JP7482701B2 - Difluoromethylene compounds and their production methods - Google Patents
Difluoromethylene compounds and their production methods Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims description 23
- -1 Difluoromethylene compounds Chemical class 0.000 title description 43
- 150000001875 compounds Chemical class 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 35
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 34
- 239000011737 fluorine Substances 0.000 claims description 34
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 claims description 15
- 239000012190 activator Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 150000004694 iodide salts Chemical group 0.000 claims description 4
- 150000004673 fluoride salts Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000004970 halomethyl group Chemical group 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000008204 material by function Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 125000001976 hemiacetal group Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- GPCDGGKVBPVZCT-UHFFFAOYSA-N 1,1-difluorocyclopropane Chemical compound FC1(F)CC1 GPCDGGKVBPVZCT-UHFFFAOYSA-N 0.000 description 1
- 229940124810 Alzheimer's drug Drugs 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、新規なジフルオロメチレン化合物及びその製造方法に関する。 The present invention relates to a novel difluoromethylene compound and a method for producing the same.
ジフルオロメチレン化合物は、医農薬や機能性材料の合成中間体として有用である。ジフルオロメチレン部位を有する化合物は、例えば抗アルツハイマー薬や抗生物質等の生理活性物質として知られている。また、ジフルオロメチレン部位はエーテル部位と構造等価体と考えられており、医農薬や材料開発において、既存化合物のエーテル部位をジフルオロメチレン部位に変換することにより、生理活性や化合物の安定性の向上、活性選択性の改質、材料の改質等が見込まれる。 Difluoromethylene compounds are useful as synthetic intermediates for pharmaceuticals, agrochemicals, and functional materials. Compounds with a difluoromethylene moiety are known as physiologically active substances, such as anti-Alzheimer's drugs and antibiotics. In addition, the difluoromethylene moiety is considered to be structurally equivalent to the ether moiety, and in pharmaceutical, agrochemical, and material development, converting the ether moiety of an existing compound to a difluoromethylene moiety is expected to improve physiological activity and compound stability, improve activity selectivity, and modify materials.
従来技術として、特許文献１及び非特許文献１には、分子内にエステル部位と、ハロメチル部位を有する２官能性ジフルオロメチレン化合物が開示されている。また特許文献２には、分子内に複数の置換基とハロメチル部位を有するジフルオロメチレン化合物が開示されている。
しかし、分子内に種々の官能基変換が可能なアルデヒド水和物またはヘミアセタール部位と、ハロメチル部位の両方を有し、取り扱い容易な多官能性ジフルオロメチレン化合物は知られていなかった。
As prior art, Patent Document 1 and Non-Patent Document 1 disclose bifunctional difluoromethylene compounds having an ester moiety and a halomethyl moiety in the molecule, while Patent Document 2 discloses difluoromethylene compounds having multiple substituents and halomethyl moieties in the molecule.
However, no polyfunctional difluoromethylene compounds have been known that have both an aldehyde hydrate or hemiacetal moiety capable of undergoing various functional group conversions within the molecule, and a halomethyl moiety, and that are easy to handle.
特許文献３、特許文献４、非特許文献２～非特許文献４には、種々の２官能性ジフルオロメチレン化合物の製造方法が開示されているが、上記のようなアルデヒド水和物またはヘミアセタール部位と、ハロメチル部位の両方を有するジフルオロメチレン化合物の製造方法は知られていなかった。 Patent Document 3, Patent Document 4, and Non-Patent Documents 2 to 4 disclose various methods for producing bifunctional difluoromethylene compounds, but a method for producing a difluoromethylene compound having both an aldehyde hydrate or hemiacetal moiety and a halomethyl moiety as described above was not known.
本発明の目的は、上記の背景技術に鑑み、新たな多官能性ジフルオロメチレン化合物及びその製造方法を提供することにある。 In view of the above background art, the object of the present invention is to provide a new polyfunctional difluoromethylene compound and a method for producing the same.
