JP4568002B2 - Optically active 2-fluoro-1,3-diol derivative and method for producing the same - Google Patents
Optically active 2-fluoro-1,3-diol derivative and method for producing the same Download PDFInfo
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- JP4568002B2 JP4568002B2 JP2004092771A JP2004092771A JP4568002B2 JP 4568002 B2 JP4568002 B2 JP 4568002B2 JP 2004092771 A JP2004092771 A JP 2004092771A JP 2004092771 A JP2004092771 A JP 2004092771A JP 4568002 B2 JP4568002 B2 JP 4568002B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 24
- 230000003287 optical effect Effects 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- ABTOQLMXBSRXSM-UHFFFAOYSA-N silicon tetrafluoride Chemical compound F[Si](F)(F)F ABTOQLMXBSRXSM-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000004593 Epoxy Substances 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000000047 product Substances 0.000 description 27
- 239000000126 substance Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- -1 acetylenyl group Chemical group 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 150000003863 ammonium salts Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000006735 epoxidation reaction Methods 0.000 description 3
- 239000004973 liquid crystal related substance Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OUKLLLHFVOTRDH-IBGZPJMESA-N CCCCCCCCC[C@](F)(CO)COCC1=CC=CC=C1 Chemical compound CCCCCCCCC[C@](F)(CO)COCC1=CC=CC=C1 OUKLLLHFVOTRDH-IBGZPJMESA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XIJVBGZHYZOBAS-IBGZPJMESA-N [(2R)-2-nonyloxiran-2-yl]methyl benzoate Chemical compound CCCCCCCCC[C@@]1(CO1)COC(=O)C2=CC=CC=C2 XIJVBGZHYZOBAS-IBGZPJMESA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000012298 atmosphere Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 239000012025 fluorinating agent Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000008204 material by function Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- XLVNRQUYVFKZHQ-LJQANCHMSA-N (2S)-2-nonyl-2-(phenylmethoxymethyl)oxirane Chemical compound C=1C=CC=CC=1COC[C@]1(CCCCCCCCC)CO1 XLVNRQUYVFKZHQ-LJQANCHMSA-N 0.000 description 1
- AMDISIQTQNGCHV-LOACHALJSA-N (2S)-3-fluoro-1-(2-methoxyethoxy)dodecan-2-ol Chemical compound CCCCCCCCCC([C@H](COCCOC)O)F AMDISIQTQNGCHV-LOACHALJSA-N 0.000 description 1
- RVCHIOZLZFGOBG-UHFFFAOYSA-N 1-fluoroundecan-1-ol Chemical compound CCCCCCCCCCC(O)F RVCHIOZLZFGOBG-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 description 1
- IAPHVRSMWMSKMT-UHFFFAOYSA-N 2-cyclohexyl-2-(phenylmethoxymethyl)oxirane Chemical compound C1CCC(CC1)C2(CO2)COCC3=CC=CC=C3 IAPHVRSMWMSKMT-UHFFFAOYSA-N 0.000 description 1
- SDPOBASYOGITLC-UHFFFAOYSA-N 2-cyclohexyl-2-fluoro-3-phenylmethoxypropan-1-ol Chemical compound C1CCC(CC1)C(CO)(COCC2=CC=CC=C2)F SDPOBASYOGITLC-UHFFFAOYSA-N 0.000 description 1
- RBCXEDQEZDUMHD-UHFFFAOYSA-N 2-fluoropropanedioic acid Chemical class OC(=O)C(F)C(O)=O RBCXEDQEZDUMHD-UHFFFAOYSA-N 0.000 description 1
- XLVNRQUYVFKZHQ-UHFFFAOYSA-N 2-nonyl-2-(phenylmethoxymethyl)oxirane Chemical compound C=1C=CC=CC=1COCC1(CCCCCCCCC)CO1 XLVNRQUYVFKZHQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- HYXDIKDDRKMKBW-UHFFFAOYSA-N C(C)OCC.C(CCC)CCCCCCC Chemical compound C(C)OCC.C(CCC)CCCCCCC HYXDIKDDRKMKBW-UHFFFAOYSA-N 0.000 description 1
- TYSAAJZTICGGFM-UHFFFAOYSA-N C1C(C)O1.C(C)(C)(C)OC Chemical compound C1C(C)O1.C(C)(C)(C)OC TYSAAJZTICGGFM-UHFFFAOYSA-N 0.000 description 1
- CXEOPFVRNAGHMZ-ZDUSSCGKSA-N C[C@](CC=C)(COCC1=CC=CC=C1)F Chemical compound C[C@](CC=C)(COCC1=CC=CC=C1)F CXEOPFVRNAGHMZ-ZDUSSCGKSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- VUOFFPJFCASFOP-IBGZPJMESA-N [(2S)-2-fluoro-2-(hydroxymethyl)undecyl] benzoate Chemical compound CCCCCCCCC[C@](CO)(COC(=O)C1=CC=CC=C1)F VUOFFPJFCASFOP-IBGZPJMESA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KFSZGBHNIHLIAA-UHFFFAOYSA-M benzyl(trimethyl)azanium;fluoride Chemical compound [F-].C[N+](C)(C)CC1=CC=CC=C1 KFSZGBHNIHLIAA-UHFFFAOYSA-M 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002391 heterocyclic compounds Chemical group 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical class OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、医薬、農薬、あるいは液晶化合物などの機能性材料を製造するための中間体として有用な光学活性な２−フルオロ−１，３−ジオール誘導体およびその製造方法に関する。 The present invention relates to an optically active 2-fluoro-1,3-diol derivative useful as an intermediate for producing functional materials such as pharmaceuticals, agricultural chemicals, and liquid crystal compounds, and a method for producing the same.
２−フルオロアルカノール類（即ちフルオロヒドリン化合物）の合成方法としては、エポキシ化合物に、アミンとアンモニウム塩もしくは水との存在下に四フッ化ケイ素を反応させる方法が知られている（非特許文献１参照）。
しかし、この合成方法では、得られる化合物はラセミ体であり、光学活性な２−フルオロアルカノール類は得られていない。
As a method for synthesizing 2-fluoroalkanols (that is, fluorohydrin compounds), a method is known in which silicon tetrafluoride is reacted with an epoxy compound in the presence of an amine and an ammonium salt or water (non-patent literature). 1).
