JP2004331649A - 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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- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 230000003287 optical effect Effects 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
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- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
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- ABTOQLMXBSRXSM-UHFFFAOYSA-N silicon tetrafluoride Chemical compound F[Si](F)(F)F ABTOQLMXBSRXSM-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
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- 238000006243 chemical reaction Methods 0.000 description 26
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- 238000004458 analytical method Methods 0.000 description 10
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
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- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 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
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- 239000013543 active substance 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
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- 230000000052 comparative effect Effects 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 239000012025 fluorinating agent 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
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 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
- LXVAZSIZYQIZCR-UHFFFAOYSA-N 2-nonyloxirane Chemical compound CCCCCCCCCC1CO1 LXVAZSIZYQIZCR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N C1CCCCC1 Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 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 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
- 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
- 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
- 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 class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 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
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 230000008707 rearrangement Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 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
- 238000011282 treatment Methods 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
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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 a functional material such as a medicine, an agricultural chemical, or a liquid crystal compound, 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 (i.e., a fluorohydrin compound), a method is known in which an epoxy compound is reacted with silicon tetrafluoride in the presence of an amine and an ammonium salt or water (Non-Patent Document) 1).
However, according to this synthesis method, the obtained compound is a racemic body, and optically active 2-fluoroalkanols have not been 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。 Further, a method of synthesizing a fluorohydrin compound by opening a ring of an epoxide using HF, BF 3 .Et 2 O, HF-KF-based reagent or HF-amine-based reagent has been known for a long time. The method (1) generally has problems that the reaction temperature is high, rearrangement side reactions are 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 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。
As a method for producing optically active 2-fluoro-2-methyl-1-alkanols represented by the above formula (1), optically active 2-methyl-1,2-epoxyalkane is reacted with amine-hydrogen fluoride. A method for reacting a complex or silicon tetrafluoride is described in Patent Document 1.
However, the above-mentioned optically active 2-fluoroalkanols described in Patent Document 1 are monoalcohols, and the above-mentioned production method has problems such as 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。 Other methods for synthesizing optically active 2-fluoroalkanols include using an NF-based electrophilic fluorinating agent, introducing a fluorine group into a malonic acid derivative, 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, involves many reaction steps, and has a low yield. In particular, it involves a complicated operation of separating an optically active substance using HPLC. There was a problem such as having to do.
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 medicine, an agricultural chemical, or a liquid crystal compound which can be easily synthesized at a high yield and at a low cost. , 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。 The present inventors have conducted intensive studies to achieve the above object, and as a result, by using a specific optically active epoxy alcohol derivative that can be easily synthesized in a large amount, a novel optically active 2-fluoro-1,3- is used. 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、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、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), which comprises an optically active epoxy compound represented by the following formula (II) and tetrafluoroepoxide. A method for producing an optically active 2-fluoro-1,3-diol derivative, which comprises reacting silicon halide with an amine or in the presence of an amine and an ammonium salt or water. is there.
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 a functional material such as a medicine, an agricultural chemical, or a liquid crystal compound, which can be easily synthesized at a high yield and at a low cost. , 3-diol derivative 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, and examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Group, cycloheptyl group, cyclooctyl group and the like.
These alkyl groups and cycloalkyl groups may have a substituent, and such substituents include olefins (eg, vinyl, propenyl, butenyl, etc.), acetylenyl groups, hydroxyl groups, halogens, amino groups, carboxyl groups, Examples include an alkoxycarbonyl group, a cyano group, a residue of a heterocyclic compound (eg, a pyrazolidinyl group, a piperidyl group, and the like), an amide group, and the like.
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 protecting group R 2 for the hydroxyl group may be an alkyl group such as a methyl group or an allyl group, or a benzyl-based protecting group such as a benzyl group, a p-methoxybenzyl group, and a triphenylmethyl group. group, arylmethyl type protecting group, methoxyethoxymethyl group or -CH 2 OCH 2 Ar group (Ar: aryl), such as alkyl ether protecting groups such as, conventionally employed as a protecting group for a hydroxyl group conventionally Protecting groups.
When an ester-based 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 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, typical examples of the optically active 2-fluoro-1,3-diol derivative represented by the formula (I) of the present invention include (+)-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 be possessed are the same as those represented by R 1 in the above formula (I), and the hydroxyl-protecting group represented by R 2 is also the same as the above-mentioned formula (I) 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, typical compounds of the optically active epoxy compound represented by the formula (II) used in the present invention include (+)-2-benzyloxymethyl-1,2-epoxyundecane and (+)- Examples thereof include 1-benzyloxy-2-cyclohexyl-2,3-epoxypropane and the above-mentioned epoxides of (-).