本発明者らは、上記課題を解決する方法について鋭意検討した結果、ビニルエーテル類とトリメチル（トリフルオロメチル）シランを、ヨウ化ナトリウム等の活性化剤存在下で反応させた後、水の存在下でハロゲンと反応させることにより、新規なジフルオロメチレン化合物を製造できることを見出し、本発明を完成させるに至った。 As a result of extensive research into methods for solving the above problems, the inventors discovered that a novel difluoromethylene compound can be produced by reacting vinyl ethers with trimethyl(trifluoromethyl)silane in the presence of an activator such as sodium iodide, and then reacting the resulting compound with a halogen in the presence of water, thus completing the present invention.
すなわち、本発明は以下に記載の発明に係る。
［１］ 下記一般式（１）で示される含フッ素化合物。
［２］ 一般式（１）におけるＲが水素原子である、［１］に記載の含フッ素化合物。
［３］ 一般式（１）におけるＸがヨウ素原子である、［１］又は［２］に記載の含フッ素化合物。
［４］ ［１］に記載の一般式（１）で示される含フッ素化合物の製造方法であって、下記一般式（２）で示されるビニルエーテル類とトリメチル（トリフルオロメチル）シランとを、活性化剤存在下で反応させた後、水の存在下でハロゲンと反応させる、［１］～［３］のいずれかに記載の製造方法を提供するものである。
［５］ 活性化剤がヨウ化物塩又はフッ化物塩である、［４］に記載の含フッ素化合物の製造方法。
［６］ 活性化剤がヨウ化ナトリウムである、［４］に記載の含フッ素化合物の製造方法。
That is, the present invention relates to the invention described below.
[1] A fluorine-containing compound represented by the following general formula (1):
[2] The fluorine-containing compound according to [1], wherein R in general formula (1) is a hydrogen atom.
[3] The fluorine-containing compound according to [1] or [2], wherein X in general formula (1) is an iodine atom.
[4] Provided is a method for producing a fluorine-containing compound represented by general formula (1) according to [1], which comprises reacting a vinyl ether represented by the following general formula (2) with trimethyl(trifluoromethyl)silane in the presence of an activator, and then reacting the resulting compound with a halogen in the presence of water.
[5] The method for producing a fluorine-containing compound according to [4], wherein the activator is an iodide salt or a fluoride salt.
[6] The method for producing a fluorine-containing compound according to [4], wherein the activator is sodium iodide.
本発明により、新規な多官能性ジフルオロメチレン化合物を得ることが可能となって、新たな含フッ素化合物群を提供でき、産業上有用である。 The present invention makes it possible to obtain novel polyfunctional difluoromethylene compounds, providing a new group of fluorine-containing compounds that are industrially useful.
以下、本発明を詳細に説明する。
本発明の一般式（１）で示される含フッ素化合物において、Ｒは水素原子または炭素数１～１０のアルキルもしくはアラルキル基である。具体的には例えば、メチル基、エチル基、ｎ－プロピル基、イソ－プロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、イソ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基、シクロヘキシル基、ｎ－ヘプチル基、ｎ－オクチル基、ｎ－ノニル基、ｎ－デシル基、ベンジル基等が挙げられる。中でもＲが水素原子である場合、カルボニル基等価体であるハイドレート部位を有し、種々の官能基変換が可能である観点から好ましい。
The present invention will be described in detail below.
In the fluorine-containing compound of the present invention represented by general formula (1), R is a hydrogen atom or an alkyl or aralkyl group having 1 to 10 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, a cyclohexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, a benzyl group, and the like. Among these, when R is a hydrogen atom, it is preferred from the viewpoint of having a hydrate moiety that is an equivalent of a carbonyl group and enabling various functional group conversions.
本発明の一般式（１）で示される含フッ素化合物において、Ｘはハロゲン原子である。具体的には、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられ、中でも反応性の観点からヨウ素原子が好ましい。 In the fluorine-containing compound of the present invention represented by general formula (1), X is a halogen atom. Specific examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and among these, an iodine atom is preferred from the viewpoint of reactivity.
本発明の一般式（１）で示される含フッ素化合物は、一般式（２）で示されるビニルエーテル類とトリメチル（トリフルオロメチル）シランとを、活性化剤存在下で反応させた後、水の存在下でハロゲンと反応させることによって得られる。 The fluorine-containing compound represented by the general formula (1) of the present invention can be obtained by reacting a vinyl ether represented by the general formula (2) with trimethyl(trifluoromethyl)silane in the presence of an activator, and then reacting the resulting mixture with a halogen in the presence of water.
本発明で用いられる一般式（２）で示されるビニルエーテル類において、Ｒは水素原子または炭素数１～１０のアルキルもしくはアラルキル基である。
具体的には例えば、メチル基、エチル基、ｎ－プロピル基、イソ－プロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、イソ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基、シクロヘキシル基、ｎ－ヘプチル基、ｎ－オクチル基、ｎ－ノニル基、ｎ－デシル基、ベンジル基等が挙げられる。入手性、取り扱いの観点から、Ｒはエチル基、ｎ－プロピル基、ｎ－ブチル基であることが好ましい。
In the vinyl ethers represented by the general formula (2) used in the present invention, R is a hydrogen atom or an alkyl or aralkyl group having 1 to 10 carbon atoms.
Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, a cyclohexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, a benzyl group, etc. From the viewpoints of availability and handling, R is preferably an ethyl group, an n-propyl group, or an n-butyl group.
本発明による含フッ素化合物の製造において、反応に用いられるトリメチル（トリフルオロメチル）シランの量は、反応に具するビニルエーテル類に対して、好ましくは１当量～５当量、さらに好ましくは１．５当量～４当量、特に好ましくは２当量～３当量である。 In the production of the fluorine-containing compound according to the present invention, the amount of trimethyl(trifluoromethyl)silane used in the reaction is preferably 1 to 5 equivalents, more preferably 1.5 to 4 equivalents, and particularly preferably 2 to 3 equivalents, relative to the vinyl ethers used in the reaction.
本発明による含フッ素化合物の製造において、反応に用いられる活性化剤は、ヨウ化ナトリウム、ヨウ化カリウム等のヨウ化物塩、テトラブチルアンモニウムフルオリド等のフッ化物塩等が挙げられる。中でも、反応性及び入手容易性の観点から、ヨウ化物塩、特にヨウ化ナトリウムが好ましい。
本発明による含フッ素化合物の製造において、反応に用いられる活性化剤の量は、反応に具するビニルエーテル類に対して、好ましくは０．０１当量～２当量、より好ましくは０．０５当量～１当量、特に好ましくは０．１当量～０．５当量である。
In the production of a fluorine-containing compound according to the present invention, examples of the activator used in the reaction include iodide salts such as sodium iodide and potassium iodide, fluoride salts such as tetrabutylammonium fluoride, etc. Among these, from the viewpoints of reactivity and availability, iodide salts, particularly sodium iodide, are preferred.
In the production of a fluorine-containing compound according to the present invention, the amount of the activator used in the reaction is preferably 0.01 to 2 equivalents, more preferably 0.05 to 1 equivalent, particularly preferably 0.1 to 0.5 equivalent, based on the vinyl ether used in the reaction.
本発明による含フッ素化合物の製造において、ビニルエーテル類とトリメチル（トリフルオロメチル）シランを、活性化剤存在下で反応させる工程に適用可能な溶媒としては、含フッ素化合物の製造に係る反応に不活性なものであれば特に限定はされないが、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、テトラヒドロフラン、アセトニトリル等が挙げられ、特にテトラヒドロフランが好ましい。これらの溶媒は単独で用いても、２種類以上を混合して用いてもよい。溶媒は反応に具するビニルエーテル類に対して、好ましくは２重量倍量～５００重量倍量、さらに好ましくは５重量倍量～２００重量倍量使用する。 In the production of fluorine-containing compounds according to the present invention, solvents applicable to the step of reacting vinyl ethers with trimethyl(trifluoromethyl)silane in the presence of an activator are not particularly limited as long as they are inert to the reaction involved in the production of fluorine-containing compounds, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, acetonitrile, etc., with tetrahydrofuran being particularly preferred. These solvents may be used alone or in combination of two or more. The solvent is preferably used in an amount of 2 to 500 times by weight, more preferably 5 to 200 times by weight, based on the vinyl ethers used in the reaction.
本発明による含フッ素化合物の製造において、ビニルエーテル類とトリメチル（トリフルオロメチル）シランを、活性化剤存在下で反応させる工程の反応温度は、０℃～１００℃の範囲で、好ましくは室温～６０℃の範囲である。
本発明による含フッ素化合物の製造において、ビニルエーテル類とトリメチル（トリフルオロメチル）シランを、活性化剤存在下で反応させる工程の反応時間は、３０分～４８時間の範囲で、好ましくは１時間～４時間の範囲である。
In the production of a fluorine-containing compound according to the present invention, the reaction temperature in the step of reacting a vinyl ether with trimethyl(trifluoromethyl)silane in the presence of an activator is in the range of 0°C to 100°C, preferably in the range of room temperature to 60°C.
In the production of a fluorine-containing compound according to the present invention, the reaction time in the step of reacting a vinyl ether with trimethyl(trifluoromethyl)silane in the presence of an activator is in the range of 30 minutes to 48 hours, preferably in the range of 1 hour to 4 hours.
本発明による含フッ素化合物の製造において、水の存在下でハロゲンと反応させる工程は、ビニルエーテル類とトリメチル（トリフルオロメチル）シランを、活性化剤存在下で反応させる工程により得られた反応液に、そのまま水とハロゲンを加えることにより実施してもよい。また、前記反応液を減圧濃縮したのち、水とハロゲンを加えることにより実施してもよい。 In the production of a fluorine-containing compound according to the present invention, the step of reacting with a halogen in the presence of water may be carried out by adding water and a halogen directly to a reaction liquid obtained in a step of reacting a vinyl ether with trimethyl(trifluoromethyl)silane in the presence of an activator. Alternatively, the reaction liquid may be concentrated under reduced pressure, and then water and a halogen may be added.
本発明による含フッ素化合物の製造において、反応に用いられる水の量は、反応に具するビニルエーテル類に対して、好ましくは２重量倍量～５００重量倍量、さらに好ましくは５重量倍量～２００重量倍量である。 In the production of the fluorine-containing compound according to the present invention, the amount of water used in the reaction is preferably 2 to 500 times by weight, more preferably 5 to 200 times by weight, relative to the amount of vinyl ethers used in the reaction.
本発明による含フッ素化合物の製造において、反応に用いられるハロゲンとしては、フッ素、塩素、臭素、ヨウ素が挙げられ、中でも反応性及び取り扱いの観点からヨウ素が好ましい。
本発明による含フッ素化合物の製造において、反応に用いられるハロゲンの量は、反応に具するビニルエーテル類に対して、好ましくは１当量～５当量、さらに好ましくは１．５当量～４当量、特に好ましくは２当量～３当量である。
In the production of a fluorine-containing compound according to the present invention, examples of the halogen used in the reaction include fluorine, chlorine, bromine and iodine, and among these, iodine is preferred from the viewpoints of reactivity and handling.
In the production of a fluorine-containing compound according to the present invention, the amount of halogen used in the reaction is preferably 1 to 5 equivalents, more preferably 1.5 to 4 equivalents, and particularly preferably 2 to 3 equivalents, based on the vinyl ether used in the reaction.