However, in this synthesis method, the obtained compound is a racemate, and optically active 2-fluoroalkanols are not obtained.
また、ＨＦ、ＢＦ3 ・Ｅｔ2 Ｏ、ＨＦ−ＫＦ系試薬またはＨＦ−アミン系試薬などを用い、エポキシドを開環させ、フルオロヒドリン化合物を合成する方法が古くから知られているが、これらの方法は、一般に、反応温度が高く、転位副反応が起こりやすい、特別な反応容器を必要とするなどの問題があった。 In addition, methods for synthesizing fluorohydrin compounds by using HF, BF 3 · Et 2 O, HF-KF reagents or HF-amine reagents to open epoxides and synthesizing fluorohydrin compounds have long been known. This method generally has problems such as a high reaction temperature, a rearrangement side reaction is likely to occur, and a special reaction vessel is required.
光学活性な２−フルオロアルカノール類としては、次式(1) で表される光学活性な２−フルオロ−２−メチル−１−アルカノール類が知られている（特許文献１参照）。 As the optically active 2-fluoroalkanols, optically active 2-fluoro-2-methyl-1-alkanols represented by the following formula (1) are known (see Patent Document 1).
また、上式(1) で表される光学活性な２−フルオロ−２−メチル−１−アルカノール類の製造方法として、光学活性な２−メチル−１，２−エポキシアルカンにアミン−フッ化水素錯体または四フッ化ケイ素を反応させる方法が、特許文献１に記載されている。
しかし、特許文献１に記載されている上記の光学活性な２−フルオロアルカノール類は、モノアルコール類であり、また上記の製造方法では、収率が低いなどの問題があった。
Further, as a method for producing optically active 2-fluoro-2-methyl-1-alkanols represented by the above formula (1), amine-hydrogen fluoride is added to optically active 2-methyl-1,2-epoxyalkane. A method of reacting a complex or silicon tetrafluoride is described in Patent Document 1.
However, the optically active 2-fluoroalkanols described in Patent Document 1 are monoalcohols, and the above production method has problems such as a low yield.
その他の光学活性な２−フルオロアルカノール類の合成方法としては、Ｎ−Ｆ系求電子フッ素化剤を用い、マロン酸誘導体にフッ素基を導入した後、あるいはフルオロマロン酸誘導体をアルキル化した後、化学変換およびＨＰＬＣによる分離により光学活性な２−フルオロ−１，３−ジオール誘導体を合成する方法が知られている（非特許文献２参照）。しかし、この方法は、高価なフッ素化剤と高価な有機試薬を使用しなければならない、反応工程が多く、収率が低い、特にＨＰＬＣを用いて光学活性体を分離するという煩雑な操作を行わなければならないなどの問題があった。 As another method for synthesizing optically active 2-fluoroalkanols, after introducing a fluorine group into a malonic acid derivative using an NF-type electrophilic fluorinating agent, or alkylating a fluoromalonic acid derivative, A method of synthesizing an optically active 2-fluoro-1,3-diol derivative by chemical conversion and separation by HPLC is known (see Non-Patent Document 2). However, this method requires the use of an expensive fluorinating agent and an expensive organic reagent, has many reaction steps, and has a low yield. In particular, this method involves complicated operations such as separation of optically active substances using HPLC. There was a problem such as having to.
また、ラセミ体から光学分割などで光学活性体を得る方法が知られている（非特許文献３参照）。しかし、この方法は、２−アリール−２−フルオロ−１−プロパンジオール類の合成に限定されており、しかも収率が低いなどの問題があり、光学活性な２−フルオロ−１，３−ジオール誘導体を効率よく得る手段は未だ確立されていない。
本発明の目的は、高収率で容易に、しかも安価に合成できる、医薬、農薬、あるいは液晶化合物などの機能性材料を製造するための中間体として有用な、光学活性な２−フルオロ−１，３−ジオール誘導体、および、その製造方法を提供することにある。 An object of the present invention is to provide an optically active 2-fluoro-1 useful as an intermediate for producing a functional material such as a pharmaceutical, agricultural chemical, or liquid crystal compound that can be synthesized easily and inexpensively in a high yield. , 3-diol derivative and a method for producing the same.
本発明者らは、前記目的を達成すべく鋭意研究した結果、大量にかつ容易に合成できる特定の光学活性なエポキシアルコール誘導体を用いることにより、新規な光学活性な２−フルオロ−１，３−ジオール誘導体を安価で収率良く製造し得ることを知見した。 As a result of diligent research to achieve the above object, the present inventors have used a specific optically active epoxy alcohol derivative that can be synthesized in large amounts and easily, thereby producing a novel optically active 2-fluoro-1,3- It has been found that diol derivatives can be produced inexpensively and with good yield.
本発明は、上記知見に基づいてなされたもので、次式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体を提供するものである。 The present invention has been made based on the above findings, and provides an optically active 2-fluoro-1,3-diol derivative represented by the following formula (I).
また、本発明は、上式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体の製造方法として、反応器内に溶媒、アミンおよび水を順次仕込み、上記溶媒としてジエチルエーテルまたはtert−ブチルメチルエーテルを使用し、次式（II）で表される光学活性なエポキシ化合物と四フッ化ケイ素とを、上記のアミンと水との存在下で反応させることを特徴とする光学活性な２−フルオロ−１，３−ジオール誘導体の製造方法を提供するものである。 Further, the present invention provides a method for producing an optically active 2-fluoro-1,3-diol derivative represented by the above formula (I), in which a solvent, an amine and water are sequentially charged in a reactor, and diethyl is used as the solvent. Using ether or tert-butyl methyl ether, an optically active epoxy compound represented by the following formula (II) and silicon tetrafluoride are reacted in the presence of the above amine and water. A method for producing an optically active 2-fluoro-1,3-diol derivative is provided.
本発明によれば、高収率で容易に、しかも安価に合成できる、医薬、農薬、あるいは液晶化合物などの機能性材料を製造するための中間体として有用な、光学活性な２−フルオロ−１，３−ジオール誘導体、および、その製造方法を提供することができる。 According to the present invention, an optically active 2-fluoro-1 useful as an intermediate for producing functional materials such as pharmaceuticals, agricultural chemicals, and liquid crystal compounds, which can be easily synthesized at a high yield and at low cost. , 3-diol derivatives and a method for producing the same.