These optically active epoxy compounds represented by the formula (II) can be prepared by asymmetric Sharpless epoxidation (JACS, 109, 5765 (1987)) or asymmetric epoxidation with a chiral ketone catalyst (Synthesis, 1979). (2000)) and an asymmetric epoxidation reaction using a chiral salen catalyst (JACS, 116, 9333 (1994)).
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 obtained. 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, diisopropylethylamine and the like.
Examples of the ammonium salt include quaternary ammonium fluorides 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 preferably performed under pressure or a pressurized atmosphere. The reaction pressure of silicon tetrafluoride is preferably in the range of 0.01 to 20 MPa, 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 low, and when the reaction pressure 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 amount of the amine to be added is preferably 0.2 to 10 equivalents, more preferably 0.5 to 5 equivalents, based on the optically active epoxy compound represented by the formula (II) as a starting material. When the amount of the amine is less than 0.2 equivalent, the reaction rate is slow and the amount of by-products is increased. When the 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 to be added is preferably 0.2 to 6 equivalents, more preferably 0.5 to 4 equivalents, based on the optically active epoxy compound represented by the formula (II) as a starting material. It is. There is no need to use ammonium salt and water together. When water is used, its amount is important. Patent Document 1 mentioned above states that when water is used in the production of optically active 2-fluoro-2-methyl-1-alkanols, the reaction mixture becomes gel-like, and the separation of the product becomes complicated. Although described, in the present invention, by accurately controlling the amount of water to be 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。
Examples of the solvent used for the reaction between the optically active epoxy compound represented by the formula (II) and silicon tetrafluoride include halogen-containing aprotic solvents such as chloroform and dichloromethane, diethyl ether, and tert-butyl methyl ether. And the like.
The reaction temperature is preferably in the range of -20C to 120C. 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., a remarkable increase in side reactions is observed. The reaction time is usually about 0.2 to 5 hours, depending on the reaction temperature and the like.
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 performing ordinary post-treatments such as hydrolysis, separation of an organic layer-aqueous layer, extraction, distillation, and column chromatography. 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
In a 100 ml three-necked flask equipped with a dropping funnel and a condenser, 20 ml of diethyl ether, 0.6 ml of diisopropylethylamine and 0.25 ml of water were sequentially charged. After the atmosphere in the reactor was set to an 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 was diluted. After undecane (94% ee) was added dropwise under ice cooling, the mixture was stirred at room temperature for 1 hour. After the reaction was stopped by adding 30 ml of a saturated aqueous KF solution, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography, and the desired product (S)-(+)-2-benzyloxymethyl-2-fluoro-1-undecanol having the following chemical formula is obtained. 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 the nuclear magnetic resonance analysis (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), 1.71-1.61ppm (m, 2H), 1.35-1.23ppm (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: tetramethylsilane, ppm)
δ 14.36, 22.87, 22.93, 29.55, 29.71, 29.75, 30.24, 32.12, 32.97 (d, J = 21.1 Hz), 65.14 (d, J = 25.5 Hz), 71.13 (d, J = 28.4 Hz), 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: 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
In a 100 ml three-necked flask equipped with a dropping funnel and a condenser, 20 ml of t-butyl methyl ether, 0.7 ml of diisopropylethylamine and 0.29 ml of water were sequentially charged. After the inside of the reactor was set to an atmospheric pressure atmosphere of silicon tetrafluoride, 1.0 g (4.1 mmol) of (S)-(+)-1-benzyloxy-2-cyclohexyl-diluted with 15 ml of t-butyl methyl ether was used. After 2,3-epoxypropane (94% ee) was added dropwise under ice cooling, the mixture was stirred at room temperature for 1 hour. After the reaction was stopped by adding 30 ml of a saturated aqueous KF solution, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography, and the desired product (S)-(+)-3-benzyloxy-2-cyclohexyl-2-fluoro-1 having the following chemical formula is obtained. 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 (BR300, 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 to 7.27 ppm (m, 5H), 4.59 ppm (d, J = 12 Hz, 1H), 4.54 ppm (d, J = 12 Hz, 1H), 3.86 to 3.67 ppm (m, 2H), 3.72 to 3.66 ppm ( m, 2H), 2.13 ppm (t, J = 6.0 Hz, 1H), 1.88-1.65 ppm (m, 6H), 1.31-1.00 ppm (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: tetramethylsilane, ppm)
δ 26.26, 26.40, 26.61 (d, J = 5.5 Hz), 41.02 (d, J = 20.7 Hz), 63.76 (d, J = 25.3 Hz), 70.49 (d, J = 27.7 Hz), 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: 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
