JP6899371B2 - 化合物のフッ素化方法 - Google Patents
化合物のフッ素化方法 Download PDFInfo
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- JP6899371B2 JP6899371B2 JP2018505464A JP2018505464A JP6899371B2 JP 6899371 B2 JP6899371 B2 JP 6899371B2 JP 2018505464 A JP2018505464 A JP 2018505464A JP 2018505464 A JP2018505464 A JP 2018505464A JP 6899371 B2 JP6899371 B2 JP 6899371B2
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- heteroaryl
- aryl
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- 238000000034 method Methods 0.000 title claims description 110
- 238000003682 fluorination reaction Methods 0.000 title description 27
- 150000001875 compounds Chemical class 0.000 title description 22
- 239000000758 substrate Substances 0.000 claims description 136
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- 125000003118 aryl group Chemical group 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- 229910052794 bromium Inorganic materials 0.000 claims description 42
- 229910052801 chlorine Inorganic materials 0.000 claims description 42
- 229910052740 iodine Inorganic materials 0.000 claims description 42
- 229910004013 NO 2 Inorganic materials 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 31
- -1 chloro, bromo, iodo Chemical group 0.000 claims description 27
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 24
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 150000004820 halides Chemical class 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
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- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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Description
Aは、Cl、Br、I、NO2、またはSO3R3であり;
Bは、H、Cl、Br、I、NO2、またはSO3R3であり;
Cは、H、Cl、Br、I、NO2、またはSO3R3であり;
R1は、H、CN、またはCO2R3であり、式中、各R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;および
R2は、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールである。使用され得るヘテロアリール基質のさらなる例は、式III-Aを有している:
X1およびX2のうちの1つはNであり、他方はCであり;
Aは、Cl、Br、I、NO2、またはSO3R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;および
R4は、H、CN、置換もしくは非置換C1-C12アルキル、置換もしくは非置換C2-C12アルケニル、置換もしくは非置換C2-C12アルキニル、OR3、CO2R3、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールである。
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、 CN、R3、COR3、またはCO2R3であり;
各Cは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、CN、R3、COR3、またはCO2R3であり;および
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
Aは、Cl、Br、I、またはSO3R3であり;
nは、0〜5であり;
各Bは、他のいずれからも独立して、Cl、Br、I、CN、SO2R3、R3、COR3、またはCO2R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、CN、NO2、SO2R3、SO2R3、R3、COR3、またはCO2R3であり;
R2は、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各R2は、互いに独立して、H、ハロゲン化物、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;および
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
各R2は、互いに独立して、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;および
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
以下の本明細書および請求の範囲において、多くの用語に関し言及が為されるが、それらは以下の意味を有すると定義されるものとする:
本明細書の記述内容および請求の範囲全体を通して、「含む(comprise)」という文言、および当該文言の他の形態、たとえば「含むこと(comprising)」および「含む(comprises)」などは、例えば他の添加物、構成要素、整数、または工程などを含むことを意味するが、それらに限定されず、およびそれらを除外することは意図されていない。
本明細書において使用される場合、「置換される」という用語は、有機化合物のすべての許容可能な置換基を含むことが予期される。広義の態様において、当該許容可能な置換基としては、非環式および環式、分枝状および非分枝状、炭素環式および複素環式、ならびに芳香族および非芳香族の、有機化合物の置換基が挙げられる。解説的な置換基としては例えば、以下に記述されるものが挙げられる。許容可能な置換基は、適切な有機化合物に対し、1つ以上であってもよく、および同一または異なっていてもよい。本開示の目的に対し、例えば窒素などのヘテロ原子は、水素置換基、および/またはヘテロ原子の価数を満たす、本明細書に記載される有機化合物の任意の許容可能な置換基を有していてもよい。本開示は、有機化合物の許容可能な置換基によって、いずれの様式でも限定されることは意図されない。また「置換」または「〜で置換される」という用語は、かかる置換が、置換される原子と置換基の許容される価数と合致しているという暗黙的な条件、および置換によって安定した化合物、たとえば転位、結晶化、脱離などによる変化を自然発生的に経ない化合物が生じるという暗黙的な条件を含む。