本発明による含フッ素化合物の製造において、水の存在下でハロゲンと反応させる工程の反応温度は、０℃～１００℃の範囲で、好ましくは室温～６０℃の範囲である。
本発明による含フッ素化合物の製造において、水の存在下でハロゲンと反応させる工程の反応時間は、３０分～４８時間の範囲で、好ましくは１時間～４時間の範囲である。
In the production of a fluorine-containing compound according to the present invention, the reaction temperature in the step of reacting with a halogen in the presence of water is in the range of 0°C to 100°C, preferably in the range of room temperature to 60°C.
In the production of a fluorine-containing compound according to the present invention, the reaction time in the step of reacting with a halogen in the presence of water is in the range of 30 minutes to 48 hours, preferably in the range of 1 hour to 4 hours.
本発明は、下記の式に示すように、ビニルエーテル類（下記式ではエチルビニルエーテルを例示）と（トリフルオロメチル）トリメチルシランとを、活性化剤（下記式ではヨウ化ナトリウムを例示）存在下で反応させて、例えばカッコ内に示すジフルオロシクロプロパンを得た後、水とヨウ素を加えることでヒドロキシ基及びハロゲン（下記式ではヨウ素原子を例示）が導入され、目的の化合物（下記式では２，２－ジフルオロ－３－ヨードプロピオンアルデヒド（水和物）を例示）が得られる、という反応機構が推定される。但しこの反応機構の推定により本発明が限定されるものではない。 In the present invention, as shown in the formula below, a vinyl ether (ethyl vinyl ether is exemplified in the formula below) and (trifluoromethyl)trimethylsilane are reacted in the presence of an activator (sodium iodide is exemplified in the formula below) to obtain, for example, difluorocyclopropane as shown in parentheses, and then water and iodine are added to introduce a hydroxyl group and a halogen (iodine atom is exemplified in the formula below) to obtain the target compound (2,2-difluoro-3-iodopropionaldehyde (hydrate) is exemplified in the formula below). The present invention is not limited by this estimated reaction mechanism, however.
本発明の一般式（１）で表される含フッ素化合物の精製方法としては、公知の方法を用いることができ、例えば、中和、溶媒抽出、乾燥、ろ過、濃縮、再結晶、デカンテーション、シリカゲルカラムクロマトグラフィー等により精製し、目的物の一般式（１）で示される含フッ素化合物を得ることができる。 The fluorine-containing compound represented by the general formula (1) of the present invention can be purified by known methods, such as neutralization, solvent extraction, drying, filtration, concentration, recrystallization, decantation, silica gel column chromatography, etc., to obtain the desired fluorine-containing compound represented by the general formula (1).
さらに、本発明の一般式（１）で表される含フッ素化合物を用いて有用な化合物を製造できる。例えば、一般式（１）で表される含フッ素化合物とベンジルアルコール等の置換基を有するもしくは有しない芳香族や炭素数１～１０の直鎖状もしくは分岐状の脂肪族アルコールとを反応させることで、２，２－ジフルオロ－３－ヨードプロピオンアルデヒドベンジルヘミアセタール等のヘミアセタールその他の生成物を得ることができる。 Furthermore, the fluorine-containing compound represented by the general formula (1) of the present invention can be used to produce useful compounds. For example, by reacting the fluorine-containing compound represented by the general formula (1) with an aromatic alcohol having or not having a substituent, such as benzyl alcohol, or a linear or branched aliphatic alcohol having 1 to 10 carbon atoms, it is possible to obtain hemiacetals such as 2,2-difluoro-3-iodopropionaldehyde benzyl hemiacetal and other products.
以下実施例により本発明を具体的に説明するが、本発明はこれらの実施例のみに限定されるものではない。
結果の解析に当たっては、１Ｈ ＮＭＲ、１９Ｆ ＮＭＲ及び１３Ｃ ＮＭＲは日本電子株式会社製ＪＮＭ－ＡＬ３００、ＩＲは日本分光株式会社（ＪＡＳＣＯ）製ＦＴ/ＩＲ－４１００、融点測定はヤマト科学株式会社製融点測定器ＭＰ－２１、元素分析はＰｅｒｋｉｎ－Ｅｌｍｅｒ社製ＣＨＮＳ/Ｏ Ａｎａｌｙｚｅｒ ２４００、質量分析は日本電子株式会社製二重収束磁場型質量分析計ＪＭＳ－７００を使用した。
The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
The results were analyzed using a JNM-AL300 manufactured by JEOL Ltd. for 1 H NMR, 19 F NMR, and 13 C NMR, a FT/IR-4100 manufactured by JASCO Corporation for IR, a Yamato Scientific MP-21 melting point analyzer for melting point, a Perkin-Elmer CHNS/O Analyzer 2400 for elemental analysis, and a JEOL JMS-700 double focusing magnetic mass spectrometer for mass analysis.
実施例１ ２，２－ジフルオロ－３－ヨードプロピオンアルデヒド水和物（１）の合成
得られた化合物の分析結果は次の通りであった。
１Ｈ ＮＭＲ（３００ＭＨｚ, ＤＭＳＯ－ｄ６）：δ（ｐｐｍ）６．８０（ｄ，Ｊ＝６．３Ｈｚ，２Ｈ），４．９２（ｑｕｉｎｔ，Ｊ＝６．２Ｈｚ，１Ｈ），３．５５（ｔ，Ｊ＝１７．６Ｈｚ，２Ｈ）．
１３Ｃ ＮＭＲ（７５．４５Ｈｚ，ＤＭＳＯ－ｄ６）：δ（ｐｐｍ）１１８．７（ｔ，Ｊ＝２４５．０Ｈｚ），８７．２（ｔ，Ｊ＝３１．９Ｈｚ），２．８（ｔ，Ｊ＝２６．７Ｈｚ）．
１９Ｆ ＮＭＲ（２８２Ｈｚ, ＣＤＣｌ３）：δ（ｐｐｍ）－１１０．３（ｔｄ，Ｊ＝１５．８，４．８Ｈｚ）
ＩＲ （ＫＢｒ）：３２７２，３０３２，２９６９，１４１６，１１９５，１０８３，１０３４，１００８ｃｍ－１．
ＨＲＭＳ（ＦＡＢ＋，ｍ／ｚ）：［Ｍ＋Ｈ］＋ 計算値Ｃ３Ｈ５Ｆ２ＩＯ２：２３８．９３８０，実測値：２３８．９３９９．
The analytical results of the obtained compound were as follows:
1 H NMR (300 MHz, DMSO-d 6 ): δ (ppm) 6.80 (d, J=6.3 Hz, 2H), 4.92 (quint, J=6.2 Hz, 1H), 3.55 (t, J=17.6 Hz, 2H).
13C NMR (75.45 Hz, DMSO- d6 ): δ (ppm) 118.7 (t, J = 245.0 Hz), 87.2 (t, J = 31.9 Hz), 2.8 (t, J = 26.7 Hz).
19F NMR (282Hz, CDCl3 ): δ(ppm) -110.3 (td, J = 15.8, 4.8Hz)
IR (KBr): 3272, 3032, 2969, 1416, 1195, 1083, 1034, 1008 cm -1 .
HRMS (FAB+, m/z) : [M+H] + calculated for C3H5F2IO2 : 238.9380 , found: 238.9399.
本発明の化合物（１）は、固体であるため取り扱いが容易であり、官能基変換が可能なハイドレート部位とハロメチル部位を有するため、医農薬及び機能性材料の合成中間体として有用である。 The compound (1) of the present invention is easy to handle because it is a solid, and because it has a hydrate moiety and a halomethyl moiety that can be converted into functional groups, it is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and functional materials.
