JPH0482865A - Fluorine-containing chiral amine and fluorine-containing chiral lithium amide and production 0f chiral enol ether - Google Patents
Fluorine-containing chiral amine and fluorine-containing chiral lithium amide and production 0f chiral enol etherInfo
- Publication number
- JPH0482865A JPH0482865A JP2193691A JP19369190A JPH0482865A JP H0482865 A JPH0482865 A JP H0482865A JP 2193691 A JP2193691 A JP 2193691A JP 19369190 A JP19369190 A JP 19369190A JP H0482865 A JPH0482865 A JP H0482865A
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- JP
- Japan
- Prior art keywords
- formula
- fluorine
- formulas
- chiral
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 32
- 239000011737 fluorine Substances 0.000 title claims abstract description 32
- 150000001412 amines Chemical class 0.000 title claims abstract description 20
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- 150000002084 enol ethers Chemical class 0.000 title claims abstract description 10
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010537 deprotonation reaction Methods 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract 3
- 125000002243 cyclohexanonyl group Chemical class *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 claims abstract 2
- 239000002904 solvent Substances 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000005595 deprotonation Effects 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001408 amides Chemical class 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 16
- 239000012267 brine Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- JHIVVAPYMSGYDF-PTQBSOBMSA-N cyclohexanone Chemical class O=[13C]1CCCCC1 JHIVVAPYMSGYDF-PTQBSOBMSA-N 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- YKFKEYKJGVSEIX-UHFFFAOYSA-N cyclohexanone, 4-(1,1-dimethylethyl)- Chemical compound CC(C)(C)C1CCC(=O)CC1 YKFKEYKJGVSEIX-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 125000006519 CCH3 Chemical group 0.000 description 2
- 238000010485 C−C bond formation reaction Methods 0.000 description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- POYYYXPQBFPUKS-UHFFFAOYSA-N 2-butylcyclohexan-1-one Chemical compound CCCCC1CCCCC1=O POYYYXPQBFPUKS-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- ASFAFOSQXBRFMV-LJQANCHMSA-N 3-n-(2-benzyl-1,3-dihydroxypropan-2-yl)-1-n-[(1r)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzene-1,3-dicarboxamide Chemical compound N([C@H](C)C=1C=CC(F)=CC=1)C(=O)C(C=1)=CC(N(C)S(C)(=O)=O)=CC=1C(=O)NC(CO)(CO)CC1=CC=CC=C1 ASFAFOSQXBRFMV-LJQANCHMSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101100460719 Mus musculus Noto gene Proteins 0.000 description 1
- FPQWVXMEZDPZIB-UHFFFAOYSA-N N#[C-].CCOP(O)(=O)OCC Chemical compound N#[C-].CCOP(O)(=O)OCC FPQWVXMEZDPZIB-UHFFFAOYSA-N 0.000 description 1
- 101100482117 Saimiri sciureus THBD gene Proteins 0.000 description 1
- 101100187345 Xenopus laevis noto gene Proteins 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 150000003979 beta-halocarboxylic acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 description 1
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- ZLCCLBKPLLUIJC-UHFFFAOYSA-L disodium tetrasulfane-1,4-diide Chemical compound [Na+].[Na+].[S-]SS[S-] ZLCCLBKPLLUIJC-UHFFFAOYSA-L 0.000 description 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 1
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 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
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、含フン素キラルアミンおよび含フッ素キラル
リチウムアミト、ならびに含フッ素キラルリチウムアミ
トを触媒として使用するキラルエノールエーテルの製法
に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing chiral enol ether using a fluorine-containing chiral amine, a fluorine-containing chiral lithium amide, and a fluorine-containing chiral lithium amide as a catalyst.
［従来の技術］
本発明者は、キラルリチウムアミドを使用する不斉反応
を提案した（有機合成化学第４８巻４６３〜４７５頁（
１，９９０年乃８キラルリチウムアミドとして、例えば
、
１式中、Ａ’、Ａ２、Ａ３、Ａ４およびＡ５は前記と同
意義である。］
て示されるキラルエノールエーテルの製法。[Prior Art] The present inventor proposed an asymmetric reaction using chiral lithium amide (Organic Synthetic Chemistry Vol. 48, pp. 463-475 (
As the 1,990-octachiral lithium amide, for example: In formula 1, A', A2, A3, A4 and A5 have the same meanings as above. ] The method for producing chiral enol ether shown in
ＣＨ，ｌ
を使用している。以下のようなキラルエノールエーテル
を製造する不斉膜プロ）・ン反応にこのキラルリチウム
アミトを使用した場合に、光学収率は７６％であり充分
なものではない。CH,l is used. When this chiral lithium amide is used in the asymmetric membrane reaction to produce a chiral enol ether as shown below, the optical yield is 76%, which is not sufficient.
Ｅ式中、ＴＭＳは（ＣＨ３）３Ｓｉ−１ＨＭ Ｐ Ａは
へキサメチルポスポルアミ１〜、ＴＨＦはテトラヒドロ
フランである。］
［発明か解決しようとする課題］
本発明の１つの目的は、不斉脱プロトン化反応を利用し
た高い光学収率を有するキラルエノールエーテルの製法
を提供することにある。In formula E, TMS is (CH3)3Si-1HMPA, hexamethylposporamide 1~, and THF is tetrahydrofuran. ] [Problem to be Solved by the Invention] One object of the present invention is to provide a method for producing chiral enol ether having a high optical yield using an asymmetric deprotonation reaction.
本発明の別の目的は、高い光学収率を与える不斉脱プロ
トン化反応に有用な含フッ素キラルリチウムアミドを提
供することにある。Another object of the present invention is to provide a fluorine-containing chiral lithium amide useful in an asymmetric deprotonation reaction that provides a high optical yield.
本発明の他の目的は、含フッ素キラルリチウムアミドの
前駆体である含フッ素キラルアミンを提供することにあ
る。Another object of the present invention is to provide a fluorine-containing chiral amine that is a precursor of a fluorine-containing chiral lithium amide.
［課題を解決するための手段］ １一つの要旨によれば、本発明は、式。[Means to solve the problem] 1 According to one aspect, the present invention provides a method for solving the problems of the formula.
［式中、Ｒ１、Ｒ２、Ｒ３およびＲ４のそれぞれは、水
素原子、メチル基、フェニル基またはペンンル基（但し
、Ｒ１、Ｒ２、Ｒ３およびＲ４の全てか同一であること
はない。）、
Ｙは、水素原子、メトキシ基、
Ｒｆは、炭素数１〜５の含フツ素アルキル基、ｎは、１
〜３の数である。］
で示される含フッ素キラルアミンに関する。[In the formula, each of R1, R2, R3, and R4 is a hydrogen atom, a methyl group, a phenyl group, or a pennyl group (however, all of R1, R2, R3, and R4 are not the same), and Y is , hydrogen atom, methoxy group, Rf is a fluorine-containing alkyl group having 1 to 5 carbon atoms, n is 1
The number is ~3. ] The present invention relates to a fluorine-containing chiral amine represented by the following.
本発明の含フッ素キラルアミンの具体例を示せば、例え
ば、以下のとおりである。Specific examples of the fluorine-containing chiral amine of the present invention are as follows.
本発明の含フッ素キラルアミンは、以下の反応式にした
かって製造することができる。ここては、Ｒ３およびＲ
′が水素であり、ｎが１である含フッ素キラルアミンに
ついての製造例を示す。The fluorine-containing chiral amine of the present invention can be produced according to the following reaction formula. Here, R3 and R
A production example of a fluorine-containing chiral amine in which ' is hydrogen and n is 1 will be shown.
［式中、Ｒ１、Ｒ２、ＹおよびＲｒは前記と同意義、ｐ
ｈはフェニル基、ＤＥＰＣはジエチルリン酸シアニドで
ある。］
別の要旨によれば、本発明は、式
［式中、Ｒ’ＳＲ２、Ｒ３およびＲ４のそれぞれは、水
素原子、メチル基、フェニル基またはペンンル基（但し
、Ｒ１、Ｒ２、Ｒ３およびＲ４の全てか同一であること
はない。）、
Ｙは、水素原子、メトキシ基、
Ｒｆは、炭素数１〜５の含フツ素アルキル基、ｎは、１
〜３の数である。コ
て示される含フッ素キラルリチウムアミドに関する。[In the formula, R1, R2, Y and Rr have the same meanings as above, p
h is a phenyl group, and DEPC is diethyl phosphate cyanide. ] According to another gist, the present invention provides a method for applying the formula [wherein each of R'SR2, R3 and R4 is a hydrogen atom, a methyl group, a phenyl group or a pennyl group (provided that ), Y is a hydrogen atom, methoxy group, Rf is a fluorine-containing alkyl group having 1 to 5 carbon atoms, n is 1
The number is ~3. This invention relates to a fluorine-containing chiral lithium amide.
本発明の含フッ素キラルリチウムアミｌ−の具体例とし
ては、前記含フッ素キラルアミンの具体例において窒素
に結合する水素がＬｉに置換した化合物を挙げることが
できる。Specific examples of the fluorine-containing chiral lithium amyl- of the present invention include compounds in which the hydrogen bonded to nitrogen in the specific examples of the fluorine-containing chiral amines is replaced with Li.