本明細書において、可溶性無水フッ化物の源としてフッ化テトラメチルアンモニウム(NMe4F)を使用する、特定の基質をフッ素化する方法が開示される。NMe4Fは、たとえば以下のようなある利点を提供することができる:(1)安価なNMe4ClとKF、またはNMe4OHとHFから調製することができる(Dermeik, S.; et al., J. Org. Chem. 1989;54:4827;Tunder, R.; et al., J. Inorg. Nucl. Chem. 1963:25:1097; Christe, K.O.; et al., J. Am. Chem. Soc. 1990;112:7619;EP 0457966 A1;DE1191813 B。これら文献は、NMe4Fの調製に関する教示に関し、その全体で本明細書に援用される);および(2)(加熱での脱離に感受性のあるNBu4Fとは異なり)高い温度で厳密に乾燥させることができる(Sharma, R.K.; et al., J. Org. Chem. 1983;48:2112)。(ヘテロ)アレーンフッ素化反応における無水NMe4Fの使用に関し、いくつかの文献報告が存在する。たとえば、Grushinは、DMSO中、90〜110℃でNMe4Fを用いた、不活化臭化アリールのフッ素化を報告している(Grushin, V.V.; et al., Organometallics 2008;27:4825)。これらの反応により、中程度の収率(10〜65%)で、位置異性体産物の混合物が得られ、この変換に関し、アライン(aryne)メカニズムが提唱されている。Clarkらは、無水NMe4Fを使用した、ニトロアレーンのSNArフッ素化脱窒素反応(fluorodenitration)の例を多く示している(Boechat, N.; et al., J. Chem. Soc., Chem. Commun. 1993;921; Adams, D.J.; et al., J. Fluorine Chem. 1998;92:127; Clark, J.H.; et al. J. Fluorine Chem. 1995;70:201; Clark, J.H.; et al., Tetrahedron Lett. 1993;34:3901; Clark, J.H.; et al., J. Chem. Res. 1994;478)。多くの場合、これらの反応は60〜100℃の範囲の温度で行われ、様々な副産物(たとえば、アリールエーテル類、フェノール類)がこれらの系で形成される(同上、Adams, D.J.; et al., Tetrahedron 1999;55:7725; Adams, D.J.; et al., J. Fluorine Chem. 1999;94:51; Maggini, M.; et al., J. Org. Chem. 1991;56:6406)。NMe4Fを使用したフッ素化脱窒素は良く研究されている一方で、SNArハロゲン交換反応(halex reaction)におけるその使用は数例のみが報告されている。かかる反応の基質範囲は、あまり研究されていない(同上; Filatov, A.A.; et al., J. Fluorine Chem. 2012;143:123; Smyth, T.; et al., Tetrahedron 1995;51:8901)。実際に、これら報告の多くにおいて、フッ素化アリールへの塩化アリールの転換は、フッ素化脱窒素反応の望ましくない副反応物として報告されている(Adams, D.J.; et al., Tetrahedron1999;55:7725; Adams, D.J.; et al., J. Fluorine Chem. 94:51, 1999)。また、脱離基に応じた、SNArフッ素化の速度に関する系統だった研究は比較的少なく、これらの多くは、放射性フッ素化(radiofluorination)との関連で行われている(Karramakam, M.; et al., Bioorg. Med. Chem. 2003;11:2769; Al-Labadi, A.; et al., J. Radioanal. Nucl. Chem.2006;270:313; Guo, N.; et al., Appl. Radiat. Isot. 2008;66:1396; Dolci, L.; et al., J. Labelled Compd. Radiopharm. 1999;42:975)。
本開示方法の利点は、広範な基質のフッ素化に有効であり得ることである。特に、アリール基質およびヘテロアリール基質のフッ素化に良く適している。特定の例において、フッ化テトラメチルアンモニウムは、ヘテロアリール基質と混合されてもよく、そのヘテロアリール基質は式I-Aまたは式I-Bを有している:
Aは、Cl、Br、I、NO2、またはSO3R3であり;
Bは、H、Cl、Br、I、NO2、またはSO3R3であり;
Cは、H、Cl、Br、I、NO2、またはSO3R3であり;
R1は、H、CN、SO2R3、またはCO2R3であり、式中、各R3は、他のいずれからも独立して、任意で置換されるC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;および
R2は、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールである。得られたフッ素化産物は、式II-Aまたは式II-Bを有していてもよい
X1およびX2のうちの1つはNであり、他方はCHまたはC-Aであり;
Aは、Cl、Br、I、NO2、またはSO3R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;および
R4は、H、置換もしくは非置換C1-C12アルキル、置換もしくは非置換C2-C12アルケニル、置換もしくは非置換C2-C12アルキニル、CN、SO2R3、OR3、CO2R3、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールである。得られたフッ素化産物は、式III-Aに記載されるとおりであってもよく、式中、Aは、Fにより置換されており、または以下の式III-Bに示されるとおりであってもよい。
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、 CN、R3、COR3、またはCO2R3であり;
各Cは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、 CN、R3、COR3、またはCO2R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。得られたフッ素化産物は、式IV-Bを有していてもよい
Aは、Cl、Br、I、またはSO3R3であり;
nは、0〜5であり;
各Bは、他のいずれからも独立して、Cl、Br、I、CN、SO2R3、R3、COR3、またはCO2R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。得られたフッ素化産物は、式V-Bを有していてもよい。