以下、本発明の光学活性な２−フルオロ−１，３−ジオール誘導体およびその製造方法について詳述する。 Hereinafter, the optically active 2-fluoro-1,3-diol derivative of the present invention and the production method thereof will be described in detail.
前記式（Ｉ）において、Ｒ1 で示されるアルキル基としては、炭素数４〜２０の直鎖あるいは分岐アルキル基が挙げられ、シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基などが挙げられる。
これらのアルキル基およびシクロアルキル基は置換基を有していてもよく、斯かる置換基としては、オレフィン（例えばビニル、プロペニル、ブテニルなど）、アセチレニル基、水酸基、ハロゲン、アミノ基、カルボキシル基、アルコキシカルボニル基、シアノ基、複素環化合物残基（例えばピラゾリジニル基、ピペリジル基など）、アミド基などを挙げることができる。
In the formula (I), examples of the alkyl group represented by R 1 include a linear or branched alkyl group having 4 to 20 carbon atoms. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and cyclohexyl. Group, cycloheptyl group, cyclooctyl group and the like.
These alkyl groups and cycloalkyl groups may have a substituent, such as an olefin (for example, vinyl, propenyl, butenyl, etc.), an acetylenyl group, a hydroxyl group, a halogen, an amino group, a carboxyl group, An alkoxycarbonyl group, a cyano group, a heterocyclic compound residue (for example, a pyrazolidinyl group, a piperidyl group, etc.), an amide group, etc. can be mentioned.
また、前記式（Ｉ）において、水酸基の保護基Ｒ2 としては、メチル基やアリル基などのようなアルキル基、ベンジル基、ｐ−メトキシベンジル基およびトリフェニルメチル基などのようなベンジル系保護基、アリールメチル系保護基、メトキシエトキシメチル基や−ＣＨ2 ＯＣＨ2 Ａｒ基（Ａｒ：アリール）などのようなアルキルエーテル系保護基などの、従来より水酸基の保護基として慣用的に用いられている保護基を挙げることができる。
アセチル基やベンゾイル基のようなエステル系保護基を用いた場合、本発明の２−フルオロ−１，３−ジオール誘導体は得られるものの、その収率は低く、分子内転位により１，２，３−トリオール誘導体を主生成物として与えるため、あまり好ましくない。
In the formula (I), the hydroxyl protecting group R 2 is an alkyl group such as a methyl group or an allyl group, a benzyl group protecting group such as a benzyl group, a p-methoxybenzyl group and a triphenylmethyl group. Conventionally used as a protecting group for a hydroxyl group, such as an alkyl ether protecting group such as a group, an arylmethyl protecting group, a methoxyethoxymethyl group or a —CH 2 OCH 2 Ar group (Ar: aryl) The protecting group which can be mentioned can be mentioned.
When an ester protecting group such as an acetyl group or a benzoyl group is used, the 2-fluoro-1,3-diol derivative of the present invention can be obtained, but the yield is low, and 1,2,3 due to intramolecular rearrangement. -It is less preferred because it gives the triol derivative as the main product.
従って、本発明の前記式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体の代表的化合物としては、（＋）−２−ベンジロキシメチル−２−フルオロ−１−ウンデカノール、（＋）−３−ベンジロキシ−２−フルオロ−２−シクロヘキシルプロパノールなど、並びに（−）の上記２−フルオロ−１，３−ジオール誘導体類を挙げることができる。 Therefore, as a representative compound of the optically active 2-fluoro-1,3-diol derivative represented by the above formula (I) of the present invention, (+)-2-benzyloxymethyl-2-fluoro-1- Examples include undecanol, (+)-3-benzyloxy-2-fluoro-2-cyclohexylpropanol, and the above-mentioned 2-fluoro-1,3-diol derivatives of (−).
次に、本発明の前記式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体の製造方法について説明する。
本発明の製造方法で出発原料として使用される前記式（II）で表される光学活性なエポキシ化合物において、Ｒ1 で示される炭素数４〜２０のアルキル基、シクロアルキル基、並びにこれらの基が有していてもよい置換基としては、前述した前記式（Ｉ）におけるＲ1 で示されるものと同様のものを例示でき、またＲ2 で示される水酸基の保護基も、前述した前記式（Ｉ）におけるＲ2 で示されるものと同様のものが例示される。
Next, a method for producing the optically active 2-fluoro-1,3-diol derivative represented by the formula (I) of the present invention will be described.
In the optically active epoxy compound represented by the formula (II) used as a starting material in the production method of the present invention, an alkyl group having 4 to 20 carbon atoms, a cycloalkyl group represented by R 1 , and these groups Examples of the substituent which may have may be the same as those represented by R 1 in the above-mentioned formula (I), and the hydroxyl protecting group represented by R 2 may also be the above-mentioned formula. Examples are the same as those represented by R 2 in (I).
従って、本発明で使用される前記式（II）で表される光学活性なエポキシ化合物の代表的化合物としては、（＋）−２−ベンジロキシメチル−１，２−エポキシウンデカン、（＋）−１−ベンジロキシ−２−シクロヘキシル−２，３−エポキシプロパンなど、並びに（−）の上記エポキシド類を挙げることができる。
これらの前記式（II）で表される光学活性なエポキシ化合物は、シャープレス不斉エポキシ化反応（J.A.C.S., 109, 5765 (1987)) 、キラルなケトン触媒による不斉エポキシ化反応（Synthesis, 1979 (2000)) 、キラルサレン触媒による不斉エポキシ化反応（J.A.C.S., 116, 9333 (1994)) などにより、大量にかつ容易に合成することができる。
Therefore, as a representative compound of the optically active epoxy compound represented by the formula (II) used in the present invention, (+)-2-benzyloxymethyl-1,2-epoxyundecane, (+)- Examples thereof include 1-benzyloxy-2-cyclohexyl-2,3-epoxypropane, and (-) epoxides.