本発明の含フッ素キラルリチウムアミドは、含フッ素キ
ラルアミンをｎ−ブチルリチウムと反応することにより
製造することができる。ｎ−ブチルリチウムの量は含フ
ッ素キラルアミン１モルに対して１．０〜２０モルであ
る。反応において溶媒、例えば、テトラヒドロフラン、
ジエチルエーテル、ジメトキシエタン（ＤＭＥ） 、）
ルエンを用いる。溶媒の量は含フッ素キラルアミン１モ
ルに対して５００〜５００Ｃ１＋（！である。反応温度
は１００〜Ｏ′Ｃ１反応時間は５〜３０分である。The fluorine-containing chiral lithium amide of the present invention can be produced by reacting a fluorine-containing chiral amine with n-butyllithium. The amount of n-butyllithium is 1.0 to 20 moles per mole of fluorine-containing chiral amine. Solvents in the reaction, such as tetrahydrofuran,
diethyl ether, dimethoxyethane (DME), )
Use luene. The amount of solvent is 500 to 500 C1+ (!) per mole of fluorine-containing chiral amine. The reaction temperature is 100 to O'C1, and the reaction time is 5 to 30 minutes.
本発明の含フッ素キラルリチウムアミドは、例えば、エ
ナンチオ選択的不斉脱プロトン化反応、不斉プロトン化
反応、不斉炭素−炭素結合形成反応、不斉脱ハロゲン化
水素反応において不斉源として使用できる。The fluorine-containing chiral lithium amide of the present invention is used as an asymmetric source in, for example, enantioselective asymmetric deprotonation reactions, asymmetric protonation reactions, asymmetric carbon-carbon bond formation reactions, and asymmetric dehydrohalogenation reactions. can.
不斉脱プロトン化反応の原料は、例えば、エポキンド類
、フクロヘキサノン類、光学活性３−ケトステロイド類
である。Raw materials for the asymmetric deprotonation reaction are, for example, epokinds, fuclohexanones, and optically active 3-ketosteroids.
不斉プロトン化反応において、例えば、工／ラードをケ
トンに転化することができる。In an asymmetric protonation reaction, for example, a lard can be converted to a ketone.
不斉炭素−炭素結合形成反応としては、例えば不斉アル
キル化反応、不斉アルドール反応、不斉タルツエン反応
および不斉［２，３］ウィノティッヒ転位反応を挙げる
ことかできる。Examples of the asymmetric carbon-carbon bond forming reaction include an asymmetric alkylation reaction, an asymmetric aldol reaction, an asymmetric tartzene reaction, and an asymmetric [2,3] Winotig rearrangement reaction.
不斉脱ハロゲン化水素反応の原料は、例えば、フロキラ
ルなβ−ハロカルボン酸である。The raw material for the asymmetric dehydrohalogenation reaction is, for example, a furochiral β-halocarboxylic acid.
他の要旨によれば、本発明は、式
で示される置換シクロヘキサノンを、溶媒中、前記含フ
ッ素キラルリチウムアミトおよび塩化トリメチルシリル
の存在下で脱プロトン化することからなる、式
［式中、Ａ１、Ａ２、Ａ３、Ａ４およびＡ５は前記と同
意義である。］
で示されるキラルエノ＝ルエーテルの製法に関する。According to another gist, the present invention provides a method of deprotonating a substituted cyclohexanone represented by the formula [wherein A1, A2, A3, A4 and A5 have the same meanings as above. ] This relates to a method for producing chiral eno-lether shown in the following.
置換シクロヘキサノンの具体例は、例えば、以下のとお
りである。Specific examples of substituted cyclohexanone are as follows.
［式中、Ａ１、Ａ２、Ａ３、Ａ４およびＡ５のそれぞれ
は、水素原子、メチル基、エチル基、プロピル基または
ブチル基である（但し、Ａ１、Ａ２、Ａ３、Ａ４および
Ａ５の少なくとも１つは水素原子てはない。）。］
［式中、ｐｈはフェニル基である。］
溶媒としては、例えば、テトラヒドロフラン、ジエチル
エーテル、ジメトキシエタン（ＤＭＥ）、トルエンが挙
げられる。溶媒の量は、原料の置換シクロへキサノン１
モルに対して、５００〜５００（ＪｍＱである。[In the formula, each of A1, A2, A3, A4 and A5 is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a butyl group (provided that at least one of A1, A2, A3, A4 and A5 is It is not a hydrogen atom.) ] [In the formula, ph is a phenyl group. ] Examples of the solvent include tetrahydrofuran, diethyl ether, dimethoxyethane (DME), and toluene. The amount of solvent is 1% of the raw material substituted cyclohexanone
500 to 500 (JmQ) per mole.
含フッ素キラルリチウムアミドの量は、原料の置換シク
ロヘキサノン１モルに対して、１、Ｏ〜２．０モルであ
る。The amount of fluorine-containing chiral lithium amide is 1.0 to 2.0 moles per mole of substituted cyclohexanone as a raw material.
塩化トリメチルシリル（ＴＭＳＣｉ２）の量は、原料の
置換シクロへキサノン１モルに対して１〜５モルである
。The amount of trimethylsilyl chloride (TMSCi2) is 1 to 5 moles per mole of substituted cyclohexanone as a raw material.
本発明の製法において、ヘキサメチルホスホルアミド（
ＨＭＰＡ）を添加することが好ましい。ＨＭＰＡの好ま
しい添加量は、含フッ素キラルリチウムアミド１モルに
対して１〜３モルである。In the production method of the present invention, hexamethylphosphoramide (
HMPA) is preferably added. The preferred amount of HMPA added is 1 to 3 moles per mole of fluorine-containing chiral lithium amide.
本発明の製法において、反応温度は一１００〜０°Ｃ１
反応時間は、５〜３０分である。In the production method of the present invention, the reaction temperature is -100~0°C1
Reaction time is 5-30 minutes.
本発明の製法によれば、キラルエノールエーテルを高い
光学収率で得られる。According to the production method of the present invention, chiral enol ether can be obtained in high optical yield.
本発明で得られたキラルエノールエーテルは、各種光学
活性化合物の合成のためのキラルシントンとして有用で
ある。The chiral enol ether obtained in the present invention is useful as a chiral synthon for the synthesis of various optically active compounds.
［発明の好ましい態様］ 以下に実施例を示し、本発明を具体的に説明する。[Preferred embodiment of the invention] EXAMPLES The present invention will be specifically explained below with reference to Examples.
製造例１
アルゴン雰囲気下、室温にてアミン１（１，９０ｇ、９
．３０１１１ＲＯのをエタノール（４０１のに溶解し、
同温でナトリウムメトキシド（９６％Ｘ１６０ｘＣ。Production Example 1 Amine 1 (1,90 g, 9
．． Dissolve 30111RO in ethanol (401,
Sodium methoxide (96% x 160xC) at the same temperature.
２．８５ｍｍｏσ）、続いてエチルフルオロアセテート
（１６ｍρ、１６．６Ｍｍｏのを加え、４７時間還流撹
拌した。反応液を減圧留去して得られる残渣に、飽和塩
化アンモニウム水（２好）を加え、飽和ＮａＨＣＯ３水
溶液で液性をｐＨ８に調整し、塩化メチレンで抽出（７
０πＣＸ３）ｔ、た。次いで、塩化メチレン層をブライ
ンで洗い、無水Ｎａ２Ｓ○４て乾燥した後、溶媒を減圧
留去して淡黄色油状物質（２４４ｇ）を得た。これを水
冷下ＥｔＯＨ−ＨＣρにより無色アモルファスの塩酸塩
（２，４，０ｇ）を得、エタノール エーテル−５・１
から再結晶をし、無色プリズム晶（２，０７ｇ、融点１
５２５〜１５３℃、収率７４％）を得た。2.85 mmoσ), followed by ethyl fluoroacetate (16 mρ, 16.6 Mmo) were added, and the mixture was stirred under reflux for 47 hours. The reaction solution was distilled off under reduced pressure. To the residue obtained, saturated ammonium chloride water (2%) was added. The pH was adjusted to pH 8 with saturated NaHCO3 aqueous solution, and extracted with methylene chloride (7
0πCX3)t. The methylene chloride layer was then washed with brine, dried over anhydrous Na2S4, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil (244 g). This was treated with EtOH-HCρ under water cooling to obtain colorless amorphous hydrochloride (2.4.0 g), and ethanol ether-5.1
Recrystallize from to give colorless prismatic crystals (2.07 g, melting point 1
525-153°C, yield 74%).
ｌ Ｒ（ＫＢ ｒ）（シｍ、、ｘ）ｃｍ−’：１６９０
（ｃｍｏ）［α］ ’ｆ＝’−一６５．７６ （ｃ、１
．０２８．ＥｔＯＨ）
水冷下、塩酸塩（１，８５ｇ）を１０％水酸化ナトリウ
ム水（３０ｙｄ）及び水に溶解し、エーテル抽出（２５
ｘＣＸ３）Ｌ、た有機層を、ブライン洗い、無水に、Ｃ
ｏ３て乾燥した後、溶媒を減圧留去し無水油状物質２（
１，４，５ｇ）を得た。l R (KB r) (sym,, x) cm-': 1690
(cmo) [α] 'f='--65.76 (c, 1
．． 028. EtOH) Hydrochloride (1.85 g) was dissolved in 10% sodium hydroxide solution (30 yd) and water under water cooling, and extracted with ether (25 yd).
xCX3) The organic layer was washed with brine and dried, C
After drying at o3, the solvent was distilled off under reduced pressure to obtain anhydrous oily substance 2 (
1,4,5g) were obtained.
１、ＨＮＭＲ（１００ＭＨｚ／ＣＤＣ（ｌａ／ＴＭ□−
一一一−
ＣＨ２ＣＨ，ＣＨ２）、２．０〜２．６（６Ｈ，ｍ、Ｎ
ＣＨ２×３）、４．８０（］、Ｈ，ｄ、 Ｊ＝４７．
６ＨｚＣＨ７Ｆ）、４．．９５（ＬＨ，ｄｄ、Ｊ＝７．
３５゜６．６２Ｈｚ、ＣＨ）、７．３（５Ｈ，ｍ、Ｐｈ
）、７３〜７．４（］、Ｈ，ｂ ｒ、ＮＨＣＯ）ＩＲに
−ト）（シｍ、、ｘ）Ｃｍ−’ ： １６６０〜１６
８０（ＣｍＯ）
ＭＳ（ｍ／ｅ）： ２６５ｍ”＋１，２６３ｍ”−１２
３１ｍ”−ＣＨ７Ｆ、 Ｉ ８８ｍ’−ＮＨＣＯＣＲ
２［α］も５−−７３．０６（ｃ、ｏ、９８０． Ｅ
ｔＯＨ）
一部のアミド体２（１４０ｍｇ）をエーテルに溶かし、
水冷下６０％ＨＣＱＯ４水溶液（０，１９ｇ）を加え無
色結晶（１３０ｍｇ、融点１２４〜１３２°Ｃ）を得た
。これをエタノールから２回再結晶し無水針状晶（６０
ｍｇ、融点１６８°Ｃから湿り１７３〜１７４°Ｃて融
解）を得た。1. HNMR (100MHz/CDC(la/TM□-
111- CH2CH, CH2), 2.0-2.6 (6H, m, N
CH2×3), 4.80(], H, d, J=47.
6HzCH7F), 4. ．． 95 (LH, dd, J=7.
35°6.62Hz, CH), 7.3 (5H, m, Ph
), 73-7.4 (], H, br, NHCO) IR-t) (sym,, x) Cm-': 1660-16
80 (CmO) MS (m/e): 265m"+1,263m"-12
31m"-CH7F, I 88m'-NHCOCR
2 [α] is also 5--73.06 (c, o, 980. E
tOH) Some of the amide compound 2 (140 mg) was dissolved in ether,
A 60% aqueous HCQO4 solution (0.19 g) was added under water cooling to obtain colorless crystals (130 mg, melting point 124-132°C). This was recrystallized twice from ethanol and anhydrous needle crystals (60
mg, melting point from 168°C to moist 173-174°C).
元素分析、計算値（ＣＩ５Ｈ７，Ｎ２０５ＣρＦとして
）：Ｎ、７．６８；Ｃ，４９，３９；Ｈ，６，０８実測
値 Ｎ、７．５８；Ｃ，４９，１，７；Ｈ。Elemental analysis, calculated value (as CI5H7, N205CρF): N, 7.68; C, 49,39; H, 6,08 Actual value N, 7.58; C, 49,1,7; H.
６．０５
ＩＲ（ＫＢｒＸνｍ、、、）ｃｍ−’： ６２０，１１
００（ＣｅＯ２）、１６８０（ＣｍＯ）
実施例１
アルゴン雰囲気下、Ｏ′Ｃにてアミド２（２，０７ｇ、
７．８３＋ｍｏののＴＨＦ（１，０ｔｆｆ）溶液に
ボー７ンテトラヒドロフラン錯体１．０Ｍ溶液（４７ｆ
ｆＣ。6.05 IR(KBrXνm,,,)cm-': 620,11
00 (CeO2), 1680 (CmO) Example 1 Amide 2 (2,07 g,
A 1.0M solution of 7.83+ mo of boron tetrahydrofuran complex (47f) in THF (1,0tff) was added.
fC.
４７ｍｘｏのを１８分で加え、０°Ｃにて４時間撹拌し
た。水冷下、過剰の試薬をメタノール（５０ｘ（りてク
エンチし濃塩酸（５０ｕρ）を加え、室温にて３８時間
撹拌した。溶媒を減圧留去した残渣にメタノール（１０
０ｍｆ２）を加え溶媒を減圧留去する操作を３回繰り返
して粉状晶を得た。これをエーテル洗浄（４０ｍ１２Ｘ
２）Ｌ、水（５０尻の、ＮａＨＣＯ２（３３ｇ）を加え
て液性をｐＨ８に調整し、エーテル抽出（６０ｉＣＸ３
）後、エーテル層をブラインで洗い、無水に、ＣＯ３て
乾燥し、溶媒を減圧留去して黄色油状物質（２，６６ｇ
）を得た。これをシリカゲルカラムクロマトグラフィー
（１００ｇ、 クロロホルム：メタノール−２０，１
溶出）により精製し、溶媒を減圧留去後、黄色油状物質
（２，３３ｇ）を得た。47mxo was added over 18 minutes and stirred at 0°C for 4 hours. Under water cooling, excess reagent was quenched with methanol (50x), concentrated hydrochloric acid (50μ) was added, and the mixture was stirred at room temperature for 38 hours.
The operation of adding 0mf2) and distilling off the solvent under reduced pressure was repeated three times to obtain powder crystals. Wash this with ether (40m12X
2) Add L, water (50 g), NaHCO2 (33 g) to adjust the liquid to pH 8, and extract with ether (60 iCX3
), the ether layer was washed with brine, anhydrous, dried with CO3, and the solvent was evaporated under reduced pressure to give a yellow oil (2.66 g
) was obtained. This was subjected to silica gel column chromatography (100 g, chloroform:methanol-20.1
After the solvent was distilled off under reduced pressure, a yellow oil (2.33 g) was obtained.
水冷下、Ｍｅ ０Ｈ−ＨＣ（！（２０ｍＱ）を加えて生
成した無色結晶（２，１６ｇ、融点２１４〜２１６°Ｃ
）を、エタノール（１７ＩＩ＋のから再結晶して無色針
状晶（１，８１ｇ、融点２１７〜２１９°Ｃ２収率７２
％）を得た。Under water cooling, colorless crystals (2.16 g, melting point 214-216 °C
) was recrystallized from ethanol (17II+) to give colorless needle crystals (1.81 g, melting point 217-219°C2, yield 72
%) was obtained.
元素分析、計算値（Ｃ１５Ｈｌ、Ｎ ２Ｃρ、Ｆとして
）・Ｎ、８．６７；Ｃ，５５，７３；Ｈ，７，７９実測
値：Ｎ、８．４０：Ｃ，５５，７２；Ｈ，７゜［α］も
’＝−３，４４（ｃ、０．９３８．ＭｅＯＨ）氷冷下、
塩酸塩（１５０ｍｇ）を１０％水酸化ナトリウム水溶液
（１，０ｍの及び水に溶かしてエーテル抽出（１５ｍσ
×３）した有機層を、ブラインで洗い、無水に２Ｃ○３
で乾燥した後、溶媒を減圧留去し無色油状物質３（１，
］、 Ｏｍｇ）を得た。Elemental analysis, calculated value (as C15Hl, N2Cρ, F)・N, 8.67; C, 55,73; H, 7,79 Actual value: N, 8.40: C, 55,72; H, 7゜ [α] also' = -3,44 (c, 0.938.MeOH) under ice cooling,
Hydrochloride (150 mg) was dissolved in a 10% aqueous sodium hydroxide solution (1.0 m) and water and extracted with ether (15 mσ
×3) Wash the organic layer with brine and dry it with 2C○3
After drying with
], Omg) were obtained.
］、Ｈ−ＮＭＲ（１００ＭＨｚ／ＣＤＣρ、／ＴＭＳ）
ｒ”□’−□
用パひトＣＨ７）、１．．８〜２．９（９Ｈ，ｍ、ＮＣ
Ｈ３Ｘ４．ＮＨ）、３．８０（］、Ｈ，ｄｄ、 Ｊ＝
４゜１．７，４．８０Ｈｚ、ＣＩ（）、４．４６（ＩＨ
，ｄｄｄ、−Ｔ ＝５．０，５．０，４６．６Ｊ（Ｚ、
ＣＨ２Ｆ）。], H-NMR (100MHz/CDCρ, /TMS)
H3X4. NH), 3.80(], H, dd, J=
4゜1.7, 4.80Hz, CI (), 4.46 (IH
, ddd, -T = 5.0, 5.0, 46.6J (Z,
CH2F).
６ ９−７．６（５Ｈ，ｍ、Ｐｈ）
３Ｃ−ＮＭＲ（１００ＭＨｚ／ＣＤＣｌ２３／ＴＭＳ）
δ：１４２．５８（ｓ）、 １２８．１７（ｄｌ
１２７、．１．９（ｄ）、 １２６．９６（ｄ）、８
４．．１５，８２．５０（ＪｏＦ−１６５，８Ｈｚ）、
６６．３３（ｔ）５９．３７（ｄ）、 ５４．３９（
ｔ）、４７．５２ ４７．３３（Ｊｃｃｐ＝１９Ｈｚ）
、２５．９６（ｔ）、２４．３３（ｔ） ＩＲ（ＣＨ
Ｃρ３）（νｍａｘ） Ｃｍ −’ ： １６０３、
１４９２． １．４６８（Ｐｈ）ＭＳ（ｍ／ｅ）：２５
１ｍ”＋１，２５０ｍ” ２４９ｍ’−１
［α］ Ｖ）’＝−７９．３９ （ｃ、０．９５６．
ＭｅＯＨ）
製造例２
アルゴン雰囲気下、室温にてアミン１（１１２゜６ｍｇ
、０．５５ｉｚｏのをエタノール（２肩のに溶解し、同
温でナトリウムメトキシド（９６％）（９，６ｍｇ。6 9-7.6 (5H, m, Ph) 3C-NMR (100MHz/CDCl23/TMS)
δ: 142.58 (s), 128.17 (dl
127,. 1.9(d), 126.96(d), 8
4. ．． 15,82.50 (JoF-165,8Hz),
66.33(t) 59.37(d), 54.39(
t), 47.52 47.33 (Jccp=19Hz)
, 25.96(t), 24.33(t) IR(CH
Cρ3)(νmax) Cm-': 1603,
1492. 1.468 (Ph) MS (m/e): 25
1m"+1,250m"249m'-1 [α] V)'=-79.39 (c, 0.956.
Production Example 2 Amine 1 (112゜6 mg
, 0.55 izo of sodium methoxide (96%) (9.6 mg) was dissolved in ethanol (2 ml) at the same temperature.
０ 、１７ ＋ｕ＋ｏ（り、 続いてエチルジフルオロ
アセテート（０，１ｏ２． ０．９９銘０のを加え、室
温で１６時間撹拌した。反応液を減圧留去して得られた
残渣に、飽和塩化アンモニウム水（、２ＩＱ）を加え飽
和ＮａＨＣＯ３水溶液で液性をｐＨ８に調節し、塩化メ
チレンで抽出（５０ｘＱＸ３）した。次いで塩化メチレ
ン層をブライン洗い、無水Ｎａ２５ｏ４で乾燥した後、
溶媒を減圧留去して淡黄色あめ状物質（１８０ｍｇ）を
得た。これをシリカゲルカラムクロマトグラフィー（５
，２ｇ、酢酸エチル、ベンゼン−３：１溶出）にて精製
し、溶媒を減圧留去後、淡黄色あめ状物質４（１，５６
，］、ｍｇ、収率１００％）を得た。Subsequently, ethyl difluoroacetate (0,102.0.99%) was added and stirred at room temperature for 16 hours.The reaction solution was distilled off under reduced pressure. Water (2IQ) was added and the pH was adjusted to pH 8 with a saturated aqueous NaHCO3 solution, and extracted with methylene chloride (50xQX3).The methylene chloride layer was then washed with brine and dried over anhydrous Na25O4.
The solvent was distilled off under reduced pressure to obtain a pale yellow candy-like substance (180 mg). This was subjected to silica gel column chromatography (5
, 2g, ethyl acetate, benzene - 3:1 elution), and after distilling off the solvent under reduced pressure, a pale yellow candy-like substance 4 (1,56
, ], mg, yield 100%) was obtained.
］ Ｈ−ＮＭＲ（１００ＭＨｚ／ＣＤＣ１７３／ＴＭＳ
）
［α］ Ｖ）’−−８４．６４（ｃ、ｏ、９７０．Ｍｅ
ＯＨ）
実施例２
ｄ、 Ｊ＝７．６Ｈｚ、 ＮＣＪ（−）、 ４．８（Ｉ
Ｈ，ｂｒＣＨ）、５．８９０（ＩＨ，ｄｄ、Ｊ＝５４．
５，５４、．５Ｈｚ、ＣＦ３Ｉ）、７．０〜７．３（５
ＨｍＰｈ）、７．４５（ＩＨ，ｂｒ、ＮＨＣ○）Ｉ Ｒ
（ＣＨＣＬ＋）（シｍ、、ｘ）ｃｍ−’ ： ｌ ７０
３（Ｃ＝Ｏ）ＭＳ（ｍ／ｅ）： ２８１ｍ’−１，２３
１ｍ’ −ＣＨＦ 。] H-NMR (100MHz/CDC173/TMS
) [α] V)'--84.64(c, o, 970.Me
OH) Example 2 d, J=7.6Hz, NCJ(-), 4.8(I
H, brCH), 5.890 (IH, dd, J=54.
5,54,. 5Hz, CF3I), 7.0-7.3(5
HmPh), 7.45 (IH, br, NHC○)I R
(CHCL+)(sym,,x)cm-': l 70
3(C=O)MS (m/e): 281m'-1,23
1m'-CHF.
元素分析、計算値（ｃ １５８２１１Ｎ ２０ Ｆ ２
（！： シテ）Ｎ、９．９２；Ｃ，６３，８２；Ｈ，７
，１４実測値 Ｎ、 ９．６６ ； Ｃ，６３，５３
１１７，１５
アルコン雰囲気下、０°Ｃにてアミド４（５，６９ｇ２
０ ｆｆｆｆｏ１２）のＴＨＦ（２５ｘρ）溶液にホラ
ンーテトラヒドロフラン錯体１．ＯＭ溶ｉｆｆｌ（１２
０ｍσ、１２Ｑ ｍｍｏ（りを１５分で加え、室温にて
２１時間撹拌した。水冷下、過剰の試薬をメタノール＜
７０ＲＱ：）でクエンチしＭｅＯＨ−ＨＣ（２（３７％
）（３０ｍのを加え、溶媒を減圧留去した。さらに、Ｍ
ｅ ＯＨＨＩＪ（３７％）（５０＊のを加え溶媒を減
圧留去する操作を５回繰り返し、メタノール（１５０ｍ
Ｃ）を加え溶媒を減圧留去する操作を５回繰り返して無
色アモルファス（６，７１ｇ）を得た。これをエーテル
（２０Ｍ）中激しく撹拌し結晶化させ、無色粉状部（６
，４５ｇ、融点１４８〜１４９°Ｃ）を得た。Elemental analysis, calculated value (c 158211N 20 F 2
(!: Shite) N, 9.92; C, 63, 82; H, 7
, 14 actual measurement value N, 9.66; C, 63,53
117,15 Amide 4 (5,69 g2
Phoran-tetrahydrofuran complex 1.0 ffffo12) in THF (25xρ) solution. OM melt iffl(12
0 mσ, 12Q mmo(ri) was added over 15 minutes and stirred at room temperature for 21 hours. Excess reagent was poured into methanol under water cooling.
Quench with 70RQ: ) and add MeOH-HC (2 (37%
) (30 m) was added, and the solvent was distilled off under reduced pressure.
e OHHIJ (37%) (50*) was added and the solvent was distilled off under reduced pressure, which was repeated 5 times, and methanol (150 m
The operation of adding C) and distilling off the solvent under reduced pressure was repeated five times to obtain colorless amorphous (6.71 g). This was vigorously stirred in ether (20M) to crystallize, and a colorless powder (6
, 45 g, melting point 148-149°C).
これに、飽和Ｎ ａ ＨＣ○３水溶液（７０１１Ｑ、）
を加えて液性をｐＨ８に調整し、ヘキサン抽出（１００
ｍＣ×３）後、ヘキサン層をブラインで洗い、無水Ｎａ
２ＳＯ４で乾燥し、溶媒を減圧留去して無色曲状物質（
５，２４ｇ）を得た。ついてシリカケル力うｌ＼クロマ
トグラフィー（１６０ｇ、 ヘキサン、エーテル−１６
１溶出）により精製し、溶媒を減圧留去後、無色曲状物
質（５，１５ｇ）を得た。これをクライゼン蒸留（０，
４〜０．５ｍｍＨｇ／ｌ ］−０〜１１２°Ｃ）して無
色曲状物質５ （４，、４，１，ｇ、収率８２％）を得
た。To this, saturated Na HC○3 aqueous solution (7011Q,)
was added to adjust the pH to 8, and hexane extraction (100
After mC x 3), the hexane layer was washed with brine and anhydrous Na
After drying with 2SO4, the solvent was distilled off under reduced pressure to obtain a colorless curved substance (
5.24g) was obtained. Silica gel chromatography (160g, hexane, ether-16
After the solvent was distilled off under reduced pressure, a colorless, curved substance (5.15 g) was obtained. This is subjected to Claisen distillation (0,
4 to 0.5 mmHg/l] -0 to 112°C) to obtain colorless curved material 5 (4,4,1,g, yield 82%).
１．８−ＮＭＲ，（４，ＯＯＭ）（ｚ／ＣＤＣρ３／Ｔ
ＭＳ）
ＮＣＨ２Ｘ４．、ＮＨ）、３．８１９（ＩＨ，ｄｄ、Ｊ
３．６６４．ｌ ０．９９６Ｈｚ、ＣＨ）、５．７６７
（ＩＨ，ｄｄｄｄ、Ｊ＝３．３００，５．１３２５６．
４，５６．５Ｈｚ、ＣＦ、Ｈ）、７．２３〜７゜３７（
５Ｈ，ｍ、Ｐｈ）
３ＣＮ Ｍ Ｒ（１００Ｍ Ｈｚ／ ＣＤ Ｃ（２３／
Ｔ Ｍ Ｓ ）δ １４２．１０（ｓ）、 １２
８．３９（ｄ）、 １２７．３０（ｄ）、 １．１
８．４１． １１６．０１． １１３．６２（Ｊｃｒ＝
２３９．４．８ｚ）、６６．３２（ｔ）。1.8-NMR, (4,OOM)(z/CDCρ3/T
MS) NCH2X4. , NH), 3.819 (IH, dd, J
3.664. l 0.996Hz, CH), 5.767
(IH, dddd, J=3.300, 5.13256.
4,56.5Hz, CF, H), 7.23~7°37(
5H, m, Ph) 3CN M R (100MHz/ CD C (23/
T M S ) δ 142.10 (s), 12
8.39(d), 127.30(d), 1.1
8.41. 116.01. 113.62 (Jcr=
239.4.8z), 66.32(t).