In a 100 ml three-necked flask equipped with a dropping funnel and a condenser, 20 ml of diethyl ether, 0.8 ml of diisopropylethylamine and 0.35 ml of water were sequentially charged. After the atmosphere in the reactor was set to an atmospheric pressure of silicon tetrafluoride, 1.0 g (4.9 mmol) of (S)-(+)-1-benzyloxy-2-allyl-2,3 diluted with 15 ml of diethyl ether was used. -Epoxypropane (92% ee) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was stopped by adding 30 ml of a saturated aqueous KF solution, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography, and the desired product (S)-(−)-2-benzyloxymethyl-2-fluoro-4-pentene having the following chemical formula is obtained. 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 (BR300, 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 to 7.27 ppm (m, 5H), 5.73 to 5.87 ppm (m, 1H), 5.12 to 5.17 ppm (m, 2H), 4.59 ppm (d, J = 12 Hz, 1H), 4.54 ppm (d, J = 12 Hz, 1H), 3.77 ppm (d, J = 6.6 Hz, 1H), 3.71 ppm (d, J = 6.5 Hz, 1H), 3.65 ppm (dd, J 1 = 13 Hz, J 2 = 10.4 Hz, 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: 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: CFCl 3 )
δ -169.21〜-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
In a 100 ml three-necked flask equipped with a dropping funnel and a condenser, 20 ml of diethyl ether, 0.6 ml of diisopropylethylamine and 0.25 ml of water were sequentially charged. After the inside of the reactor was set to an atmospheric pressure atmosphere of silicon tetrafluoride, 1.0 g (3.47 mmol) of (R)-(+)-2- (2-methoxyethoxy) methoxymethyl-diluted with 15 ml of diethyl ether was diluted. After dropping 1,2-epoxyundecane (96% ee) under ice-cooling, the mixture was stirred at room temperature for 1 hour. After the reaction was stopped by adding 30 ml of a saturated aqueous KF solution, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography, and the desired product (S)-(+)-2- (2-methoxyethoxy) methoxymethyl-2- having the following chemical formula is obtained. 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 (BR300, 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 ~ 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: tetramethylsilane, ppm)
δ 14.08, 22.51 (d, J = 4.8 Hz), 22.64, 29.27, 29.46, 29.48, 29.97, 31.84, 32.65 (d, J = 19.1 Hz), 58.98, 63.88 (d, J = 27.2 Hz), 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: CFCl 3 )
δ -170.91〜-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
In a 100 ml three-necked flask equipped with a dropping funnel and a condenser, 25 ml of t-butyl methyl ether, 0.7 ml of diisopropylethylamine and 0.3 ml of water were sequentially charged. After the inside of the reactor was set to an atmospheric pressure atmosphere of silicon tetrafluoride, 1.0 g (4.1 mmol) of (R)-(+)-2-methoxyethoxymethyl-1, diluted with 15 ml of t-butyl methyl ether. After 2-epoxyundecane (96% ee) was added dropwise under ice-cooling, the mixture was stirred at room temperature for 1 hour. After the reaction was stopped by adding 30 ml of a saturated aqueous KF solution, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography, and the desired product (S)-(+)-2-methoxyethoxymethyl-2-fluoro-1-undecanol having the following chemical formula is obtained. 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 (BR300, 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), 3.73-3.62ppm (m, 2H), 3.39ppm (s, 3H), 2.03 ppm (t, J = 6.6Hz, 1H), 1.75 ~ 1.63ppm (m, 2H), 1.40 ~ 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: tetramethylsilane, ppm)
δ 14.09, 22.65, 22.69, 29.27, 29.45, 29.47, 29.98, 31.84, 32.59 (d, J = 21.4 Hz), 55.43, 64.71 (d, J = 24.9 Hz), 68.37 (d, J = 27.9 Hz), 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: CFCl 3 )
δ -170.05〜-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 the atmosphere in the reactor was set to an atmospheric pressure of silicon tetrafluoride, 1.0 g (3.45 mmol) of (R) -2-benzoyloxymethyl-1,2-epoxyundecane (96 g) diluted with 15 ml of diethyl ether was used. % Ee) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After an aqueous KF solution was added to stop the reaction, the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified 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 a 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. After 480 mg (3.34 mmol) of BF 3 .Et 2 O was added dropwise under ice cooling, the mixture was stirred at room temperature for 24 hours. After adding 5% aqueous sodium bicarbonate, the organic layer was separated. The organic layer was washed with water and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified 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.
Claims (2)
The optically active epoxy compound represented by the following formula (II) is reacted with silicon tetrafluoride in the presence of an amine or in the presence of an amine and an ammonium salt or water. A method for producing an optically active 2-fluoro-1,3-diol derivative of the above.
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| JP2004331649A true JP2004331649A (en) | 2004-11-25 |
| JP4568002B2 JP4568002B2 (en) | 2010-10-27 |
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| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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