These optically active epoxy compounds represented by the above formula (II) are sharpened asymmetric epoxidation reaction (JACS, 109, 5765 (1987)), chiral ketone-catalyzed asymmetric epoxidation reaction (Synthesis, 1979 (2000)), asymmetric epoxidation reaction with chiral salen catalyst (JACS, 116, 9333 (1994)), etc., and can be synthesized in large quantities and easily.
前記式（II）で表される光学活性なエポキシ化合物を、四フッ化ケイ素と反応させることにより、本発明の前記式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体が得られる。
この前記式（II）で表される光学活性なエポキシ化合物と四フッ化ケイ素との反応は、アミンの存在下、またはアミンとアンモニウム塩もしくは水との存在下で行う。
By reacting the optically active epoxy compound represented by the formula (II) with silicon tetrafluoride, the optically active 2-fluoro-1,3-diol represented by the formula (I) of the present invention is used. A derivative is obtained.
The reaction between the optically active epoxy compound represented by the formula (II) and silicon tetrafluoride is carried out in the presence of an amine or in the presence of an amine and an ammonium salt or water.
上記アミンの例としては、プロピルアミン、イソプロピルアミン、ジイソプロピルアミン、トリエチルアミン、N,N,N',N'-テトラメチルエチレンジアミン、ジイソプロピルエチルアミンなどのアミン類が挙げられる。
また、上記アンモニウム塩の例としては、テトラブチルアンモニウムフルオリド、テトラエチルアンモニウムフルオリド、ベンジルトリメチルアンモニウムフルオリドなどのフッ化第四アンモニウムなどが挙げられる。
Examples of the amine include amines such as propylamine, isopropylamine, diisopropylamine, triethylamine, N, N, N ′, N′-tetramethylethylenediamine and diisopropylethylamine.
Examples of the ammonium salt include quaternary ammonium fluoride such as tetrabutylammonium fluoride, tetraethylammonium fluoride, and benzyltrimethylammonium fluoride.
前記式（II）で表される光学活性なエポキシ化合物と四フッ化ケイ素との反応は、四フッ化ケイ素の使用量を過剰量で行うのが好ましく、一般的には四フッ化ケイ素の常圧または加圧雰囲気下で行うのが好ましい。四フッ化ケイ素の反応圧力は、０．０１〜２０ＭＰａの範囲が好ましく、０．０１〜１０ＭＰａの範囲がより好ましい。該反応圧力が０．０１ＭＰａより低い場合、反応速度が遅く、また２０ＭＰａより高い場合、反応操作が難しくなる。 The reaction between the optically active epoxy compound represented by the formula (II) and silicon tetrafluoride is preferably carried out in an excessive amount of silicon tetrafluoride. It is preferable to carry out under pressure or a pressurized atmosphere. The reaction pressure of silicon tetrafluoride is preferably in the range of 0.01 to 20 MPa, and more preferably in the range of 0.01 to 10 MPa. When the reaction pressure is lower than 0.01 MPa, the reaction rate is slow, and when it is higher than 20 MPa, the reaction operation becomes difficult.
上記アミンの添加量は、出発原料の前記式（II）で表される光学活性なエポキシ化合物に対して、好ましくは０．２〜１０当量、より好ましくは０．５〜５当量である。該アミンの添加量が０．２当量より少ない場合、反応速度が遅く、副生成物の量が増加し、また１０当量より多い場合、反応後の生成物の単離が煩雑である。 The addition amount of the amine is preferably 0.2 to 10 equivalents, more preferably 0.5 to 5 equivalents, with respect to the optically active epoxy compound represented by the formula (II) as a starting material. When the addition amount of the amine is less than 0.2 equivalent, the reaction rate is slow and the amount of by-products increases. When the addition amount is more than 10 equivalents, isolation of the product after the reaction is complicated.
上記のアンモニウム塩もしくは水の添加量は、出発原料の前記式（II）で表される光学活性なエポキシ化合物に対して、好ましくは０．２〜６当量、より好ましくは０．５〜４当量である。アンモニウム塩と水を併用する必要はない。水を使用する場合、その添加量が重要である。前述の特許文献１には、光学活性な２−フルオロ−２−メチル−１−アルカノール類の製造において、水を使用する場合、反応混合物がゲル状となり、生成物の分離が煩雑となる旨が記載されているが、本発明においては、正確に水の添加量を上記範囲内に制御することにより、反応混合物がゲル状にならず、生成物の分離が容易である。 The amount of the ammonium salt or water added is preferably 0.2 to 6 equivalents, more preferably 0.5 to 4 equivalents with respect to the optically active epoxy compound represented by the formula (II) as a starting material. It is. It is not necessary to use ammonium salt and water together. When water is used, the amount added is important. In Patent Document 1 described above, when water is used in the production of optically active 2-fluoro-2-methyl-1-alkanols, the reaction mixture becomes a gel and the separation of the product becomes complicated. Although described, in the present invention, by accurately controlling the amount of water added within the above range, the reaction mixture does not become a gel and the product can be easily separated.
前記式（II）で表される光学活性なエポキシ化合物と四フッ化ケイ素との反応に使用される溶媒としては、クロロホルム、ジクロロメタンなどの含ハロゲン非プロトン性溶媒、ジエチルエーテル、tert−ブチルメチルエーテルなどのジアルキルエーテルなどが好ましい。
反応温度は、−２０℃〜１２０℃の範囲で行うことが好ましい。反応温度が−２０℃より低い場合、反応速度が非常に遅く、また反応温度が１２０℃より高い場合、副反応の顕著な増加が見られる。反応時間は、反応温度などにもよるが、通常、凡そ０．２〜５時間である。
Solvents used for the reaction of the optically active epoxy compound represented by the formula (II) with silicon tetrafluoride include halogen-containing aprotic solvents such as chloroform and dichloromethane, diethyl ether, tert-butyl methyl ether Dialkyl ethers such as are preferred.
The reaction temperature is preferably -20 ° C to 120 ° C. When the reaction temperature is lower than −20 ° C., the reaction rate is very slow, and when the reaction temperature is higher than 120 ° C., there is a significant increase in side reactions. Although the reaction time depends on the reaction temperature and the like, it is usually about 0.2 to 5 hours.