実施例２ ２，２－ジフルオロ－３－ヨードプロピオンアルデヒド水和物（１）の合成
実施例３ ２，２－ジフルオロ－３－ヨードプロピオンアルデヒドブチルヘミアセタール（２）の合成
得られた化合物の分析結果は次の通りであった。
１Ｈ ＮＭＲ（３００ＭＨｚ, ＣＤＣｌ３）：δ（ｐｐｍ）４．８８（ｍ，１Ｈ）,３．８７（ｄｔ,Ｊ＝９．３，６．６Ｈｚ，１Ｈ）,３．５６（ｄｔ，Ｊ＝９．６，６．６ Ｈｚ，１Ｈ），３．５１（ｔ，Ｊ＝１６．８Ｈｚ，２Ｈ），２．６９（ｂｒｄ，Ｊ＝８．４Ｈｚ，１Ｈ），１．５９（ｍ，２Ｈ），１．３９（ｓｅｘｔ，Ｊ＝７．２Ｈｚ，２Ｈ），０．９４（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ）．
１３Ｃ ＮＭＲ（７５．４５Ｈｚ，ＣＤＣｌ３）：δ（ｐｐｍ）１１７．２（ｔ，Ｊ＝２４６．２Ｈｚ），９３．８（ｔ，Ｊ＝２９．７Ｈｚ），６８．８，３１．４，１９．１，１３．７，０．０７（ｔ，Ｊ＝２７．９Ｈｚ）．
１９Ｆ ＮＭＲ（２８２Ｈｚ, ＣＤＣｌ３）：δ（ｐｐｍ）－１０８．５５（ｄｄｄｄ，Ｊ＝２４８．７，１８．３，１３．６，４．５Ｈｚ，１Ｆ），－１１４．００（ｄｄｔ，Ｊ＝２４８．７，１８．３，９．０Ｈｚ，１Ｆ）
ＩＲ（ｎｅａｔ）：３３８４，２９５９，２９３４，２８７４，１４１７，１２１４，１０９４，１０１９ｃｍ－１．
ＨＲＭＳ（ＦＡＢ－，ｍ／ｚ）：［Ｍ－Ｈ］－ 計算値Ｃ７Ｈ１２Ｆ２Ｏ２Ｉ：２９２．９８５０，実測値：２９２．９８４２．
The analytical results of the obtained compound were as follows:
1H NMR (300 MHz, CDCl3 ): δ (ppm) 4.88 (m, 1H), 3.87 (dt, J = 9.3, 6.6 Hz, 1H), 3.56 (dt, J = 9.6, 6.6 Hz, 1H), 3.51 (t, J = 16.8 Hz, 2H), 2.69 (brd, J = 8.4 Hz, 1H), 1.59 (m, 2H), 1.39 (sext, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H).
13C NMR (75.45 Hz, CDCl3 ): δ (ppm) 117.2 (t, J = 246.2 Hz), 93.8 (t, J = 29.7 Hz), 68.8, 31.4, 19.1, 13.7, 0.07 (t, J = 27.9 Hz).
19F NMR (282Hz, CDCl3 ): δ (ppm) -108.55 (dddd, J = 248.7, 18.3, 13.6, 4.5Hz, 1F), -114.00 (ddt, J = 248.7, 18.3, 9.0Hz, 1F)
IR(neat): 3384, 2959, 2934, 2874, 1417, 1214, 1094, 1019 cm -1 .
HRMS (FAB-, m/z): [M−H] − calculated for C 7 H 12 F 2 O 2 I: 292.9850, found: 292.9842.