５９．４．０（ｄ）、５４．４．９（ｔ）、４９．５８
，４９．３４，４．９．０９（ＪＣｏｒ−２３，４Ｈｚ
）、２６０５（ｔ）、２４．３７（ｔ）
Ｉ Ｒ（ＣＨＣｌ ３）（νｍａｘ）Ｃｍ−’ ：
１４９０，１４６７（Ｐｈ）
ＭＳ（ｍ／ｅ）： ２６７ｍ’−］、２４９ｍ’−１９
、２］、］７ｍ’−ＣＨＦ
元素分析、計算値（Ｃ，５Ｈ，２Ｎ 、Ｆ ２として）
：Ｎ。59.4.0(d), 54.4.9(t), 49.58
, 49.34, 4.9.09 (JCor-23, 4Hz
), 2605(t), 24.37(t) IR(CHCl3)(νmax)Cm-':
1490, 1467 (Ph) MS (m/e): 267m'-], 249m'-19
, 2], ]7m'-CHF elemental analysis, calculated value (as C, 5H, 2N, F 2)
:N.
１０．４４ 、Ｃ，６７，１４，； Ｈ，８，２６実測
値 Ｎ、１０．１７；Ｃ，６６，９７；Ｈ［α］ ！、
’−一−７８，２］、 （ｃ、 １．、１３８．Ｍｅ
ＯＨ）
穀測皿翠
アルコン雰囲気下、室温にてアミン］（］、、７３ｇ、
８ ４７ｚｚｏのを塩化メチレン（メタノールフリＸ８
．５Ｒのに溶解し、トリエチルアミン（１，７７ｍρ、
１２．７ｉｍｏＱ）を加えた後、−１０°Ｃにてト
リフルオロ無水酢酸（１，８０ｘＣ，１２，７１１ｍｏ
Ｑ）を６分かけて滴下し、室温にて１５時間撹拌した。10.44, C, 67, 14,; H, 8, 26 actual measurement value N, 10.17; C, 66, 97; H [α]! ,
'-1-78,2], (c, 1., 138.Me
OH) Amine](], 73g,
8 47zzo in methylene chloride (methanol free
．． Triethylamine (1,77 mρ,
After adding trifluoroacetic anhydride (1,80xC, 12,711moQ) at -10°C,
Q) was added dropwise over 6 minutes, and the mixture was stirred at room temperature for 15 hours.
反応液を塩化メチレン（１５ｆｆＱ）で希釈し、飽和Ｎ
ａ ＨＣＯ３水溶液（１０ｍので洗い、ブラインで洗
った後、無水Ｎａ２５ｏ４で乾燥し、溶媒を減圧留去し
て黄色油状物質（２，５２ｇ）を得た。これをシリカゲ
ルカラムクロマトグラフイー（７５ｇ、ヘキサン アセ
トン−８：１溶出）により精製し、溶媒を減圧留去後、
黄色油状物質６（１，９４ｇ収率７６％）を得た。The reaction solution was diluted with methylene chloride (15ffQ) and saturated N
a HCO3 aqueous solution (10 m), washed with brine, dried over anhydrous Na25O4, and the solvent was distilled off under reduced pressure to obtain a yellow oil (2.52 g). This was purified by silica gel column chromatography (75 g, hexane). After evaporation of the solvent under reduced pressure,
A yellow oil 6 (1.94 g, yield 76%) was obtained.
ＬＨ−ＮＭＲ（１００ＭＨｚ／ＣＤＣρ３／ＴＭｄ、
Ｊ＝８．１．Ｈｚ、ＮＣＨ２）、４．８２４（ＩＨｄ
ｄ、 Ｊ−７，８，７，６Ｈ２，ＣＨ）、 ７．０
〜７５（５Ｈ，ｍ、Ｐｈ）、７．５〜７．８（ＩＨ，ｂ
ｒＮＨＣＯ）
＋Ｒ（ＣＨＣρ３）（νｍａｘ）Ｃｍ−’ ： １７２
５（Ｃｍ０）ＭＳ（ｍ／ｅ）： ３０１ｍ”−１，２９
９ｍ゛−１２３１ｍ’−ＣＦ３
元素分析、計算値（ＣＩ５８Ｉ。Ｎ２０Ｆ３として）：
Ｎ、９．３３：Ｃ，６０，００；Ｈ，６，３８実測値：
Ｎ、９．０７ ；Ｃ，６０，２９；■（，６［α］ ｂ
’＝−７４，２０（ｃ、０．９６５ ＭｅＯＨ）
実施例３
アルゴン雰囲気下、Ｏ′Ｃにてアミド６（８，００ｇ＋
２６．Ｉ３屑＊０ののＴＨＦ（３Ｑｍの溶液にホラ
ンテトラヒドロフラン錯体］ 、 Ｏ）Ｊ＠液（８０ｍ
ｐ８０ｍｘｏのを１０分で加えた後、８時間還流撹拌し
た。水冷下、過剰の試薬をメタノール（５０ｍのでクエ
ンチしＭｅＯＨ−ＨＣＩ（３７％）（５０ｍのを加え、
溶媒を減圧留去した。さらに、Ｍ ｅ ＯＨＨＣ＋（３
７％）（５０ｍのを加え溶媒を減圧留去する操作を３回
、メタノール（１５０ｍのを加え溶媒を減圧留去する操
作を５回繰り返して淡黄色アモルファスを得た。これを
エーテル中激しく撹拌し結晶化させ、無色粉状部（８，
５７ｇ、 ｍｐ、 ］４４１〜１４４°Ｃを得た。８
．５７ｇの結晶をエタノール（２２ＩＣ）から再結晶し
無色りんぺん状部（２，０５ｇ、融点１７０°Ｃ付近か
ら湿り１８９〜１９ピＣで融解）を得、さらに、２番品
をエタノール（６ｆｆＣ）エーテル（９０ｍｇ）から無
色プリズム晶（５，２５ｇ、融点１６８°Ｃがら湿り１
７３°Ｃで融解）として得た。１，２番晶全てを飽和Ｎ
ａ ＨＣＯ３水溶液（１００ｆｆのを加え液性をｐＨ８
に調整し、ヘキサン抽出（１５０７１ＱＸ３）後、ヘキ
サン層をブラインで洗い、無水Ｎ ａ 、Ｓ Ｏ，で乾
燥し、溶媒を減圧留去して無色油状物質７（５，９８ｇ
、収率７９％）を得た。一部をハルブドウバルブ（０，
３ｍｍＨｇ／ １５０〜１６０°ｃ）（１００％回収）
ニテ蒸留し以下のデータを得た。LH-NMR (100MHz/CDCρ3/TMd,
J=8.1. Hz, NCH2), 4.824 (IHd
d, J-7,8,7,6H2,CH), 7.0
~75 (5H, m, Ph), 7.5 ~ 7.8 (IH, b
rNHCO) +R(CHCρ3)(νmax)Cm-': 172
5(Cm0)MS(m/e): 301m”-1,29
9m゛-1231m'-CF3 Elemental analysis, calculated value (CI58I. As N20F3):
N, 9.33: C, 60,00; H, 6,38 actual value:
N, 9.07; C, 60,29; ■(,6[α] b
' = -74,20 (c, 0.965 MeOH) Example 3 Amide 6 (8,00 g +
26. I3 scrap*0 THF (holane tetrahydrofuran complex in 3Qm solution), O) J@ solution (80m
After adding p80mxo over 10 minutes, the mixture was stirred under reflux for 8 hours. Under water cooling, excess reagents were quenched with methanol (50 m) and MeOH-HCI (37%) (50 m) was added.
The solvent was removed under reduced pressure. Furthermore, M e OHHC+(3
The operation of adding 50 m of methanol (7%) and distilling off the solvent under reduced pressure was repeated three times, and the operation of adding 150 m of methanol and distilling off the solvent under reduced pressure was repeated five times to obtain a pale yellow amorphous substance. This was vigorously stirred in ether. and crystallize to form a colorless powder (8,
57g, mp, ]441-144°C was obtained. 8
．． 57 g of crystals were recrystallized from ethanol (22 IC) to obtain a colorless phosphorus-like part (2.05 g, melting point from around 170°C to wet temperature of 189 to 19 picoC), and a second product was recrystallized from ethanol (6ffC). Ether (90 mg) to colorless prismatic crystals (5.25 g, melting point 168°C)
(melted at 73°C). Saturation of all 1st and 2nd crystals N
a Add HCO3 aqueous solution (100ff) to adjust the pH to 8.
After hexane extraction (15071QX3), the hexane layer was washed with brine, dried over anhydrous Na, SO, and the solvent was distilled off under reduced pressure to obtain colorless oily substance 7 (5.98 g).
, yield 79%). A part of the Haldo valve (0,
3mmHg/150-160°c) (100% recovery)
The following data were obtained by distillation.
Ｉ Ｈ−ＮＭＲ（１００ＭＨｚ／ＣＤＣＣ５／ＴＭＳ）
Ｈ＝ＣＨ２ＣＨ２）、２．０〜２．７ （６Ｈ，ｍ
Ｎ ＣＨ２Ｘ３）１２．８〜３．０（ＬＨ，ｂ ｒ、Ｎ
Ｈ）、３゜０４７（２Ｈ，Ｑ、Ｊ＝９．８Ｈｚ、ＮＣＲ
，ＣＦ３）。I H-NMR (100MHz/CDCC5/TMS) H=CH2CH2), 2.0-2.7 (6H, m
N CH2X3) 12.8~3.0 (LH,br,N
H), 3°047 (2H, Q, J=9.8Hz, NCR
, CF3).
３．９５（１，Ｈ，ｄｄ、 Ｊ ＝４．２． １０．
２Ｈｚ。3.95 (1, H, dd, J = 4.2. 10.
2Hz.
