WO2005085171A1 - 光学活性フルオロ化合物の製造方法 - Google Patents
光学活性フルオロ化合物の製造方法 Download PDFInfo
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- WO2005085171A1 WO2005085171A1 PCT/JP2005/003480 JP2005003480W WO2005085171A1 WO 2005085171 A1 WO2005085171 A1 WO 2005085171A1 JP 2005003480 W JP2005003480 W JP 2005003480W WO 2005085171 A1 WO2005085171 A1 WO 2005085171A1
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- WO
- WIPO (PCT)
- Prior art keywords
- optically active
- general formula
- represented
- diol
- compound
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/12—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids
- C07C29/124—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids of halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a method for producing an optically active fluoro compound, and more particularly, to a method for producing a selective monofluoro compound by introducing a protective group into an optically active diol, and an optically active fluoro compound obtained by the monofluoro compound power.
- the present invention relates to a method for producing alcohol.
- An optically active fluoro compound for example, an optically active fluoro alcohol (ie, fluorohydrin) is a compound useful as a raw material for pharmaceuticals, agricultural chemicals, and functional chemicals.
- Fluoroalcohol reacts epoxy compounds with HF, HFZ pyridine, KHF, etc.
- Non-Patent Documents 1 and 2 it is known that the compound can be easily synthesized by causing the reaction.
- Non-Patent Documents 1 and 2 when trying to obtain optically active fluorinated alcohols in which a fluorine atom is bonded to an asymmetric carbon atom, it is difficult to selectively synthesize a specific optical isomer by the above method, resulting in a mixture of isomers. . Separation of the desired optical isomer from them requires complicated purification operations such as optical resolution, and it is difficult to finally obtain a product with high optical purity in high yield.
- a method for introducing a fluorine atom into a specific site of an organic compound a method using a fluorinating agent is known.
- the fluorinating agent is broadly classified into two types: an electrophilic fluorinating agent that generates fluorine cations and a nucleophilic fluorinating agent that generates fluorine ions.
- various compounds including HF are known as nucleophilic fluorinating agents, among which getylaminosulfur trifluoride (DAST), 2,2-difluoro-1,3-dimethylimidazolidine. (DFI) and the like are known to be capable of nucleophilic substitution of an oxygen atom with a fluorine atom under mild conditions when reacted with an alcohol (Non-Patent Documents 3, 4, and 5).
- Non-patent document 1 Tetrahedron Letters, vol. 31, No. 49, 1990, pp7209-7212
- Non-patent document 2 Journal of Fluorine Chemistry, vol. 16, 1980, pp 540-541
- Non-patent document 3 Journal of Organic Chemistry, vol.40, No. 5, 1975, pp574 ⁇ 5 78
- Non-Patent Document 4 Fine Chemical, vol. 31, No. 10 (2002) pp5-12
- Non-Patent Document 5 Chemistry and Industry, Vol. 55, No. 3 (2002) pp259-262
- Patent document 1 Japanese Patent Application Laid-Open No. 181022
- An object of the present invention is to provide an optically active fluorinated compound capable of selectively producing optically active fluorinated alcohols from optically active diols, with a high optical purity and a high yield, and with a simple operation. It is to provide a manufacturing method.
- optically active diols as a raw material and a specific fluoramine, thermally or in the vicinity of microwave and Z or near microwave. It has been found that the desired optically active fluoro compound is produced with high selectivity by performing the reaction under the irradiation of the electromagnetic wave, and the above object is achieved, and the present invention has been completed.
- optically active fluoro compound having a structure in which only one hydroxyl group of the optically active diols as a raw material is selectively substituted with fluorine and the configuration is inverted. Wear.
- the other hydroxyl group of the optically active diols forms an ester bond by reaction with fluoramine, which is suitable for introducing a protecting group.
- the optically active fluoro compound can be easily obtained.
- the present invention provides the following optically active fluoro compound and a method for producing an optically active fluoro alcohol.
- a process for producing an optically active fluorinated compound represented by the general formula (3) characterized by reacting a fluoroamine represented by the general formula (1) with an optically active diol represented by the general formula (2). .
- R, R and R in the general formula (1) each have a hydrogen atom or a substituent
- Alkyl group or aryl group which may be the same or different from each other. Also,
- R, R, R, and R are a hydrogen atom or an alkyl group which may have a substituent
- 0 is an integer of 3.
- optically active fluoridone according to the above 1, wherein R is a phenyl group, and R and R are ethyl groups.
- R and R are hydrogen sources
- R and R and R and R are different from each other
- n is an integer from 0-3.
- the optically active fluorinated compound represented by the general formula (3) is obtained by reacting the fluorinated amine represented by the general formula (1) with an optically active diol represented by the general formula (2).
- the optically active fluoroalcohol of the general formula (4) is obtained by hydrolyzing the obtained optically active fluorocompound.
- R, R, R, R, R, R, R, and R in the general formula (1)-(4) of the present invention are a hydrogen atom
- alkyl group or an aryl group which may have a substituent.
- alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group.
- substituent of the aryl group include an alkyl group and an alkoxy group.
- the aryl group include a phenyl group, a methylphenyl group, and a methoxyphenyl group.
- Optically active diols used as a raw material of the optically active fluoro compound of the present invention are:
- R and R and R and R are different from each other
- optically active diol represented by the general formula (2) examples include (2R, 3R) butane 2,3-diol, (2S, 3S) -butane-2,3-diol, (2R, 4R) —Pentane— 2,4-Diol, (2S, 4S) Pentane 2,4-Diol, (1R, 2R) —Diphene-leutane 1,2-Diol, (IS, 2S) —Diphene-Luetane 1, 2-Diol Is mentioned.
- a compound having a protective group attached to a hydroxyl group of a saccharide to form a diol structure for example, 1,2; 5,6-O-dicyclohexylidene-D-mantol can also be used.
- Examples of the fluoroamine represented by the general formula (1) include N, N-dimethyl-a, a-difluoromethylamine, N, N-ethyl- ⁇ , ⁇ -difluoromethylamine, ⁇ , ⁇ -di ( ⁇ -propyl ) ