPME; 5 mL). The mixture was cooled to −78 ° C. and 1-bromo-2,6-dimethylbenzene (0.140 mL, 1.02 mmol), tert-butyllithium (t-BuLi; 1.64M, 0.64 mL, 1.04 mmol), and cyclopentylmethyl A 2,6-dimethylphenyllithium solution prepared from ether (CPME; 2 mL) was added at -78 ° C. The reaction mixture was heated to 70 ° C. and stirred for 18 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.05 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 8b + · TFA - was obtained as a green solid. Obtained (40.9 mg, 63.4 μmol, 36%).
1 H NMR (400 MHz, CD 3 OD): δ 7.86-7.81 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.41 (t, J = 8.0 Hz 1H) , 7.29-7.26 (m, 4H), 3.62 (q, J = 7.2 Hz 8H), 2.34 and 2.33 (double singlet, 6H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.3. HRMS (ESI): m / z calcd. For C 31 H 36 N 2 OPS 2 : 547.2007 ([M-CF 3 CO 2 ] + ); found. 547.2002.
トルエン(2mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 80.5mg, 0.174mmol)の溶液に、トリクロロシラン(90.0μL, 0.890mmol)を加え、室温で撹拌した。15時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,6-ジメチルベンゼン(0.140mL, 1.02mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.64mL, 1.04mmol)、及びシクロペンチルメチルエーテル(CPME; 2mL)から調製した2,6-ジメチルフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、18時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8b+・TFA-を得た(40.9mg, 63.4μmol, 36%)。
1H NMR (400 MHz, CD3OD): δ 7.86-7.81 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.41 (t, J = 8.0 Hz 1H), 7.29-7.26 (m, 4H), 3.62 (q, J = 7.2 Hz 8H), 2.34 and 2.33 (double singlet, 6H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.3. HRMS(ESI): m/z calcd. For C31H36N2OPS2: 547.2007 ([M-CF3CO2]+); found. 547.2002。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,6-dimethylphenyl) -1-phenyl-2H-phosphinium-1-oxide trifluoro Synthesis of acetate (
1 H NMR (400 MHz, CD 3 OD): δ 7.86-7.81 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.41 (t, J = 8.0 Hz 1H) , 7.29-7.26 (m, 4H), 3.62 (q, J = 7.2 Hz 8H), 2.34 and 2.33 (double singlet, 6H), 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.3. HRMS (ESI): m / z calcd. For C 31 H 36 N 2 OPS 2 : 547.2007 ([M-CF 3 CO 2 ] + ); found. 547.2002.
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-(2,6-ジメトキシフェニル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物8c
+
・TFA
-
)の合成
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 42.1mg, 0.0918mmol)の溶液に、トリクロロシラン(45.0μL, 0.445mmol)を加え、室温で撹拌した。5時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,6-ジメトキシベンゼン(119mg, 0.546mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 5mL)から調製した2,6-ジメトキシフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、13時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.1mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8c+・TFA-を得た(42.9mg, 63.4μmol, 69%)。
1H NMR (600 MHz, CD3OD): δ 7.86-7.83 (m, 2H), 7.71-7.69 (m, 1H), 7.63-7.60 (m, 2H), 7.56 (t, J = 9.0 Hz, 1H), 7.15 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.864 and 3.855 (double singlet, 6H), 3.60 (q, J = 7.2 Hz, 8H), 1.24 (t, 6.6 Hz, 12H). 31P{1H} NMR (CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C31H36N2O3PS2: 579.1905 ([M-CF3CO2]+); found. 579.1904。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,6-dimethoxyphenyl) -1-phenyl-2H-phosphinium-1-oxide trifluoro acetate (compound 8c + · TFA -) bis synthesis in toluene (1 mL) of [5- (diethylamino) thieno] [2,3-b; 3 ' , 2'-e] -4- keto-1-phenyl - Trichlorosilane (45.0 μL, 0.445 mmol) was added to a solution of 2H-phosphinium-1-oxide (Compound 7; 42.1 mg, 0.0918 mmol), and the mixture was stirred at room temperature. After stirring for 5 hours, the mixture was filtered through a silica gel pad (THF as eluent) under a nitrogen atmosphere. The solvent was removed under reduced pressure followed by the addition of anhydrous cyclopentyl methyl ether (CPME; 5 mL). The mixture was cooled to -78 ° C. and 1-bromo-2,6-dimethoxybenzene (119 mg, 0.546 mmol), tert-butyllithium (t-BuLi; 1.64M, 0.32 mL, 0.523 mmol), and cyclopentyl methyl ether A 2,6-dimethoxyphenyllithium solution prepared from (CPME; 5 mL) was added at -78 ° C. The reaction mixture was heated to 70 ° C. and stirred for 13 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.1 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure. The obtained solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 8c + · TFA - was obtained as a green solid. Obtained (42.9 mg, 63.4 μmol, 69%).
1 H NMR (600 MHz, CD 3 OD): δ 7.86-7.83 (m, 2H), 7.71-7.69 (m, 1H), 7.63-7.60 (m, 2H), 7.56 (t, J = 9.0 Hz, 1H ), 7.15 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.864 and 3.855 (double singlet, 6H), 3.60 ( q, J = 7.2 Hz, 8H), 1.24 (t, 6.6 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 31 H 36 N 2 O 3 PS 2 : 579.1905 ([M-CF 3 CO 2 ] + ); found. 579.1904.
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 42.1mg, 0.0918mmol)の溶液に、トリクロロシラン(45.0μL, 0.445mmol)を加え、室温で撹拌した。5時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,6-ジメトキシベンゼン(119mg, 0.546mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 5mL)から調製した2,6-ジメトキシフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、13時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.1mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8c+・TFA-を得た(42.9mg, 63.4μmol, 69%)。
1H NMR (600 MHz, CD3OD): δ 7.86-7.83 (m, 2H), 7.71-7.69 (m, 1H), 7.63-7.60 (m, 2H), 7.56 (t, J = 9.0 Hz, 1H), 7.15 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.864 and 3.855 (double singlet, 6H), 3.60 (q, J = 7.2 Hz, 8H), 1.24 (t, 6.6 Hz, 12H). 31P{1H} NMR (CD3OD, 162 MHz) δ 5.2. HRMS(ESI): m/z calcd. For C31H36N2O3PS2: 579.1905 ([M-CF3CO2]+); found. 579.1904。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,6-dimethoxyphenyl) -1-phenyl-2H-phosphinium-1-oxide trifluoro acetate (
1 H NMR (600 MHz, CD 3 OD): δ 7.86-7.83 (m, 2H), 7.71-7.69 (m, 1H), 7.63-7.60 (m, 2H), 7.56 (t, J = 9.0 Hz, 1H ), 7.15 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.864 and 3.855 (double singlet, 6H), 3.60 ( q, J = 7.2 Hz, 8H), 1.24 (t, 6.6 Hz, 12H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.2. HRMS (ESI): m / z calcd. For C 31 H 36 N 2 O 3 PS 2 : 579.1905 ([M-CF 3 CO 2 ] + ); found. 579.1904.
ビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-(2,4,6-トリイソプロピルフェニル)-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物8d
+
・TFA
-
)の合成
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 40.3mg, 0.0872mmol)の溶液に、トリクロロシラン(44.0μL, 0.436mmol)を加え、室温で撹拌した。6時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,4,6-トリイソプロピルベンゼン(0.13mL, 0.523mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 1mL)から調製した2,4,6-トリスイソプロピルフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、16時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8d+・TFA-を得た(25.5mg, 34.3μmol, 39%)。
1H NMR (400 MHz, CD3OD): δ 7.82-7.72 (m, 3H), 7.67-7.62 (m, 2H), 7.29-7.26 (m, 4H), 3.62 (q, J = 6.8 Hz,8H), 3.02-2.92 (m, 3H), 1.33-1.23 (m, 30H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.3. HRMS(ESI): m/z calcd. For C38H50N2OPS2: 645.3102 ([M-CF3CO2]+); found. 645.3098。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,4,6-triisopropylphenyl) -1-phenyl-2H-phosphinium-1-oxide Synthesis of trifluoroacetate (compound 8d + .TFA − ) bis [5- (diethylamino) thieno] [2,3-b; 3 ′, 2′-e] -4-keto-1 in toluene (1 mL) To a solution of -phenyl-2H-phosphinium-1-oxide (compound 7; 40.3 mg, 0.0872 mmol) was added trichlorosilane (44.0 μL, 0.436 mmol), and the mixture was stirred at room temperature. After stirring for 6 hours, the mixture was filtered through a silica gel pad (THF as eluent) under a nitrogen atmosphere. The solvent was removed under reduced pressure followed by the addition of anhydrous cyclopentyl methyl ether (CPME; 5 mL). The mixture was cooled to −78 ° C. and 1-bromo-2,4,6-triisopropylbenzene (0.13 mL, 0.523 mmol), tert-butyllithium (t-BuLi; 1.64M, 0.32 mL, 0.523 mmol), And a 2,4,6-trisisopropylphenyllithium solution prepared from cyclopentyl methyl ether (CPME; 1 mL) was added at -78 ° C. The reaction mixture was heated to 70 ° C. and stirred for 16 hours. The mixture was then cooled to room temperature and 34.5% aqueous H 2 O 2 (0.05 mL) was added. After stirring for 5 minutes, the reaction was quenched with Na 2 SO 3 aqueous solution. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 8d + · TFA - was obtained as a green solid. Obtained (25.5 mg, 34.3 μmol, 39%).
1 H NMR (400 MHz, CD 3 OD): δ 7.82-7.72 (m, 3H), 7.67-7.62 (m, 2H), 7.29-7.26 (m, 4H), 3.62 (q, J = 6.8 Hz, 8H ), 3.02-2.92 (m, 3H), 1.33-1.23 (m, 30H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.3. HRMS (ESI): m / z calcd. For C 38 H 50 N 2 OPS 2 : 645.3102 ([M-CF 3 CO 2 ] + ); found. 645.3098.
トルエン(1mL)中のビス[5-(ジエチルアミノ)チエノ][2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド(化合物7; 40.3mg, 0.0872mmol)の溶液に、トリクロロシラン(44.0μL, 0.436mmol)を加え、室温で撹拌した。6時間撹拌した後、窒素雰囲気下で混合物をシリカゲルパッド(溶離液としてTHF)でろ過した。溶媒を減圧下で除去し、続いて無水シクロペンチルメチルエーテル(CPME; 5mL)を添加した。この混合物を-78℃に冷却し、1-ブロモ-2,4,6-トリイソプロピルベンゼン(0.13mL, 0.523mmol)、tert-ブチルリチウム(t-BuLi; 1.64M, 0.32mL, 0.523mmol)、及びシクロペンチルメチルエーテル(CPME; 1mL)から調製した2,4,6-トリスイソプロピルフェニルリチウム溶液を-78℃で添加した。反応混合物を70℃に加熱し、16時間撹拌した。次いで、混合物を室温まで冷却し、34.5%H2O2水溶液(0.05mL)を添加した。5分間撹拌した後、Na2SO3水溶液で反応をクエンチした。得られた溶液をCHCl3で抽出し、溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物8d+・TFA-を得た(25.5mg, 34.3μmol, 39%)。
1H NMR (400 MHz, CD3OD): δ 7.82-7.72 (m, 3H), 7.67-7.62 (m, 2H), 7.29-7.26 (m, 4H), 3.62 (q, J = 6.8 Hz,8H), 3.02-2.92 (m, 3H), 1.33-1.23 (m, 30H). 31P{1H} NMR(CD3OD, 162 MHz) δ 5.3. HRMS(ESI): m/z calcd. For C38H50N2OPS2: 645.3102 ([M-CF3CO2]+); found. 645.3098。 Bis [5- (diethylamino) thieno] [2,3-b; 3 ', 2'-e] -4- (2,4,6-triisopropylphenyl) -1-phenyl-2H-phosphinium-1-oxide Synthesis of trifluoroacetate (
1 H NMR (400 MHz, CD 3 OD): δ 7.82-7.72 (m, 3H), 7.67-7.62 (m, 2H), 7.29-7.26 (m, 4H), 3.62 (q, J = 6.8 Hz, 8H ), 3.02-2.92 (m, 3H), 1.33-1.23 (m, 30H). 31 P { 1 H} NMR (CD 3 OD, 162 MHz) δ 5.3. HRMS (ESI): m / z calcd. For C 38 H 50 N 2 OPS 2 : 645.3102 ([M-CF 3 CO 2 ] + ); found. 645.3098.
[実施例4]
[Example 4]
[式中、Phはフェニル基を示す。Et2NHはジエチルアミンを示す。DMFはジメチルホルムアミドを示す。Ph2C=NHはベンゾフェノンイミンを示す。Pd(OAc)2は酢酸パラジウムを示す。BINAPは2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチルを示す。THFはテトラヒドロフランを示す。以下同様である。]
[Wherein, Ph represents a phenyl group. Et 2 NH represents diethylamine. DMF represents dimethylformamide. Ph 2 C═NH represents benzophenone imine. Pd (OAc) 2 represents palladium acetate. BINAP represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. THF represents tetrahydrofuran. The same applies hereinafter. ]
ジチエノ[2,3-b;3’,2’-e]-4-(2,5-ジオキソラニル)-1-フェニル-2H-ホスフィン-1-オキシド(化合物3)の合成
実施例1と同様に、化合物3を合成した。 Synthesis of dithieno [2,3-b; 3 ′, 2′-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) As in Example 1.Compound 3 was synthesized.
実施例1と同様に、化合物3を合成した。 Synthesis of dithieno [2,3-b; 3 ′, 2′-e] -4- (2,5-dioxolanyl) -1-phenyl-2H-phosphine-1-oxide (compound 3) As in Example 1.
ビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4)の合成
実施例1と同様に、化合物4を合成した。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) As in Example 1,Compound 4 was synthesized.
実施例1と同様に、化合物4を合成した。 Synthesis of bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (compound 4) As in Example 1,
5-(ジエチルアミノ)チエノ[2,3-b]-5’-ブロモチエノ[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物9)の合成
ジメチルホルムアミド(DMF; 1mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 50.9mg, 0.107mmol)の溶液に、ジエチルアミン(0.11mL, 1.05mmol)を添加し、80℃で撹拌した。同じ温度で12時間撹拌した後、減圧下で溶媒を除去した。得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3, Rf= 0.21)で精製し、橙色固体として化合物9を得た(42.7mg, 91.6μmol, 89%)。
1H NMR (400 MHz, CDCl3): δ 7.73-7.67 (m 2H), 7.57-7.53 (m, 1H), 7.45-7.44 (m, 2H), 7.28 (d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 7.2 Hz, 4H), 1.32 (t, J = 7.2 Hz, 6H). 31P{1H} NMR (CDCl3, 162 MHz) δ 1.4。 Synthesis of 5- (diethylamino) thieno [2,3-b] -5'-bromothieno [3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (Compound 9) Dimethyl Bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (formula 4; 50.9) in formamide (DMF; 1 mL) To a solution of mg, 0.107 mmol) was added diethylamine (0.11 mL, 1.05 mmol), and the mixture was stirred at 80 ° C. After stirring at the same temperature for 12 hours, the solvent was removed under reduced pressure. The obtained solid was purified by silica gel column chromatography (CHCl 3 , R f = 0.21 as an eluent) to obtain Compound 9 as an orange solid (42.7 mg, 91.6 μmol, 89%).
1 H NMR (400 MHz, CDCl 3 ): δ 7.73-7.67 (m 2H), 7.57-7.53 (m, 1H), 7.45-7.44 (m, 2H), 7.28 (d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 7.2 Hz, 4H), 1.32 (t, J = 7.2 Hz, 6H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 1.4.
ジメチルホルムアミド(DMF; 1mL)中のビス(5-ブロモチエノ)[2,3-b;3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物4; 50.9mg, 0.107mmol)の溶液に、ジエチルアミン(0.11mL, 1.05mmol)を添加し、80℃で撹拌した。同じ温度で12時間撹拌した後、減圧下で溶媒を除去した。得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3, Rf= 0.21)で精製し、橙色固体として化合物9を得た(42.7mg, 91.6μmol, 89%)。
1H NMR (400 MHz, CDCl3): δ 7.73-7.67 (m 2H), 7.57-7.53 (m, 1H), 7.45-7.44 (m, 2H), 7.28 (d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 7.2 Hz, 4H), 1.32 (t, J = 7.2 Hz, 6H). 31P{1H} NMR (CDCl3, 162 MHz) δ 1.4。 Synthesis of 5- (diethylamino) thieno [2,3-b] -5'-bromothieno [3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (Compound 9) Dimethyl Bis (5-bromothieno) [2,3-b; 3 ′, 2′-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (
1 H NMR (400 MHz, CDCl 3 ): δ 7.73-7.67 (m 2H), 7.57-7.53 (m, 1H), 7.45-7.44 (m, 2H), 7.28 (d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 7.2 Hz, 4H), 1.32 (t, J = 7.2 Hz, 6H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 1.4.
[5-(ジエチルアミノ)チエノ][2,3-b]-{5’-[(1,1-ジフェニルメチル)イミノ]チエノ}[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物10)の合成
無水トルエン(25mL)中の5-(ジエチルアミノ)チエノ[2,3-b]-5’-ブロモチエノ[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物9; 380mg, 0.815mmol)に、ベンゾフェノンイミン(Ph2C=NH; 219mg, 1.21mmol)、酢酸パラジウム(Pd(OAc)2; 20.7mg, 92.2μmol)、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(rac-BINAP; 77.7mg, 0.122mmol)、及びCs2CO3(400mg, 1.23mmol)を添加し、90℃で撹拌した。同じ温度で15時間加熱した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 20/1, Rf= 0.30)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3/酢酸エチル= 20/1)で精製し、赤色固体として化合物10を得た(0.244g, 0.701mmol, 86%)。
1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H), 7.70-7.65 (m, 2H), 7.54-7.36 (m, 10H), 7.21 (d, J = 6.8 Hz, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 3.38 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H). 31P{1H} NMR (CDCl3, 162 MHz) δ 2.2。 [5- (Diethylamino) thieno] [2,3-b]-{5 '-[(1,1-diphenylmethyl) imino] thieno} [3', 2'-e] -4-keto-1-phenyl Synthesis of -2H -phosphine-1-oxide (Compound 10) 5- (Diethylamino) thieno [2,3-b] -5'-bromothieno [3 ', 2'-e] -4 in anhydrous toluene (25 mL) -Keto-1-phenyl-2H-phosphine-1-oxide (compound 9; 380 mg, 0.815 mmol), benzophenone imine (Ph 2 C = NH; 219 mg, 1.21 mmol), palladium acetate (Pd (OAc) 2 ; 20.7 mg, 92.2 μmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (rac-BINAP; 77.7 mg, 0.122 mmol), and Cs 2 CO 3 (400 mg, 1.23 mmol) And stirred at 90 ° C. After heating at the same temperature for 15 hours, it was quenched with saturated aqueous NH 4 Cl. The resulting solution was extracted with CHCl 3 . The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. Volatiles were removed under reduced pressure, and the resulting solid was subjected to silica gel column chromatography (CHCl 3 / ethyl acetate = 20/1, R f = 0.30 as eluent) and HPLC (silica gel Wakosil-II 5SIL-Prep, elution) The solution was purified by CHCl 3 / ethyl acetate = 20/1) to obtain Compound 10 as a red solid (0.244 g, 0.701 mmol, 86%).
1 H NMR (400 MHz, CDCl 3 ): δ 7.73 (d, J = 7.2 Hz, 2H), 7.70-7.65 (m, 2H), 7.54-7.36 (m, 10H), 7.21 (d, J = 6.8 Hz , 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 3.38 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H ). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 2.2.
無水トルエン(25mL)中の5-(ジエチルアミノ)チエノ[2,3-b]-5’-ブロモチエノ[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物9; 380mg, 0.815mmol)に、ベンゾフェノンイミン(Ph2C=NH; 219mg, 1.21mmol)、酢酸パラジウム(Pd(OAc)2; 20.7mg, 92.2μmol)、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(rac-BINAP; 77.7mg, 0.122mmol)、及びCs2CO3(400mg, 1.23mmol)を添加し、90℃で撹拌した。同じ温度で15時間加熱した後、飽和NH4Cl水溶液でクエンチした。得られた溶液をCHCl3で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過した。揮発物質を減圧下で除去し、得られた固体をシリカゲルカラムクロマトグラフィー(溶離液としてCHCl3/酢酸エチル= 20/1, Rf= 0.30)及びHPLC(silica gel Wakosil-II 5SIL-Prep, 溶離液としてCHCl3/酢酸エチル= 20/1)で精製し、赤色固体として化合物10を得た(0.244g, 0.701mmol, 86%)。
1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H), 7.70-7.65 (m, 2H), 7.54-7.36 (m, 10H), 7.21 (d, J = 6.8 Hz, 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 3.38 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H). 31P{1H} NMR (CDCl3, 162 MHz) δ 2.2。 [5- (Diethylamino) thieno] [2,3-b]-{5 '-[(1,1-diphenylmethyl) imino] thieno} [3', 2'-e] -4-keto-1-phenyl Synthesis of -2H -phosphine-1-oxide (Compound 10) 5- (Diethylamino) thieno [2,3-b] -5'-bromothieno [3 ', 2'-e] -4 in anhydrous toluene (25 mL) -Keto-1-phenyl-2H-phosphine-1-oxide (
1 H NMR (400 MHz, CDCl 3 ): δ 7.73 (d, J = 7.2 Hz, 2H), 7.70-7.65 (m, 2H), 7.54-7.36 (m, 10H), 7.21 (d, J = 6.8 Hz , 2H), 7.09 (d, J = 5.2 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 3.38 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H ). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 2.2.
[5-(ジエチルアミノ)チエノ][2,3-b]-(5’-アミノチエノ)[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィニウム-1-オキシド・トリフルオロアセテート(化合物11
+
・TFA
-
)の合成
無水テトラヒドロフラン(THF; 1mL)中の2-ブロモトルエン(0.022μL, 0,183mmol)の溶液に、-78℃でtert-ブチルリチウム(t-BuLi; 1.64M, 0.11mL, 0.183mmol)を添加した。混合物を-78℃で1時間攪拌し、無水テトラヒドロフラン(THF; 2mL)中の[5-(ジエチルアミノ)チエノ][2,3-b]-{5’-[(1,1-ジフェニルメチル)イミノ]チエノ}[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物10; 51.8mg, 0.0914mmol)の溶液を添加した。反応混合物を室温まで昇温し、3時間攪拌した。次いで、トリフルオロ酢酸(TFA; 0.5mL)を添加して反応をクエンチした。1時間攪拌した後、蒸留水を添加した。得られた溶液をCHCl3で抽出し、減圧下で溶媒を除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物11+・TFA-を得た(11.3mg, 19.2μmol, 21%)。
1H NMR (400 MHz, CD3OD): δ 7.84-7.78 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.50-7.40 (m, 3H),7.34 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 3.64 (q, J = 6.8 Hz, 8H), 2.37 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CDCl3, 162 MHz) δ 4.9。 [5- (Diethylamino) thieno] [2,3-b]-(5'-aminothieno) [3 ', 2'-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide trifluoro acetate (compound 11 + · TFA -) synthesis anhydrous tetrahydrofuran (THF; 1 mL) solution of 2-bromotoluene (0.022μL, 0,183mmol) in a solution of at -78 ° C. tert-butyllithium (t-BuLi; 1.64M , 0.11 mL, 0.183 mmol) was added. The mixture was stirred at −78 ° C. for 1 hour and [5- (diethylamino) thieno] [2,3-b]-{5 ′-[(1,1-diphenylmethyl) imino in anhydrous tetrahydrofuran (THF; 2 mL) ] Thieno} [3 ', 2'-e] -4-keto-1-phenyl-2H-phosphine-1-oxide (Compound 10; 51.8 mg, 0.0914 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. Then trifluoroacetic acid (TFA; 0.5 mL) was added to quench the reaction. After stirring for 1 hour, distilled water was added. The resulting solution was extracted with CHCl 3 and the solvent was removed under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-DispoPack AT, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent). The eluent was extracted with CHCl 3 . The solvent was removed from the combined solution under reduced pressure. The resulting solid was purified by reverse phase HPLC (YMC-Actus Triart, 30/80 to 80/20 CH 3 CN / H 2 O containing 0.1% TFA as eluent), and compound 11 + • TFA - was obtained as a green solid. Obtained (11.3 mg, 19.2 μmol, 21%).
1 H NMR (400 MHz, CD 3 OD): δ 7.84-7.78 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.50 -7.40 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 3.64 (q, J = 6.8 Hz, 8H), 2.37 (s, 3H) , 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 4.9.
無水テトラヒドロフラン(THF; 1mL)中の2-ブロモトルエン(0.022μL, 0,183mmol)の溶液に、-78℃でtert-ブチルリチウム(t-BuLi; 1.64M, 0.11mL, 0.183mmol)を添加した。混合物を-78℃で1時間攪拌し、無水テトラヒドロフラン(THF; 2mL)中の[5-(ジエチルアミノ)チエノ][2,3-b]-{5’-[(1,1-ジフェニルメチル)イミノ]チエノ}[3’,2’-e]-4-ケト-1-フェニル-2H-ホスフィン-1-オキシド(化合物10; 51.8mg, 0.0914mmol)の溶液を添加した。反応混合物を室温まで昇温し、3時間攪拌した。次いで、トリフルオロ酢酸(TFA; 0.5mL)を添加して反応をクエンチした。1時間攪拌した後、蒸留水を添加した。得られた溶液をCHCl3で抽出し、減圧下で溶媒を除去した。得られた固体を逆相HPLC(溶離液としてYMC-DispoPack AT, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製した。溶離液をCHCl3で抽出した。合わせた溶液から溶媒を減圧下で除去した。得られた固体を逆相HPLC(溶離液としてYMC-Actus Triart, 30/80 to 80/20 CH3CN/H2O containing 0.1% TFA)で精製し、緑色固体として化合物11+・TFA-を得た(11.3mg, 19.2μmol, 21%)。
1H NMR (400 MHz, CD3OD): δ 7.84-7.78 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.50-7.40 (m, 3H),7.34 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 3.64 (q, J = 6.8 Hz, 8H), 2.37 (s, 3H), 1.25 (t, J = 7.2 Hz, 12H). 31P{1H} NMR(CDCl3, 162 MHz) δ 4.9。 [5- (Diethylamino) thieno] [2,3-b]-(5'-aminothieno) [3 ', 2'-e] -4-keto-1-phenyl-2H-phosphinium-1-oxide trifluoro acetate (
1 H NMR (400 MHz, CD 3 OD): δ 7.84-7.78 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.50 -7.40 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 3.64 (q, J = 6.8 Hz, 8H), 2.37 (s, 3H) , 1.25 (t, J = 7.2 Hz, 12H). 31 P { 1 H} NMR (CDCl 3 , 162 MHz) δ 4.9.
[試験例1:光物性]
実施例1の化合物1+・TFA-、実施例2の化合物6+・TFA-及び実施例4の化合物11+・TFA-について、ジメチルスルホキシド(DMSO)と水(クエン酸/Na2HPO4水溶液)との混合溶媒(DMSO/水 = 1/99体積%)中に、濃度1.10×10-5M(1+・TFA-)、1.24×10-5M(6+・TFA-)、又は1.73×10-5M(11+・TFA-)で溶解させた後、pHを4.0の緩衝液とした場合の紫外可視近赤外吸光スペクトル及び蛍光スペクトル、絶対蛍光量子収率等の測定を行った。また、実施例3の化合物8a+・TFA-、8b+・TFA-、8c+・TFA-、及び8d+・TFA-について、ジメチルスルホキシド(DMSO)と水(Na2HPO4/NaH2PO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.78×10-5Mで溶解させた後、pHを7.4の緩衝液とした場合の紫外可視近赤外吸光スペクトル及び蛍光スペクトル、絶対蛍光量子収率等の測定を行った。結果を表1及び図1~6に示す。 [Test Example 1: Optical properties]
Forcompound 1 + · TFA − of Example 1, compound 6 + · TFA − of Example 2 and compound 11 + · TFA − of Example 4, dimethyl sulfoxide (DMSO) and water (citric acid / Na 2 HPO 4 aqueous solution) ) In a mixed solvent (DMSO / water = 1/99% by volume), concentration 1.10 × 10 −5 M (1 + · TFA − ), 1.24 × 10 −5 M (6 + · TFA − ), or 1.73 × 10 -5 M (11 + · TFA -) was dissolved in an ultraviolet-visible near-infrared absorption spectrum and the fluorescence spectrum in the case where the the pH 4.0 buffer, the measurement of such absolute fluorescence quantum yield went . Further, with respect to the compounds 8a + · TFA − , 8b + · TFA − , 8c + · TFA − , and 8d + · TFA − of Example 3, dimethyl sulfoxide (DMSO) and water (Na 2 HPO 4 / NaH 2 PO 4 UV-visible near-infrared absorption spectrum when dissolved in a mixed solvent (DMSO / water = 1/99% by volume) with a concentration of 1.78 x 10 -5 M and then buffered at pH 7.4 Measurement of fluorescence spectrum, absolute fluorescence quantum yield, etc. The results are shown in Table 1 and FIGS.
実施例1の化合物1+・TFA-、実施例2の化合物6+・TFA-及び実施例4の化合物11+・TFA-について、ジメチルスルホキシド(DMSO)と水(クエン酸/Na2HPO4水溶液)との混合溶媒(DMSO/水 = 1/99体積%)中に、濃度1.10×10-5M(1+・TFA-)、1.24×10-5M(6+・TFA-)、又は1.73×10-5M(11+・TFA-)で溶解させた後、pHを4.0の緩衝液とした場合の紫外可視近赤外吸光スペクトル及び蛍光スペクトル、絶対蛍光量子収率等の測定を行った。また、実施例3の化合物8a+・TFA-、8b+・TFA-、8c+・TFA-、及び8d+・TFA-について、ジメチルスルホキシド(DMSO)と水(Na2HPO4/NaH2PO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.78×10-5Mで溶解させた後、pHを7.4の緩衝液とした場合の紫外可視近赤外吸光スペクトル及び蛍光スペクトル、絶対蛍光量子収率等の測定を行った。結果を表1及び図1~6に示す。 [Test Example 1: Optical properties]
For
以上の結果から、本発明のジチエノホスホリン化合物は、近赤外蛍光色素の代表格であるICGと同程度に吸収極大波長及び蛍光極大波長を長くすることができ、また、蛍光量子収率も十分に高いことが理解できる。
From the above results, the dithienophosphorine compound of the present invention can increase the absorption maximum wavelength and the fluorescence maximum wavelength to the same extent as ICG, which is a typical near-infrared fluorescent dye, and the fluorescence quantum yield. Can be understood to be sufficiently high.
[試験例2:光に対する安定性]
実施例1の化合物1+・TFA-について、ジメチルスルホキシド(DMSO)と水(クエン酸/Na2HPO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.10×10-5Mで溶解させた後、pHを4.01の緩衝液とした。この試験液に対して、300Wキセノンランプ(朝日分光(株)MAX-301)を用いて、バンドパスフィルターを使用し、749nmの波長の光を照射し、吸光度の維持率(相対吸光度)を評価した。測定は、照射直後の吸光度(A0)と一定時間経過後の吸光度(A)の測定を行い、A/A0を維持率として評価した。結果を図8に示す。また、実施例3の化合物8a+・TFA-、8b+・TFA-、8c+・TFA-、及び8d+・TFA-について、ジメチルスルホキシド(DMSO)と水(Na2HPO4/NaH2PO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.10×10-5Mで溶解させた後、pHを7.4の緩衝液とした。この試験液に対して、300Wキセノンランプ(朝日分光(株)MAX-301)を用いて、バンドパスフィルターを使用し、749nmの波長の光を照射し、吸光度の維持率(相対吸光度)を評価した。測定は、照射直後の吸光度(A0)と一定時間経過後の吸光度(A)の測定を行い、A/A0を維持率として評価した。結果を図9に示す。この結果、近赤外蛍光色素の代表格であるICGは照射直後から吸光度が低下し、約2時間経過後には相対吸光度が0.4程度であるのに対し、本発明のジチエノホスホリン化合物は、光に対する安定性が高く、特に、化合物1+・TFA-は照射開始から8時間以上経過しても吸光度がほとんど低下せず相対吸光度が0.95程度であり、酸性条件下での安定性を飛躍的に向上させることができたことが理解できる。 [Test Example 2: Stability to light]
Concentration 1.10 × in the mixed solvent (DMSO / water = 1/99 vol%) of dimethyl sulfoxide (DMSO) and water (citric acid / Na 2 HPO 4 aqueous solution) for thecompound 1 + · TFA − of Example 1 After dissolving at 10 −5 M, a pH 4.01 buffer was used. Using a 300 W xenon lamp (Asahi Spectroscopy Co., Ltd., MAX-301), irradiate the test solution with light at a wavelength of 749 nm, and evaluate the absorbance maintenance rate (relative absorbance). did. The measurement was carried out by measuring the absorbance immediately after irradiation (A 0 ) and the absorbance after a certain period of time (A), and evaluating A / A 0 as the maintenance rate. The results are shown in FIG. Further, with respect to the compounds 8a + · TFA − , 8b + · TFA − , 8c + · TFA − , and 8d + · TFA − of Example 3, dimethyl sulfoxide (DMSO) and water (Na 2 HPO 4 / NaH 2 PO 4 In a mixed solvent (DMSO / water = 1/99% by volume) with a concentration of 1.10 × 10 −5 M, and a buffer solution having a pH of 7.4 was obtained. Using a 300 W xenon lamp (Asahi Spectroscopy Co., Ltd., MAX-301), irradiate the test solution with light at a wavelength of 749 nm, and evaluate the absorbance maintenance rate (relative absorbance). did. The measurement was carried out by measuring the absorbance immediately after irradiation (A 0 ) and the absorbance after a certain period of time (A), and evaluating A / A 0 as the maintenance rate. The results are shown in FIG. As a result, ICG, which is a representative near-infrared fluorescent dye, decreases in absorbance immediately after irradiation and has a relative absorbance of about 0.4 after about 2 hours, whereas the dithienophosphorine compound of the present invention is high stability to light, in particular, compound 1 + · TFA - is the relative absorbance of about 0.95 hardly decreased absorbance even after the elapse 8 hours or more from the start of irradiation dramatically the stability under acidic conditions It can be understood that it was able to be improved.
実施例1の化合物1+・TFA-について、ジメチルスルホキシド(DMSO)と水(クエン酸/Na2HPO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.10×10-5Mで溶解させた後、pHを4.01の緩衝液とした。この試験液に対して、300Wキセノンランプ(朝日分光(株)MAX-301)を用いて、バンドパスフィルターを使用し、749nmの波長の光を照射し、吸光度の維持率(相対吸光度)を評価した。測定は、照射直後の吸光度(A0)と一定時間経過後の吸光度(A)の測定を行い、A/A0を維持率として評価した。結果を図8に示す。また、実施例3の化合物8a+・TFA-、8b+・TFA-、8c+・TFA-、及び8d+・TFA-について、ジメチルスルホキシド(DMSO)と水(Na2HPO4/NaH2PO4水溶液)との混合溶媒(DMSO/水= 1/99体積%)中に、濃度1.10×10-5Mで溶解させた後、pHを7.4の緩衝液とした。この試験液に対して、300Wキセノンランプ(朝日分光(株)MAX-301)を用いて、バンドパスフィルターを使用し、749nmの波長の光を照射し、吸光度の維持率(相対吸光度)を評価した。測定は、照射直後の吸光度(A0)と一定時間経過後の吸光度(A)の測定を行い、A/A0を維持率として評価した。結果を図9に示す。この結果、近赤外蛍光色素の代表格であるICGは照射直後から吸光度が低下し、約2時間経過後には相対吸光度が0.4程度であるのに対し、本発明のジチエノホスホリン化合物は、光に対する安定性が高く、特に、化合物1+・TFA-は照射開始から8時間以上経過しても吸光度がほとんど低下せず相対吸光度が0.95程度であり、酸性条件下での安定性を飛躍的に向上させることができたことが理解できる。 [Test Example 2: Stability to light]
Concentration 1.10 × in the mixed solvent (DMSO / water = 1/99 vol%) of dimethyl sulfoxide (DMSO) and water (citric acid / Na 2 HPO 4 aqueous solution) for the
[試験例3:さまざまなpHの水中での安定性]
実施例1の化合物1+・TFA-、実施例2の化合物6+・TFA-、実施例3の化合物8a+・TFA-及び実施例4の11+・TFA-について、ジメチルスルホキシド(DMSO)と種々のpH緩衝液(pH= 3~6: クエン酸/Na2HPO4水溶液、pH= 6~8: NaH2PO4/Na2HPO4水溶液、pH = 8~11: Na2CO3/NaHCO3水溶液、pH= 11~12: Na2HPO4/NaOH水溶液、pH= 12~13.5: NaOH/KCl水溶液)との混合溶媒(DMSO/緩衝液= 1/99体積%)中に、濃度1.10×10-5M(化合物1+・TFA-)、1.24×10-5M(化合物6+・TFA-)、1.78×10-5M(化合物8a+・TFA-)、又は1.73×10-5M(11+・TFA-)で溶解させた場合の紫外可視近赤外吸光スペクトルの測定を行い、750nmにおける吸光度をプロットした。結果を図10~13に示す。この結果、化合物1+・TFA-及び化合物6+・TFA-はpH= 5以上の領域で吸光度が低下し、化合物11+・TFA-はpH= 6以上の領域で吸光度が低下したのに対し、化合物8a+・TFA-はpH= 12まで吸光度がほとんど低下せず、幅広いpH条件での色素の化学的安定性が実現できたことが理解できる。 [Test Example 3: Stability in water at various pHs]
Compound 1 + • TFA − of Example 1, Compound 6 + • TFA − of Example 2, Compound 8a + • TFA − of Example 3 and 11 + • TFA − of Example 4 are combined with dimethyl sulfoxide (DMSO) Various pH buffers (pH = 3-6: citric acid / Na 2 HPO 4 aqueous solution, pH = 6-8: NaH 2 PO 4 / Na 2 HPO 4 aqueous solution, pH = 8-11: Na 2 CO 3 / NaHCO 3 aqueous solution, pH = 11-12: Na 2 HPO 4 / NaOH aqueous solution, pH = 12-13.5: NaOH / KCl aqueous solution) mixed solvent (DMSO / buffer = 1/99 vol%), concentration 1.10 × 10 -5 M (compound 1 + • TFA − ), 1.24 × 10 −5 M (compound 6 + • TFA − ), 1.78 × 10 −5 M (compound 8a + • TFA − ), or 1.73 × 10 −5 M (11 + · TFA -) was measured in the ultraviolet-visible-near infrared absorption spectrum when dissolved in, and plotting absorbance at 750 nm. The results are shown in FIGS. As a result, Compound 1 + · TFA - and Compound 6 + · TFA - decreases the absorbance at pH = 5 or more regions, Compound 11 + · TFA - whereas the absorbance at pH = 6 or more areas has decreased Thus, it can be understood that the compound 8a + .TFA − showed almost no decrease in absorbance until pH = 12 and realized chemical stability of the dye under a wide range of pH conditions.