ＣＨ）、７．１〜７．４（５Ｈ，ｍ、Ｐｈ）”Ｃ−ＮＭ
Ｒ（１００ＭＨｚ／ＣＤＣｌ２３／ＴＭＳ）δ： Ｉ
４．１．４８（Ｓ）、 Ｉ ３０゜１３．１．２７３
４、 １２４．５５． １２］、７６（ＪｏＦ−２７８
゜７Ｈｚ）、１２８．４６（ｄ）、１２７．４７（ｄ）
＋２７．４４（＋ｄ）、６６．３３（ｔ）、５８．０７
（ａ）５４．４７（ｔ）、４８．１９，４７．９０．４
７５９．４７．２８（ＪｏｏＦ−２９，２Ｈｚ）、２６
．１２（ｔ）、２４．．４−１（ｔ）
ＩＲ（ＣＨＣ１２３）（νｍａｘ）Ｃｍ−’ ： １６
０３． １４９２、 １４６９（Ｐｈ）
ＭＳ（ｍ／ｅ）： ２８７ｍ”＋１，２８５ｍ” −Ｌ
２６７ｍ’−１９
元素分析、計算値（Ｃ，５Ｈ、Ｎ ２０ Ｆ３として）
Ｎ、９．７８：Ｃ，６２，９２；Ｈ，７，３９実測値・
Ｎ、９．５８；Ｃ，６２，６６；Ｈ７゜［α］ ｂ’−
−８２，７（ｃ、 １．．２０４．、ＭｅＯＨ）製造例
４
アルコン雰囲気下、室温にてアミン１（１，６９ｇ、８
．２７ｍ１ｏのを塩化メチレン（メタノールフリー）（
１７ｉＱ）に溶解し、トリメチルアミン（２゜３２ｍＱ
、 ］、 ６．５４．ｍｍｏのを加えた後、−１０°
Ｃにて無水酢酸（０，９５１１＋２． ９．９３ｉ１１
ｏのを３分かけて滴下し、室温にて１時間撹拌した。反
応液に水（５ｘの、１０％ＨＣｌ２水（２５ｙｘＱ）を
加え抽出後、水層に水冷下１０％ＮａＯＨ水溶液（２０
ｆｆρ）を加え液性をｐＨ１０に調整し、塩化メチレン
で抽出（３０ｘσ×３）した。有機層を飽和ＮａＨＣＯ
３水溶液（２０ｉので洗い、ブラインで洗った後、Ｋ、
ＣＯ２て乾燥し、溶媒を減圧留去して淡黄色あめ状物質
８（］、８４ｇ、収率９０％）を得た。CH), 7.1-7.4 (5H, m, Ph)"C-NM
R (100MHz/CDCl23/TMS) δ: I
4.1.48(S), I 30°13.1.273
4, 124.55. 12], 76 (JoF-278
゜7Hz), 128.46(d), 127.47(d)
+27.44 (+d), 66.33 (t), 58.07
(a) 54.47(t), 48.19, 47.90.4
759.47.28 (JooF-29, 2Hz), 26
．． 12(t), 24. ．． 4-1(t) IR(CHC123)(νmax)Cm-': 16
03. 1492, 1469 (Ph) MS (m/e): 287m"+1,285m" -L
267m'-19 Elemental analysis, calculated value (as C, 5H, N 20 F3)
N, 9.78: C, 62,92; H, 7,39 actual value・
N, 9.58; C, 62,66; H7゜[α] b'-
-82,7 (c, 1..204., MeOH) Production Example 4 Amine 1 (1,69 g, 8
．． 27ml of methylene chloride (methanol free) (
17iQ) and trimethylamine (2°32mQ).
, ], 6.54. -10° after adding mmo
Acetic anhydride (0,9511+2.9.93i11
o was added dropwise over 3 minutes, and the mixture was stirred at room temperature for 1 hour. Water (5x, 10% HCl2 water (25yxQ) was added to the reaction solution, and after extraction, the aqueous layer was diluted with 10% NaOH aqueous solution (20xQ) under water cooling.
ffρ) was added to adjust the pH to 10, and the mixture was extracted with methylene chloride (30 x σ x 3). Saturate the organic layer with NaHCO
3 aqueous solution (washed with 20i, washed with brine, K,
The mixture was dried with CO2, and the solvent was distilled off under reduced pressure to obtain pale yellow candy-like substance 8 (84 g, yield 90%).
２．２〜２．６（６Ｈ，ｍ、 ＮＣＨ２Ｘ３）、
４’、９０（ＬＨ，ｄｄ、ＣＨ）、７．２（５Ｈ，ｍ
、Ｐｈ）６．６５（ＩＨ，ｂｒ、ＮＨＣＯ）
Ｉ Ｒ（ＣＨＣｌ ３Ｘνｍａｘ）ｃｍ−’ ： １
６６０（Ｃ−ＭＳ（ｍ／ｅ）： ２４５ｍ’−］
実施貫Ｉ−
アルコン雰囲気下、０°Ｃにて水素化リチウムアルミニ
ウム（０，９１ｇ）にＴＨＦ（１５ｍのを加え、そこへ
ＴＨＥ（２ｘＱ）に溶解させたアミド８（１，８９ｇ、
７．６７ｕのを３分かけて滴下した。室温で１３５時間
撹拌、さらに１５時間還流撹拌後、水冷下反応液に水（
０，９１ｍの、１５％ＮａＯＨ水（０，９ｆｆ１２）、
水（２，７ｔＱ）、無水に、ＣＯ３を加え撹拌した。こ
の反応液を濾過し、濾液の溶媒を減圧留去して淡黄色油
状物質（１，４８ｇ）を得、アルミナカラムクロマトグ
ラフィー（１，２０ｇ、 ヘキサン：エーテル−４：１
）にて精製後、溶媒を減圧留去し、無色油状物質（１，
３５ｇ）を得た。2.2-2.6 (6H, m, NCH2X3),
4', 90 (LH, dd, CH), 7.2 (5H, m
, Ph) 6.65 (IH, br, NHCO) I R (CHCl 3Xνmax) cm-': 1
660 (C-MS (m/e): 245 m'-] Implementation I- In an alcone atmosphere, at 0 °C, add THF (15 m) to lithium aluminum hydride (0,91 g), and add THE (2xQ ) Amide 8 (1,89 g,
7.67 u was added dropwise over 3 minutes. After stirring at room temperature for 135 hours and stirring under reflux for an additional 15 hours, water (
0.91 m of 15% NaOH water (0.9ff12),
CO3 was added to water (2.7 tQ) and anhydrous and stirred. This reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure to obtain a pale yellow oil (1.48 g), which was then subjected to alumina column chromatography (1.20 g, hexane:ether-4:1
) After purification, the solvent was distilled off under reduced pressure to obtain a colorless oil (1,
35g) was obtained.
これに水冷下、ＭｅＯＨ−ＨＣＣ（７，５ＲＱ）を加え
生成した無色結晶（１，８８ｇ、ｄｐ、２３５°Ｃ）を
、エタノール（２０ｆｆＱ）−Ｉ−−チル（１０ｆｆの
から２回再結晶して無色釧状部（１，４１ｇ、融点２３
６°Ｃ，ｄｐ、２３８°Ｃ２収率６０％）を得た。To this was added MeOH-HCC (7,5RQ) under water cooling, and the resulting colorless crystals (1,88 g, dp, 235°C) were recrystallized twice from ethanol (20ffQ)-I-chill (10ff). Colorless rods (1.41 g, melting point 23
6°C, dp, 238°C2 yield 60%).
元素分析、計算値（ＣＩ５ＨｚａＮ ２ＣＩ ２として
）Ｎ、９．１８；Ｃ，５９，０１；Ｈ，８，５２実測値
：Ｎ、 ８．９４ ；Ｃ，５８，８６；Ｈ［α］ Ｐ
−９，５０（ｃ、ｏ、９９０．ＭｅＯＨ）水冷下、塩酸
塩（１，２５ｇ）を１０％水酸化ナトリウム水（２０屑
の及び水に溶かしヘキサン抽出（４０ｙｔｆ！Ｘ３）し
た有機層を、ブラインで洗い、無水に、ＣＯ３で乾燥し
た後、溶媒を減圧留去し無色油状物質９（０，９６ｇ）
を得た。Elemental analysis, calculated value (as CI5HzaN2CI2) N, 9.18; C, 59,01; H, 8,52 Actual value: N, 8.94; C, 58,86; H[α]P
-9,50 (c, o, 990. MeOH) Hydrochloride (1,25 g) was dissolved in 10% sodium hydroxide solution (20 g) and water under water cooling, and the organic layer was extracted with hexane (40 ytf!X3). After washing with brine, anhydrous and drying with CO3, the solvent was removed under reduced pressure to give a colorless oil 9 (0.96 g).
I got it.
］−Ｈ−ＮＭＲ（１００ＭＨｚ／ＣＤＣｆ２３／ＴＭＳ
）
Ｈ２）、２．１．０〜２．７０（９Ｈ，ｍ、ＮＣＨ２ｘ
４ＮＨ）、３．７６９（ＬＨ，ｄｄ、 Ｊ＝４．１．
７． １０．３０Ｈｚ、ＣＦ（）、 ７．０５〜７．
５０（５Ｈｍ、Ｐｈ）
１３Ｃ−ＮＭＲ（１００ＭＨＺ／ＣＤＣＱ３／′ＶＭＳ
）
δ：１４３．２０（ｓ）、 １２８．０３（ｄ）、
１２７．１２（ｄ）、 ］、２６．６８（ｄ）、６
６．４３（ｔ）。]-H-NMR (100MHz/CDCf23/TMS
) H2), 2.1.0 to 2.70 (9H, m, NCH2x
4NH), 3.769 (LH, dd, J=4.1.
7. 10.30Hz, CF(), 7.05~7.