実施例４ ２，２－ジフルオロ－３－ヨードプロピオンアルデヒドベンジルヘミアセタール（３）の合成
得られた化合物の分析結果は次の通りであった。
１Ｈ ＮＭＲ（３００ＭＨｚ, ＣＤＣｌ３）：δ（ｐｐｍ）７．３７（ｍ，５Ｈ），４．９５（ｄｄｄ，Ｊ＝１０．５，８．１，４．１Ｈｚ，１Ｈ）,４．６７（ｄ，Ｊ＝１１．７Ｈｚ，１Ｈ）３，５１（ｍ，２Ｈ），２．８２（ｄｄ，Ｊ＝１０．５，１．８Ｈｚ，１Ｈ）．
１３Ｃ ＮＭＲ（７５．４５Ｈｚ，ＣＤＣｌ３）：δ（ｐｐｍ）１３６．２，１２８．５，１２８．２，１２８．１，１１７．１（ｔ，Ｊ＝２４５．６Ｈｚ），９２．７（ｄｄ，Ｊ＝３４．１，２８．５Ｈｚ，７０．１，０．０１（ｔ，Ｊ＝２７．９Ｈｚ．
１９Ｆ ＮＭＲ（２８２Ｈｚ, ＣＤＣｌ３）：δ（ｐｐｍ）－１０８．１８（ｄｄｄｄ，Ｊ＝２４８．７，１９．４，１３．７，４．５Ｈｚ，１Ｆ），－１１３．７７（ｄｄｔ，Ｊ＝２４８．４，２０．５，７．９Ｈｚ，１Ｆ）
ＩＲ（ｎｅａｔ）：３３９９，３０３４，２９３４，２８８４，１４５５，１４１６，１２１４，１０９２，１０２４，７４１，６９９ｃｍ－１．
The analytical results of the obtained compound were as follows:
1H NMR (300MHz, CDCl3 ): δ (ppm) 7.37 (m, 5H), 4.95 (ddd, J = 10.5, 8.1, 4.1 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H) 3,51 (m, 2H), 2.82 (dd, J = 10.5, 1.8 Hz, 1H).
13C NMR (75.45 Hz, CDCl3 ): δ (ppm) 136.2, 128.5, 128.2, 128.1, 117.1 (t, J = 245.6 Hz), 92.7 (dd, J = 34.1, 28.5 Hz, 70.1, 0.01 (t, J = 27.9 Hz.
19F NMR (282Hz, CDCl3 ): δ (ppm) -108.18 (dddd, J = 248.7, 19.4, 13.7, 4.5Hz, 1F), -113.77 (ddt, J = 248.4, 20.5, 7.9Hz, 1F)
IR(neat): 3399, 3034, 2934, 2884, 1455, 1416, 1214, 1092, 1024, 741, 699 cm -1 .
本発明により、新規な多官能性ジフルオロメチレン化合物の製造が可能となった。このようなジフルオロメチレン化合物は医農薬及び機能性材料の合成中間体として有用である。 The present invention makes it possible to produce novel polyfunctional difluoromethylene compounds. Such difluoromethylene compounds are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, and functional materials.
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| US2889358A (en) | 1956-12-03 | 1959-06-02 | Union Carbide Corp | Chlorinated esters of 1, 1-diols and process for their production |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2889358A (en) | 1956-12-03 | 1959-06-02 | Union Carbide Corp | Chlorinated esters of 1, 1-diols and process for their production |
| JP2018145175A (en) | 2017-03-01 | 2018-09-20 | 国立大学法人東京農工大学 | Difluoromethylene compound and production method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Oleg V. FEDOROV et al.，Halogenative Difluorohomologation of Ketones，The Journal of Organic Chemistry，2015年05月18日，Vol. 80, No,11，p.5870-5876 |
| Sofya I. SCHERBININA et al.，Synthesis of 3-Fluoropyridines via Photoredox-Mediated Coupling of α,α-Difluoro-β-iodoketones with Silyl Enol Ethers，The Journal of Organic Chemistry，2017年11月30日，Vol. 82, No. 24，p.12967-12974 |
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