実施例1の化合物1+・TFA-、実施例2の化合物6+・TFA-、実施例3の化合物8a+・TFA-及び実施例4の11+・TFA-について、ジメチルスルホキシド(DMSO)と種々のpH緩衝液(pH= 3~6: クエン酸/Na2HPO4水溶液、pH= 6~8: NaH2PO4/Na2HPO4水溶液、pH = 8~11: Na2CO3/NaHCO3水溶液、pH= 11~12: Na2HPO4/NaOH水溶液、pH= 12~13.5: NaOH/KCl水溶液)との混合溶媒(DMSO/緩衝液= 1/99体積%)中に、濃度1.10×10-5M(化合物1+・TFA-)、1.24×10-5M(化合物6+・TFA-)、1.78×10-5M(化合物8a+・TFA-)、又は1.73×10-5M(11+・TFA-)で溶解させた場合の紫外可視近赤外吸光スペクトルの測定を行い、750nmにおける吸光度をプロットした。結果を図10~13に示す。この結果、化合物1+・TFA-及び化合物6+・TFA-はpH= 5以上の領域で吸光度が低下し、化合物11+・TFA-はpH= 6以上の領域で吸光度が低下したのに対し、化合物8a+・TFA-はpH= 12まで吸光度がほとんど低下せず、幅広いpH条件での色素の化学的安定性が実現できたことが理解できる。 [Test Example 3: Stability in water at various pHs]
Claims (11)
- 一般式(1):
で表される基を示す。R2は一般式(3A)、(3B)又は(3C):
で表される基を示す。R3及びR4は同一又は異なって、水素原子、ハロゲン原子、スルホニル基、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R5及びR6は同一又は異なって、水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。Xはアニオンを示す。nは1又は2を示し、R2が一般式(3A)又は(3C)で表される基の場合は1、R2が一般式(3B)で表される基の場合は2である。]
で表される、ジチエノホスホリン化合物。 General formula (1):
The group represented by these is shown. R 2 is the general formula (3A), (3B) or (3C):
The group represented by these is shown. R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a sulfonyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. R 5 and R 6 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. X represents an anion. n represents 1 or 2, and is 1 when R 2 is a group represented by the general formula (3A) or (3C), and 2 when R 2 is a group represented by the general formula (3B). ]
A dithienophosphorine compound represented by: - 前記一般式(1)において、R1が一般式(2A)で表される基である、請求項1に記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to claim 1, wherein R 1 in the general formula (1) is a group represented by the general formula (2A).
- 前記一般式(1)において、R7が置換されていてもよいアリール基である、請求項2に記載のジチエノホスホリン。 In the general formula (1), it has R 7 is an optionally substituted aryl group, dithienothiophene phospholine of claim 2.
- 前記一般式(1)において、R2が一般式(3A)で表される基であり、nが1である、請求項1~3のいずれかに記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to any one of claims 1 to 3, wherein, in the general formula (1), R 2 is a group represented by the general formula (3A), and n is 1.
- 前記一般式(1)において、Yが酸素原子である、請求項4に記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to claim 4, wherein in the general formula (1), Y is an oxygen atom.
- 前記一般式(1)において、R8が置換されていてもよいアリール基である、請求項4又は5に記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to claim 4 or 5, wherein in the general formula (1), R 8 is an optionally substituted aryl group.
- 前記一般式(1)において、R3及びR4がいずれも水素原子である、請求項1~6のいずれかに記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to any one of claims 1 to 6, wherein in the general formula (1), R 3 and R 4 are both hydrogen atoms.
- 前記一般式(1)において、R5及びR6がいずれも同一又は異なって、水素原子又は置換されていてもよいアルキル基である、請求項1~7のいずれかに記載のジチエノホスホリン化合物。 The dithienophosphorine according to any one of claims 1 to 7, wherein, in the general formula (1), R 5 and R 6 are the same or different and each is a hydrogen atom or an optionally substituted alkyl group. Compound.
- 650~850nmに吸収極大波長を有する、請求項1~8のいずれかに記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to any one of claims 1 to 8, which has an absorption maximum wavelength at 650 to 850 nm.
- 750~1000nmに蛍光極大波長を有する、請求項1~9のいずれかに記載のジチエノホスホリン化合物。 The dithienophosphorine compound according to any one of claims 1 to 9, which has a fluorescence maximum wavelength at 750 to 1000 nm.
- 請求項1~10のいずれかに記載のジチエノホスホリン化合物を含有する蛍光色素。 A fluorescent dye containing the dithienophosphorine compound according to any one of claims 1 to 10.
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WO2021176755A1 (en) | 2020-03-04 | 2021-09-10 | 国立大学法人京都大学 | Dithienophosphorine compound, and colorless near-infrared absorbing material and electrochromic material each using same |
WO2023219010A1 (en) * | 2022-05-13 | 2023-11-16 | 富士フイルム株式会社 | Resin composition, film, optical filter, solid-state imaging element, image display device, infrared sensor, camera module, and compound |
WO2024008805A1 (en) | 2022-07-06 | 2024-01-11 | Phosuma Photonic & Sustainable Materials Gmbh | Heteroaromatic ketones and their use in radical and cationic polymerization |
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WO2021176755A1 (en) | 2020-03-04 | 2021-09-10 | 国立大学法人京都大学 | Dithienophosphorine compound, and colorless near-infrared absorbing material and electrochromic material each using same |
WO2023219010A1 (en) * | 2022-05-13 | 2023-11-16 | 富士フイルム株式会社 | Resin composition, film, optical filter, solid-state imaging element, image display device, infrared sensor, camera module, and compound |
WO2024008805A1 (en) | 2022-07-06 | 2024-01-11 | Phosuma Photonic & Sustainable Materials Gmbh | Heteroaromatic ketones and their use in radical and cationic polymerization |
DE102022116865A1 (en) | 2022-07-06 | 2024-01-11 | PhoSuMa Photonic & Sustainable Materials | HETEROAROMATIC KETONES AND THEIR USE IN RADICAL AND CATIONIC POLYMERIZATION |
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