上記の反応終了後、当該生成物について、加水分解、有機層−水層分離、抽出、蒸留、カラムクロマトグラフィーなどの通常の後処理を行うことにより、本発明の前記式（Ｉ）で表される光学活性な２−フルオロ−１，３−ジオール誘導体を得ることができる。 After completion of the above reaction, the product is represented by the above formula (I) of the present invention by subjecting the product to usual post-treatment such as hydrolysis, organic layer-aqueous layer separation, extraction, distillation, column chromatography and the like. An optically active 2-fluoro-1,3-diol derivative can be obtained.
以下に本発明の実施例を挙げるが、本発明は以下の実施例に制限されるものではない。 Examples of the present invention will be described below, but the present invention is not limited to the following examples.
実施例１
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ジエチルエーテル２０ｍｌ、ジイソプロピルエチルアミン０．６ｍｌおよび水０．２５ｍｌを順次仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ジエチルエーテル１５ｍｌで希釈した１．０ｇ（３．４５ｍｍｏｌ）の（Ｓ）−（＋）−２−ベンジロキシメチル−１，２−エポキシウンデカン（９４％ e.e.)を氷冷下で滴下した後、室温で１時間攪拌した。３０ｍｌの飽和ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物である下記の化学式を有する（Ｓ）−（＋）−２−ベンジロキシメチル−２−フルオロ−１−ウンデカノール０．８９ｇを得た。収率は８３％、比旋光度 [α]20 D は＋６．２２（ｃ＝１．３９ ＣＨＣｌ3 ）であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が９４％ e.e. であることが分かった。
Example 1
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was charged with 20 ml of diethyl ether, 0.6 ml of diisopropylethylamine and 0.25 ml of water in this order. After making the inside of the reactor atmospheric pressure of silicon tetrafluoride, 1.0 g (3.45 mmol) of (S)-(+)-2-benzyloxymethyl-1,2-epoxy diluted with 15 ml of diethyl ether Undecane (94% ee) was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. 30 ml of saturated aqueous KF solution was added to stop the reaction, and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography, and (S)-(+)-2-benzyloxymethyl-2-fluoro-1-undecanol having the following chemical formula as the target product 0.89 g was obtained. The yield was 83%, and the specific rotation [α] 20 D was +6.22 (c = 1.39 CHCl 3 ). As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 94% ee.
上記目的生成物の構造は、核磁気共鳴分析などで確認した。核磁気共鳴分析（VARIAN社製、AS500)の結果は、以下の通りである。 The structure of the target product was confirmed by nuclear magnetic resonance analysis or the like. The results of nuclear magnetic resonance analysis (manufactured by VARIAN, AS500) are as follows.
1Ｈ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン）
δ 7.37〜7.28ppm(m, 5H)、4.60ppm(d,J=12Hz, 1H) 、4.55ppm(d,J=12Hz, 1H) 、3.75ppm(d,J=6.5Hz, 1H)、3.71ppm(d,J=6.5Hz, 1H)、3.65ppm(dd,J1=15Hz, J2=10.2Hz, 1H)、3.59ppm(dd,J1=20Hz, J2=10.2Hz, 1H)、2.04ppm(t,J=6.5Hz, 1H)、1.71〜1.61ppm(m, 2H)、1.35〜1.23ppm(m, 14H) 、0.83ppm(t,J=7Hz, 3H)
1 H-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane)
δ 7.37-7.28ppm (m, 5H), 4.60ppm (d, J = 12Hz, 1H), 4.55ppm (d, J = 12Hz, 1H), 3.75ppm (d, J = 6.5Hz, 1H), 3.71ppm (d, J = 6.5Hz, 1H ), 3.65ppm (dd, J 1 = 15Hz, J 2 = 10.2Hz, 1H), 3.59ppm (dd, J 1 = 20Hz, J 2 = 10.2Hz, 1H), 2.04 ppm (t, J = 6.5Hz, 1H), 1.71 to 1.61ppm (m, 2H), 1.35 to 1.23ppm (m, 14H), 0.83ppm (t, J = 7Hz, 3H)
13Ｃ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン、ppm ）
δ 14.36, 22.87, 22.93, 29.55, 29.71, 29.75, 30.24, 32.12, 32.97(d,J=21.1Hz) 、65.14(d,J=25.5Hz) 、71.13(d,J=28.4Hz) 、73.68, 97.46(d,J=172.5Hz) 、127.67, 127.83, 128.45, 137.72
13 C-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane, ppm)
δ 14.36, 22.87, 22.93, 29.55, 29.71, 29.75, 30.24, 32.12, 32.97 (d, J = 21.1Hz), 65.14 (d, J = 25.5Hz), 71.13 (d, J = 28.4Hz), 73.68, 97.46 (d, J = 172.5Hz), 127.67, 127.83, 128.45, 137.72
19Ｆ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：ＣＦＣｌ3 ）
δ -169.76〜-169.99ppm(m, 1F)
19 F-NMR (solvent: CDCl 3 , standard substance: CFCl 3 )
δ -169.76〜-169.99ppm (m, 1F)
実施例２
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ｔ−ブチルメチルエーテル２０ｍｌ、ジイソプロピルエチルアミン０．７ｍｌおよび水０．２９ｍｌを順次仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ｔ−ブチルメチルエーテル１５ｍｌで希釈した１．０ｇ（４．１ｍｍｏｌ）の（Ｓ）−（＋）−１−ベンジロキシ−２−シクロヘキシル−２，３−エポキシプロパン（９４％ e.e.)を氷冷下で滴下した後、室温で１時間攪拌した。３０ｍｌの飽和ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物である下記の化学式を有する（Ｓ）−（＋）−３−ベンジロキシ−２−シクロヘキシル−２−フルオロ−１−プロパノール０．７７ｇを得た。収率は７２％、比旋光度 [α]20 D は＋６．９７（ｃ＝０．９３ ＣＨＣｌ3 ）であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が９４％ e.e. であることが分かった。
Example 2
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was sequentially charged with 20 ml of t-butyl methyl ether, 0.7 ml of diisopropylethylamine and 0.29 ml of water. After making the inside of the reactor atmospheric pressure of silicon tetrafluoride, 1.0 g (4.1 mmol) of (S)-(+)-1-benzyloxy-2-cyclohexyl- diluted with 15 ml of t-butyl methyl ether 2,3-epoxypropane (94% ee) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. 30 ml of saturated aqueous KF solution was added to stop the reaction, and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the product was purified by silica gel column chromatography, and (S)-(+)-3-benzyloxy-2-cyclohexyl-2-fluoro-1 having the following chemical formula, which was the target product. -0.77 g of propanol was obtained. The yield was 72%, and the specific rotation [α] 20 D was +6.97 (c = 0.93 CHCl 3 ). As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 94% ee.