50 (5Hm, Ph) 13C-NMR (100MHZ/CDCQ3/'VMS
) δ: 143.20 (s), 128.03 (d),
127.12(d), ], 26.68(d), 6
6.43(t).
５９．９２（ｄ）、５４．４４（ｔ）、４１．９１（Ｄ
。59.92(d), 54.44(t), 41.91(D
.
２５．９８（ｔ）、２ａ、３４（ｔ）、 １５．２９
（ｑ）ＩＲ（ＣＨＣ１２３Ｘν、ｎａｘ）ｃｍ−’ ：
１６０３． １４９２、 １４６８（Ｐｈ）
ＭＳ（ｍ／ｅ）： ２３３ｍ’＋Ｌ ２３１ｍ”−１
［α］Ｐ−８１，８３（ｃ、１．１７８．ＭｅＯＨ）
実施例５
アルゴン雰囲気下、アミン５（６７１，ｍｇ、２５ ｍ
１１ｏのをＴＨＦ（Ｎａ−ベンゾフェノン）（５０πの
に溶かし、−７８°Ｃに冷却後１，５１Ｎｎ−ＢｕＬ
ｉ（１，５０ＩＱ、 ２．４ｉｘｏρ）を加え３０分
撹拌した。続いてヘキサメチルポルホルアミド（ＨＭＰ
Ａ）（０，５（ＪｒｒｒＱ、 ２．９龍ｏのを加え２
０分撹拌した。その後、反応液を一１００’Ｃに冷却し
、塩化トリメチルシリル（ＴＭＳＣの（１，、２７ｆｆ
ρ、１０ｎｎｏρ）と４−ｔｅｒｔ−ブチルシクロへキ
サノンＡ（３０８ｍｇ、 ２０ｒｔｔｍｏののＴＨＦ
（４ｘＱ）混合液を２４０秒かけて加え１５分撹拌後、
トリエチルアミン（４屑の及び飽和ＮａＨＣＯ３水（１
０Ｆのを加えて反応を停止させ自然昇温さぜた。少量の
水を加えヘキサン抽出（５０＋＋ｏ２Ｘ３）Ｌ、有機層
を水洗（２０吋×２）し、０．ＩＮクエン酸水溶液（１
００７１ρＸ ２．５０ｘＱＸ ３）で洗い、水洗（２
０ｍのし、飽和ＮａＨＣＯ３水溶液（２０ＩＱ）で洗い
、ブライン（５０ｍ１２）で洗い、無水Ｎａ２５ｏ、て
乾燥した後、溶媒を減圧留去して淡黄色油状物質（６２
０ｍｇ）を得た。これをシリカケルカラムクロマトグラ
フィー（５ｇ、ヘキサン溶出）にて精製し、溶媒を減圧
留去後、バルブ トウバルブ蒸留（１５０’Ｃ１０，５
ｍｍＨｇ）に付し、無色油状のＴＭＳＭ７Ｃ３，１，５
７ｍｇ、収率９２％）を得た。25.98(t), 2a, 34(t), 15.29
(q) IR (CHC123Xν, nax) cm-':
1603. 1492, 1468 (Ph) MS (m/e): 233m'+L 231m''-1
[α]P-81,83 (c, 1.178.MeOH) Example 5 Amine 5 (671, mg, 25 m
11O was dissolved in THF (Na-benzophenone) (50π), and after cooling to -78°C, 1,51Nn-BuL was dissolved.
i (1,50IQ, 2.4ixoρ) was added and stirred for 30 minutes. This was followed by hexamethylporforamide (HMP).
A) (0,5(JrrrQ, add 2.9 dragon o's and 2
Stirred for 0 minutes. Thereafter, the reaction solution was cooled to -100'C, and trimethylsilyl chloride (TMSC (1,,27ff)
ρ, 10nnoρ) and 4-tert-butylcyclohexanone A (308 mg, 20 rttmo of THF)
Add the (4xQ) mixture over 240 seconds and stir for 15 minutes.
triethylamine (4 scraps and saturated NaHCO3 water (1
0F was added to stop the reaction, and the temperature was allowed to rise naturally. Add a small amount of water, extract with hexane (50++ o2 x 3), wash the organic layer with water (20 inches x 2), IN citric acid aqueous solution (1
0071ρX 2.50xQX 3), then rinse with water (2
After washing with saturated NaHCO3 aqueous solution (20IQ), brine (50mL), and drying over anhydrous Na25O, the solvent was distilled off under reduced pressure to give a pale yellow oil (62mL).
0 mg) was obtained. This was purified by silica gel column chromatography (5 g, hexane elution), and the solvent was distilled off under reduced pressure, followed by bulb-to-bulb distillation (150'C10,5
mmHg), colorless oily TMSM7C3,1,5
7 mg, yield 92%).
ＬＨ−ＮＭＲ（６０ＭＨｚ／ＣＣＱ、／ＴＭＳ）δ ０
．１４（９Ｈ，ｓ、５ｉＣＨ３）、Ｑ、８７（９Ｈ，ｓ
、ＣＣＨ，）、１．Ｏ〜２．３（７Ｈ，ｍ）４．６５（
ＩＨ，ｂｒ、ｍ、ＣＨ＝Ｃ）ＩＲに−ト）（νｍ、ｘ）
ｃｍ−’： ］ ６６５（（、−Ｃ）［α］３：ｉ
ｉ ’−＋ ２１６．．６（Ｃ，１，，５５４，、ベン
ゼン）
火旌最ｌ
アルコン雰囲気下、アミン５（６７１ｍｇ、２５ ｍｒ
ｎｏＱ）をＴＨＦ（Ｎａ−ペンツフェノン）（５０ｍの
に溶かし、−７８°Ｃに冷却後１．６１Ｎ ｎ−Ｂｕ
Ｌ ｉ（］、５０＊ｌｌ！、２．４ｍｍｏのを加え３０
分撹拌した。続いてＨＭＰＡ（０，５０好、２．９ｕ１
１ｏのを加え２０分撹拌後、ＴＭＳＣρ（１，２７ｍＱ
、 １０ｚＩｌ。LH-NMR (60MHz/CCQ,/TMS) δ 0
．． 14 (9H, s, 5iCH3), Q, 87 (9H, s
,CCH,),1. O ~ 2.3 (7H, m) 4.65 (
IH,br,m,CH=C)IR-t)(νm,x)
cm-': ] 665((,-C)[α]3:i
i'-+ 216. ．． 6 (C, 1,,554,, benzene) Amine 5 (671 mg, 25 mr
NoQ) was dissolved in THF (Na-pentuphenone) (50m, and after cooling to -78°C, 1.61N n-Bu
L i(], 50*ll!, add 2.4 mm and 30
Stir for 1 minute. Then HMPA (0.50 good, 2.9 u1
After adding 1o and stirring for 20 minutes, TMSCρ (1,27mQ
, 10zIl.
のと４−ｔｅｒｔ−ブチルシクロへキサノンＡ（３０８
ｍｇ＋ ２０ ｍｍｏののＴＨＦ（４ｍｇ）混合液を
３００秒かけて加え３０分撹拌した。トリエチルアミン
（４，ｍＱ）及び飽和ＮａＨＣＯ３水溶液（１０ｍＱ）
を加えて反応を停止させ自然昇温させ、少量の水を加工
ヘキサン抽出（５０ｘＣＸ３）した。次いで、ヘキサン
層を水洗（２０ｕ（！ｘ２）Ｌ、Ｏ，ＩＮクエン酸水溶
液（１００ｖｒ＋２Ｘ ２．５０ｍρ×３）で洗い、水
洗（２０況ρ）し、飽和ＮａＨＣ○３水溶液（２０靜）
で洗い、ブライン（５０ｘｆｆ）で洗い、無水Ｎａ２Ｓ
○４で乾燥した後、溶媒を減圧留去して淡黄色油状物質
（８３０ｍｇ）を得た。これをシリカゲルカラムクロマ
トグラフィー（６ｇ、ヘキサン溶出）にて精製し、溶媒
を減圧留去後、バルブ トウバルブ蒸留（１５０’Ｃ１
０，５ｍｍＨｇ）に付し、無色油状のＴＭＳＭ７Ｃ３１
６，１ｍｇ、収率９２％）を得た。Noto 4-tert-butylcyclohexanone A (308
A mixed solution of THF (4 mg) of mg + 20 mmo was added over 300 seconds and stirred for 30 minutes. Triethylamine (4, mQ) and saturated NaHCO3 aqueous solution (10 mQ)
was added to stop the reaction, the temperature was allowed to rise naturally, and a small amount of water was extracted with hexane (50xCX3). Next, the hexane layer was washed with water (20 u (!
Wash with brine (50xff), anhydrous Na2S
After drying with ◯4, the solvent was distilled off under reduced pressure to obtain a pale yellow oil (830 mg). This was purified by silica gel column chromatography (6 g, hexane elution), and the solvent was distilled off under reduced pressure, followed by bulb-to-bulb distillation (150'C1
0.5 mmHg), colorless oily TMSM7C31
6.1 mg, yield 92%) was obtained.
］ Ｈ−ＮＭＲ（６０ＭＨｚ／Ｃ（４４／ＴＭＳ）δ：
０．１４（９Ｈ，ｓ、 ５ｉＣＨ３）、０．８７（９
Ｈ，ｓ、ＣＣＨ３）、１．、Ｏ〜２．３（７Ｈ，ｍ）。] H-NMR (60MHz/C(44/TMS) δ:
0.14 (9H,s, 5iCH3), 0.87 (9
H, s, CCH3), 1. , O~2.3 (7H, m).