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、CN、NO2、SO2R3、SO2R3、R3、COR3、またはCO2R3であり;
R2は、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。得られたフッ素化産物は、式VI-D、VI-E、またはVI-Fを有していてもよい:
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各R2は、互いに独立して、H、ハロゲン化物、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;および
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
各R2は、互いに独立して、H、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;および
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールである。
一般的手順A:表1に報告されるフッ素化反応に関する実験詳細。
5-フルオロ-6-フェニルピコリン酸イソプロピル(2)。
Claims (16)
- フッ化テトラメチルアンモニウムと、少なくとも1つのクロロ、ブロモ、ヨード、ニトロ、またはSO3R3(R3は、C1−C12アルキル、C2−C12アルケニル、C2−C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリール)で置換された、ヘテロアリール基質とを、0℃〜55℃で混合させることを含む、フッ素化ヘテロアリール基質を調製する方法であって、前記フッ化テトラメチルアンモニウムと前記ヘテロアリール基質は、前記フッ化テトラメチルアンモニウムの等量当たり、最大で1等量の水の存在下、かつ、ジメチルホルムアミド、ジメチルアセトアミド、スルホラン、ジメチルスルホキシド、テトラヒドロフラン、N-メチルピロリドン、ベンゾニトリル、および、ジメチルホルムアミド、ジメチルアセトアミド、スルホラン又はジメチルスルホキシドの重水素化アナログから選択される1以上の溶媒の存在下で、混合させる、方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、15℃〜50℃で混合される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、20℃〜40℃で混合される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、室温で混合される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、1分〜24時間、混合される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、1分〜3.5時間、混合される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムと、前記ヘテロアリール基質とが、およそ室温で混合され、前記溶媒がジメチルホルムアミドである、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムの0.5〜10等量が、ヘテロアリール基質の、等量当たりで使用される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムの1〜2等量が、ヘテロアリール基質の、等量当たりで使用される、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムが、無水である、請求項1に記載の方法。
- 前記フッ化テトラメチルアンモニウムが、前記ヘテロアリール基質と混合され、前記ヘテロアリール基質が、式I-Aまたは式I-Bを有している、請求項1に記載の方法:
(式中、
Aは、Cl、Br、I、NO2、またはSO3R3であり;
Bは、H、Cl、Br、I、NO2、またはSO3R3であり;
Cは、H、Cl、Br、I、NO2、またはSO3R3であり;
R1は、H、CN、SO2R3、またはCO2R3であり、式中、各R3は、他のいずれからも独立して、任意で置換されるC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;ならびに
R2は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;および得られたフッ素化産物は、式II-Aまたは式II-Bを有し、
式中、DはBまたはFであり;およびGはCまたはFである。)。 - 前記フッ化テトラメチルアンモニウムが、前記ヘテロアリール基質と混合され、前記ヘテロアリール基質が、式III-Aを有している、請求項1に記載の方法:
(式中、
X1およびX2のうちの1つはNであり、他方はCHまたはC-Aであり;
Aは、Cl、Br、I、NO2、またはSO3R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;および
R4は、置換もしくは非置換C1-C12アルキル、置換もしくは非置換C2-C12アルケニル、置換もしくは非置換C2-C12アルキニル、CN、SO2R3、OR3、CO2R3、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;
および得られたフッ素化産物は、式III-Bを有している。)。
- 前記フッ化テトラメチルアンモニウムが、前記ヘテロアリール基質と混合され、前記ヘテロアリール基質が、式IV-Aを有している、請求項1に記載の方法:
(式中、
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、CN、R3、COR3、またはCO2R3であり;
各Cは、その他から独立して、H、Cl、Br、I、NO2、SO3R3、SO2R3 、CN、R3、COR3、またはCO2R3であり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;
および得られたフッ素化産物は、式IV-Bを有し、
式中、各Dは、独立して、BまたはFから選択され、および各Gは、独立して、CまたはFから選択される。)。 - 前記フッ化テトラメチルアンモニウムが、前記ヘテロアリール基質と混合され、前記ヘテロアリール基質が、式VI-A、式VI-B、または式VI-Cを有している、請求項1に記載の方法:
(式中、
Aは、Cl、Br、I、NO2、またはSO3R3であり;
各Bは、その他から独立して、H、Cl、Br、I、CN、NO2、SO2R3、SO2R3、R3、COR3、またはCO2R3であり;
R2は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールであり;
R3は、他のいずれからも独立して、任意で置換されたC1-C12アルキル、C2-C12アルケニル、C2-C12アルキニル、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、またはアリールであり;
および得られたフッ素化産物は、式VI-D、VI-E、またはVI-Fを有しており:
式中、各Dは、独立して、BまたはFから選択される。)。
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US9878983B2 (en) | 2018-01-30 |
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