上記目的生成物の構造は、核磁気共鳴分析などで確認した。核磁気共鳴分析（BRUKER社製、AV300M) の結果は、以下の通りである。 The structure of the target product was confirmed by nuclear magnetic resonance analysis or the like. The results of nuclear magnetic resonance analysis (BRUKER, AV300M) are as follows.
1Ｈ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン）
δ 7.39〜7.27ppm(m, 5H)、4.59ppm(d,J=12Hz, 1H) 、4.54ppm(d,J=12Hz, 1H) 、3.86〜3.67ppm(m, 2H)、3.72〜3.66ppm(m, 2H)、2.13ppm(t,J=6.0Hz, 1H)、1.88〜1.65ppm(m, 6H)、1.31〜1.00ppm(m, 5H)
1 H-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane)
δ 7.39-7.27ppm (m, 5H), 4.59ppm (d, J = 12Hz, 1H), 4.54ppm (d, J = 12Hz, 1H), 3.86-3.67ppm (m, 2H), 3.72-3.66ppm ( m, 2H), 2.13ppm (t, J = 6.0Hz, 1H), 1.88 to 1.65ppm (m, 6H), 1.31 to 1.00ppm (m, 5H)
13Ｃ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン、ppm ）
δ 26.26, 26.40, 26.61(d,J=5.5Hz)、41.02(d,J=20.7Hz) 、63.76(d,J=25.3Hz) 、70.49(d,J=27.7Hz) 、73.70, 98.82(d,J=173.9Hz) 、127.64, 127.81, 128.44, 137.68
13 C-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane, ppm)
δ 26.26, 26.40, 26.61 (d, J = 5.5Hz), 41.02 (d, J = 20.7Hz), 63.76 (d, J = 25.3Hz), 70.49 (d, J = 27.7Hz), 73.70, 98.82 (d , J = 173.9Hz), 127.64, 127.81, 128.44, 137.68
19Ｆ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：ＣＦＣｌ3 ）
δ -172.82〜-173.14ppm(m, 1F)
19 F-NMR (solvent: CDCl 3 , standard substance: CFCl 3 )
δ -172.82〜-173.14ppm (m, 1F)
実施例３
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ジエチルエーテル２０ｍｌ、ジイソプロピルエチルアミン０．８ｍｌおよび水０．３５ｍｌを順次仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ジエチルエーテル１５ｍｌで希釈した１．０ｇ（４．９ｍｍｏｌ）の（Ｓ）−（＋）−１−ベンジロキシ−２−アリル−２，３−エポキシプロパン（９２％ e.e.)を氷冷下で滴下した後、室温で２時間攪拌した。３０ｍｌの飽和ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物である下記の化学式を有する（Ｓ）−（−）−２−ベンジロキシメチル−２−フルオロ−４−ペンテン−１−オール０．６２ｇを得た。収率は７０％、比旋光度 [α]20 D は−２．０１（ｃ＝１．０６ ＣＨＣｌ3 ）であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が９２％ e.e. であることが分かった。
Example 3
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was charged with 20 ml of diethyl ether, 0.8 ml of diisopropylethylamine and 0.35 ml of water in this order. After making the inside of the reactor into a normal pressure atmosphere of silicon tetrafluoride, 1.0 g (4.9 mmol) of (S)-(+)-1-benzyloxy-2-allyl-2,3 diluted with 15 ml of diethyl ether. -Epoxypropane (92% ee) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. 30 ml of saturated aqueous KF solution was added to stop the reaction, and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography, and (S)-(−)-2-benzyloxymethyl-2-fluoro-4-pentene having the following chemical formula, which was the target product. 0.62 g of -1-ol was obtained. The yield was 70%, and the specific rotation [α] 20 D was −2.01 (c = 1.06 CHCl 3 ). As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 92% ee.
上記目的生成物の構造は、核磁気共鳴分析などで確認した。核磁気共鳴分析（BRUKER社製、AV300M) の結果は、以下の通りである。 The structure of the target product was confirmed by nuclear magnetic resonance analysis or the like. The results of nuclear magnetic resonance analysis (BRUKER, AV300M) are as follows.