４．６５（ＩＨ，ｂｒ、ｍ、ＣＨ＝Ｃ）ＩＲに−トＸν
、−−）ｃｍ−’ ： １６６５（Ｃ＝Ｃ）［α］、
、：： −＋２０９．８
（Ｃ，］、、６１．０． ヘンセン）実施例７
アルコン雰囲気下、アミン７（７］、 ６ｍｇ、 ２
５ ｖｒｒｔｔｏのをＴＨＦ（Ｎａ−ペンツフェノン）
（５０ｆｆのに溶かし、−７８°Ｃに冷却後１．６１Ｎ
ｎ−ＢｕＬ ｉ （１，５０ｍ１２． ２．４ ｍｍ
ｏのを加え３０分撹拌した。（−（７）後、ＴＭＳＣＣ
（１，２７＊（！、 １．０ｍ１１ｏｆｆ）を加え、
続けて４−ｔｅｒｔ−ブチルシクロへキサノンＡ（３０
８ｍｇ、２０ｍ１ｏののＴ ＨＦ （４，５（２）溶液
を３００秒かけて加え２５分撹拌した。トリエチルアミ
ン（４ｇの及び飽和ＮａＨＣＯ３水溶液（１０ｍ（りを
加えて反応を停止させ自然昇温させ、少量の水を加えヘ
キサン溶出（５０ｍ１２Ｘ３）した。このヘキサン層を
水洗（２０ｍ１２Ｘ２）Ｌ、０．１Ｎクエン酸水溶液（
１００ｍρＸ ２．５０ｘｉ２Ｘ ３）で洗い、水洗（
２０ｍのし、飽和ＮａＨＣＯ３水溶液（２０＋０で洗い
、ブライン（５０ｍので洗い、無水ＮａｚＳＯｔて乾燥
した後、溶媒を減圧留去して淡黄色油状物質（７２０ｍ
ｇ）を得た。これをシリカゲルカラムクロマトグラフィ
ー（７ｇ、ヘキサン溶出）にて精製し、溶媒を減圧留去
後、バルブ トウバルブ蒸留（１５０°Ｃ／ ０ 、５
ｍｍＨｇ）に付し、無色油状のＴＭＳＭ７Ｃ３９７，
０ｍｇ、収率８８％）を得た。4.65 (IH,br,m,CH=C)IR-tXν
, --) cm-': 1665 (C=C) [α],
, :: -+209.8 (C,], , 61.0. Hensen) Example 7 Amine 7 (7), 6 mg, 2 under alkone atmosphere
5 THF (Na-pentuphenone)
(Dissolved in 50ff, cooled to -78°C, then 1.61N
n-BuLi (1,50m12.2.4 mm
o was added and stirred for 30 minutes. (-(7) after TMSCC
Add (1,27*(!, 1.0m11off),
Subsequently, 4-tert-butylcyclohexanone A (30
A solution of 8 mg, 20 ml of THF (4,5(2)) was added over 300 seconds and stirred for 25 minutes. The reaction was stopped by adding 4 g of triethylamine and 10 ml of a saturated aqueous NaHCO3 solution, and the mixture was allowed to heat up naturally. A small amount of water was added and eluted with hexane (50ml 12x3).The hexane layer was washed with water (20ml 12x2) and 0.1N citric acid aqueous solution (
100mρX 2.50xi2X 3), then rinse with water (
After washing with 20 ml of saturated NaHCO3 aqueous solution (20+0), washing with brine (50 ml), and drying with anhydrous NazSOt, the solvent was distilled off under reduced pressure to give a pale yellow oil (720 ml).
g) was obtained. This was purified by silica gel column chromatography (7 g, hexane elution), and the solvent was distilled off under reduced pressure, followed by bulb-to-bulb distillation (150 °C/0, 5
TMSM7C397 as a colorless oil.
0 mg, yield 88%).
ＩＨ−ＮＭＲ（６０ＭＨｚ／ＣＣ（、／ＴＭＳ）δ ０
．１．４ （９Ｈ，ｓ。IH-NMR (60MHz/CC(,/TMS) δ 0
．． 1.4 (9H, s.
（９Ｈ，ｓ、ＣＣＨ３）、 １
４．６５（１，Ｈ，ｂｒ、ｍ
ＩＲ（二ｂ）（シ、、ａｘ）ｃｍ
（Ｃ＝Ｃ）
［α］３ａｇ ＝＋］、 ９８．４
Ｓ １ＣＨ３）、Ｑ、３７
０〜２．３（７Ｈ，ｍ）
ＣＨ＝ Ｃ）
（Ｃ
１，５９０
ベンゼン）
アミン３．５．７および９を用いて同様に４ｔｅｒｔ−
ブチルシクロへキサノンの脱プロトン化反応を行った。(9H, s, CCH3), 1 4.65 (1, H, br, m IR (2b) (shi,, ax) cm (C=C) [α]3ag =+], 98.4 S 1CH3 ), Q, 37 0-2.3 (7H, m) CH=C) (C 1,590 benzene) Similarly, using amines 3.5.7 and 9, 4tert-
Deprotonation reaction of butylcyclohexanone was carried out.
実施例５．６および７を含めて、反応条件および反応結
果を下記表に示す。The reaction conditions and reaction results, including Examples 5.6 and 7, are shown in the table below.
手続補正書 平成 ２年 ８月３０日 ■、小事件表示 平成 ２年 特許願 第１９３６９１号 ２、発明の名称 ３、補正をする者 事件との関係Procedural amendment Heisei 2 years August 30th ■、Small incident display Heisei 2 years Patent application No. 193691 2. Name of the invention 3. Person who makes corrections Relationship with the incident
Claims (1)
れは、水素原子、メチル基、フェニル基またはベンジル
基（但し、Ｒ＾１、Ｒ＾２、Ｒ＾３およびＲ＾４の全て
が同一であることはない。）、 Ｙは、水素原子、メトキシ基、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼または▲数式、化学式、表等がありま
す▼、 Ｒｆは、炭素数１〜５の含フッ素アルキル基、ｎは、１
〜３の数である。］ で示される含フッ素キラルアミン。 ２、式： ▲数式、化学式、表等があります▼［II］ ［式中、Ｒ＾１、Ｒ＾２、Ｒ＾３およびＲ＾４のそれぞ
れは、水素原子、メチル基、フェニル基またはベンジル
基（但し、Ｒ＾１、Ｒ＾２、Ｒ＾３およびＲ＾４の全て
が同一であることはない。）、 Ｙは、水素原子、メトキシ基、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼または▲数式、化学式、表等がありま
す▼、 Ｒｆは、炭素数１〜５の含フッ素アルキル基、ｎは、１
〜３の数である。］ で示される含フッ素キラルリチウムアミド。 ３、式： ▲数式、化学式、表等があります▼ ［式中、Ａ＾１、Ａ＾２、Ａ＾３、Ａ＾４およびＡ＾５
のそれぞれは、水素原子、メチル基、エチル基、プロピ
ル基またはブチル基である（但し、Ａ＾１、Ａ＾２、Ａ
＾３、Ａ＾４およびＡ＾５の少なくとも１つは水素原子
ではない。）。］ で示される置換シクロヘキサノンを、溶媒中、請求項２
記載の含フッ素キラルリチウムアミドおよび塩化トリメ
チルシリルの存在下で脱プロトン化することからなる、
式： ▲数式、化学式、表等があります▼または▲数式、化学
式、表等があります▼ ［式中、Ａ＾１、Ａ＾２、Ａ＾３、Ａ＾４およびＡ＾５
は前記と同意義である。］ で示されるキラルエノールエーテルの製法。[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. group, phenyl group or benzyl group (however, R^1, R^2, R^3 and R^4 are not all the same), Y is a hydrogen atom, a methoxy group, ▲ Numerical formula, chemical formula , tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, Rf is a fluorine-containing alkyl group with 1 to 5 carbon atoms, n is 1
The number is ~3. ] A fluorine-containing chiral amine represented by: 2. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, each of R^1, R^2, R^3 and R^4 is a hydrogen atom, methyl group, phenyl group or benzyl group. group (however, R^1, R^2, R^3 and R^4 are not all the same), Y is a hydrogen atom, a methoxy group, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ , ▲Mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, Rf is a fluorine-containing alkyl group with 1 to 5 carbon atoms, n is 1
The number is ~3. ] A fluorine-containing chiral lithium amide represented by: 3. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A^1, A^2, A^3, A^4 and A^5
each is a hydrogen atom, a methyl group, an ethyl group, a propyl group, or a butyl group (however, A^1, A^2, A
At least one of ^3, A^4 and A^5 is not a hydrogen atom. ). ] In a solvent, a substituted cyclohexanone represented by
deprotonation in the presence of the fluorine-containing chiral lithium amide and trimethylsilyl chloride described above,
Formulas: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A^1, A^2, A^3, A^4 and A^5
has the same meaning as above. ] A method for producing chiral enol ether shown by.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2193691A JPH0482865A (en) | 1990-07-20 | 1990-07-20 | Fluorine-containing chiral amine and fluorine-containing chiral lithium amide and production 0f chiral enol ether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2193691A JPH0482865A (en) | 1990-07-20 | 1990-07-20 | Fluorine-containing chiral amine and fluorine-containing chiral lithium amide and production 0f chiral enol ether |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0482865A true JPH0482865A (en) | 1992-03-16 |
Family
ID=16312178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2193691A Pending JPH0482865A (en) | 1990-07-20 | 1990-07-20 | Fluorine-containing chiral amine and fluorine-containing chiral lithium amide and production 0f chiral enol ether |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0482865A (en) |
-
1990
- 1990-07-20 JP JP2193691A patent/JPH0482865A/en active Pending
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