1Ｈ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン）
δ 7.39〜7.27ppm(m, 5H)、5.73〜5.87ppm(m, 1H)、5.12〜5.17ppm(m, 2H)、4.59ppm(d,J=12Hz, 1H) 、4.54ppm(d,J=12Hz, 1H) 、3.77ppm(d,J=6.6Hz, 1H)、3.71ppm(d,J=6.5Hz, 1H)、3.65ppm(dd,J1=13Hz,J2=10.4Hz, 1H) 、3.59ppm(dd,J1=15Hz,J2=10.4Hz, 1H) 、2.44〜2.55ppm(m, 2H)、1.97ppm(t,J=6.6Hz, 1H)
1 H-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane)
δ 7.39-7.27ppm (m, 5H), 5.73-5.87ppm (m, 1H), 5.12-5.17ppm (m, 2H), 4.59ppm (d, J = 12Hz, 1H), 4.54ppm (d, J = 12Hz, 1H), 3.77ppm (d , J = 6.6Hz, 1H), 3.71ppm (d, J = 6.5Hz, 1H), 3.65ppm (dd, J 1 = 13Hz, J 2 = 10.4Hz, 1H), 3.59ppm (dd, J 1 = 15Hz , J 2 = 10.4Hz, 1H), 2.44~2.55ppm (m, 2H), 1.97ppm (t, J = 6.6Hz, 1H)
13Ｃ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン、ppm ）
δ 37.23(d,J=21.8Hz) 、64.8(d,J=24.5Hz)、70.93(d,J=27.3Hz) 、73.68, 96.82(d,J=174.4Hz) 、119.28, 127.66, 127.83, 128.53, 131.46(d,J=6.6Hz) 、137.63
13 C-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane, ppm)
δ 37.23 (d, J = 21.8Hz), 64.8 (d, J = 24.5Hz), 70.93 (d, J = 27.3Hz), 73.68, 96.82 (d, J = 174.4Hz), 119.28, 127.66, 127.83, 128.53 , 131.46 (d, J = 6.6Hz), 137.63
19Ｆ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：ＣＦＣｌ3 ）
δ -169.21〜-169.60ppm(m, 1F)
19 F-NMR (solvent: CDCl 3 , standard substance: CFCl 3 )
δ -169.21 to -169.60ppm (m, 1F)
実施例４
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ジエチルエーテル２０ｍｌ、ジイソプロピルエチルアミン０．６ｍｌおよび水０．２５ｍｌを順次仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ジエチルエーテル１５ｍｌで希釈した１．０ｇ（３．４７ｍｍｏｌ）の（Ｒ）−（＋）−２−（２−メトキシエトキシ）メトキシメチル−１，２−エポキシウンデカン（９６％ e.e.)を氷冷下で滴下した後、室温で１時間攪拌した。３０ｍｌの飽和ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物である下記の化学式を有する（Ｓ）−（＋）−２−（２−メトキシエトキシ）メトキシメチル−２−フルオロ−１−ウンデカノール０．７３ｇを得た。収率は６８％、比旋光度 [α]20 D は＋１１．４９（ｃ＝０．９２ ＣＨＣｌ3 ）であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が９６％ e.e. であることが分かった。
Example 4
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was charged with 20 ml of diethyl ether, 0.6 ml of diisopropylethylamine and 0.25 ml of water in this order. After making the inside of the reactor atmospheric pressure of silicon tetrafluoride, 1.0 g (3.47 mmol) of (R)-(+)-2- (2-methoxyethoxy) methoxymethyl- diluted with 15 ml of diethyl ether 1,2-Epoxyundecane (96% ee) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. 30 ml of saturated aqueous KF solution was added to stop the reaction, and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the product was purified by silica gel column chromatography, and the target product (S)-(+)-2- (2-methoxyethoxy) methoxymethyl-2- having the following chemical formula 0.73 g of fluoro-1-undecanol was obtained. The yield was 68%, and the specific rotation [α] 20 D was +11.49 (c = 0.92 CHCl 3 ). As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 96% ee.
上記目的生成物の構造は、核磁気共鳴分析などで確認した。核磁気共鳴分析（BRUKER社製、AV300M) の結果は、以下の通りである。 The structure of the target product was confirmed by nuclear magnetic resonance analysis or the like. The results of nuclear magnetic resonance analysis (BRUKER, AV300M) are as follows.
1Ｈ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン）
δ 4.74ppm(s, 2H)、3.82〜3.60ppm(m, 6H)、3.58ppm(t,J=4.4Hz, 2H)、3.40ppm(s, 3H)、2.52ppm(t,J=6.9Hz, 1H)、1.71〜1.58ppm(m, 2H)、1.40〜1.26ppm(m, 14H) 、0.88ppm(t,J=6.8Hz, 3H)
1 H-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane)
δ 4.74ppm (s, 2H), 3.82 to 3.60ppm (m, 6H), 3.58ppm (t, J = 4.4Hz, 2H), 3.40ppm (s, 3H), 2.52ppm (t, J = 6.9Hz, 1H), 1.71-1.58ppm (m, 2H), 1.40-1.26ppm (m, 14H), 0.88ppm (t, J = 6.8Hz, 3H)
13Ｃ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン、ppm ）
δ 14.08, 22.51(d,J=4.8Hz) 、22.64, 29.27, 29.46, 29.48, 29.97, 31.84, 32.65(d,J=19.1Hz) 、58.98, 63.88(d,J=27.2Hz)、67.02, 68.08(d,J=27.5Hz)、71.71, 95.41, 97.27(d,J=172.2Hz)
13 C-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane, ppm)
δ 14.08, 22.51 (d, J = 4.8Hz), 22.64, 29.27, 29.46, 29.48, 29.97, 31.84, 32.65 (d, J = 19.1Hz), 58.98, 63.88 (d, J = 27.2Hz), 67.02, 68.08 (d, J = 27.5Hz), 71.71, 95.41, 97.27 (d, J = 172.2Hz)
19Ｆ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：ＣＦＣｌ3 ）
δ -170.91〜-171.30ppm(m, 1F)
19 F-NMR (solvent: CDCl 3 , standard substance: CFCl 3 )
δ -170.91 to -171.30ppm (m, 1F)
実施例５
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ｔ−ブチルメチルエーテル２５ｍｌ、ジイソプロピルエチルアミン０．７ｍｌおよび水０．３ｍｌを順次仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ｔ−ブチルメチルエーテル１５ｍｌで希釈した１．０ｇ（４．１ｍｍｏｌ）の（Ｒ）−（＋）−２−メトキシエトキシメチル−１，２−エポキシウンデカン（９６％ e.e.)を氷冷下で滴下した後、室温で１時間攪拌した。３０ｍｌの飽和ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物である下記の化学式を有する（Ｓ）−（＋）−２−メトキシエトキシメチル−２−フルオロ−１−ウンデカノール０．９１ｇを得た。収率は８４％、比旋光度 [α]20 D は＋６．３３（ｃ＝０．９２ ＣＨＣｌ3 ）であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が９６％ e.e. であることが分かった。
Example 5
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was sequentially charged with 25 ml of t-butyl methyl ether, 0.7 ml of diisopropylethylamine and 0.3 ml of water. After making the inside of the reactor atmospheric pressure of silicon tetrafluoride, 1.0 g (4.1 mmol) of (R)-(+)-2-methoxyethoxymethyl-1, diluted with 15 ml of t-butyl methyl ether, 2-Epoxyundecane (96% ee) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. 30 ml of saturated aqueous KF solution was added to stop the reaction, and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography, and (S)-(+)-2-methoxyethoxymethyl-2-fluoro-1-undecanol having the following chemical formula as the target product 0.91 g was obtained. The yield was 84%, and the specific rotation [α] 20 D was +6.33 (c = 0.92 CHCl 3 ). As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 96% ee.
上記目的生成物の構造は、核磁気共鳴分析などで確認した。核磁気共鳴分析（BRUKER社製、AV300M) の結果は、以下の通りである。 The structure of the target product was confirmed by nuclear magnetic resonance analysis or the like. The results of nuclear magnetic resonance analysis (BRUKER, AV300M) are as follows.
1Ｈ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン）
δ 4.66ppm(s, 2H)、3.77ppm(d, 6.7Hz, 1H) 、3.73ppm(d, 6.7Hz, 1H) 、3.73〜3.62ppm(m, 2H)、3.39ppm(s, 3H)、2.03ppm(t,J=6.6Hz, 1H)、1.75〜1.63ppm(m, 2H)、1.40〜1.26ppm(m, 14H) 、0.88ppm(t,J=6.6Hz, 3H)
1 H-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane)
δ 4.66ppm (s, 2H), 3.77ppm (d, 6.7Hz, 1H), 3.73ppm (d, 6.7Hz, 1H), 3.73 to 3.62ppm (m, 2H), 3.39ppm (s, 3H), 2.03 ppm (t, J = 6.6Hz, 1H), 1.75 to 1.63ppm (m, 2H), 1.40 to 1.26ppm (m, 14H), 0.88ppm (t, J = 6.6Hz, 3H)
13Ｃ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：テトラメチルシラン、ppm ）
δ 14.09, 22.65, 22.69, 29.27, 29.45, 29.47, 29.98, 31.84, 32.59(d,J=21.4Hz) 、55.43, 64.71(d,J=24.9Hz)、68.37(d,J=27.9Hz) 、96.77, 97.36(d,172.1Hz)
13 C-NMR (solvent: CDCl 3 , standard substance: tetramethylsilane, ppm)
δ 14.09, 22.65, 22.69, 29.27, 29.45, 29.47, 29.98, 31.84, 32.59 (d, J = 21.4Hz), 55.43, 64.71 (d, J = 24.9Hz), 68.37 (d, J = 27.9Hz), 96.77 , 97.36 (d, 172.1Hz)
19Ｆ−ＮＭＲ（溶媒：ＣＤＣｌ3 、標準物質：ＣＦＣｌ3 ）
δ -170.05〜-170.44ppm(m, 1F)
19 F-NMR (solvent: CDCl 3 , standard substance: CFCl 3 )
δ -170.05 to -170.44ppm (m, 1F)
比較例１
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ジエチルエーテル２０ｍｌおよび水０．２５ｍｌを仕込んだ。反応器内を四フッ化ケイ素の常圧雰囲気にした後、ジエチルエーテル１５ｍｌで希釈した１．０ｇ（３．４５ｍｍｏｌ）の（Ｒ）−２−ベンゾイロキシメチル−１，２−エポキシウンデカン（９６％ e.e.)を氷冷下で滴下した後、室温で１時間攪拌した。ＫＦ水溶液を添加し、反応を停止した後、有機層を分液した。有機層を飽和重曹水で洗浄し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物の（Ｓ）−２−ベンゾイロキシメチル−２−フルオロ−１−ウンデカノール０．６２ｇを得た。収率は５８％であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が６０％ e.e. であることが分かった。
Comparative Example 1
A 100 ml three-necked flask equipped with a dropping funnel and a condenser was charged with 20 ml of diethyl ether and 0.25 ml of water. After making the inside of the reactor atmospheric pressure of silicon tetrafluoride, 1.0 g (3.45 mmol) of (R) -2-benzoyloxymethyl-1,2-epoxyundecane (96) diluted with 15 ml of diethyl ether. % Ee) was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. After adding KF aqueous solution and stopping reaction, the organic layer was liquid-separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography to obtain 0.62 g of the desired product (S) -2-benzoyloxymethyl-2-fluoro-1-undecanol. The yield was 58%. As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 60% ee.
比較例２
滴下ロートおよびコンデンサーを付した１００ｍｌ三口フラスコに、ジエチルエーテル７０ｍｌおよび４４０ｍｇ（１．５２ｍｍｏｌ）の（Ｓ）−（＋）−２−ベンジロキシメチル−１，２−エポキシウンデカン（９６％ e.e.)を仕込んだ。氷冷下で４８０ｍｇ（３．３４ｍｍｏｌ）のＢＦ3 ・Ｅｔ2 Ｏを滴下した後、室温で２４時間攪拌した。５％重曹水を添加した後、有機層を分液した。有機層を水洗し、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィーにより精製を行い、目的生成物の（Ｓ）−（＋）−２−ベンジロキシメチル−２−フルオロ−１−ウンデカノール１５０ｍｇを得た。収率は３１％であった。上記目的生成物の光学純度をMosher法で測定した結果、光学純度が５６％ e.e. であることが分かった。
Comparative Example 2
A 100 ml three-necked flask equipped with a dropping funnel and condenser was charged with 70 ml of diethyl ether and 440 mg (1.52 mmol) of (S)-(+)-2-benzyloxymethyl-1,2-epoxyundecane (96% ee). It is. Under ice cooling, 480 mg (3.34 mmol) of BF 3 .Et 2 O was added dropwise, followed by stirring at room temperature for 24 hours. After adding 5% sodium bicarbonate water, the organic layer was separated. The organic layer was washed with water and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography to obtain 150 mg of the desired product (S)-(+)-2-benzyloxymethyl-2-fluoro-1-undecanol. The yield was 31%. As a result of measuring the optical purity of the target product by the Mosher method, it was found that the optical purity was 56% ee.
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| JP2004092771A Expired - Lifetime JP4568002B2 (en) | 2003-04-17 | 2004-03-26 | Optically active 2-fluoro-1,3-diol derivative and method for producing the same |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02235828A (en) * | 1989-03-10 | 1990-09-18 | Nippon Mining Co Ltd | Optically active 2-fluoro-2-methyl-1-alkanols and preparation thereof |
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- 2004-03-26 JP JP2004092771A patent/JP4568002B2/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02235828A (en) * | 1989-03-10 | 1990-09-18 | Nippon Mining Co Ltd | Optically active 2-fluoro-2-methyl-1-alkanols and preparation thereof |
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| JP2004331649A (en) | 2004-11-25 |
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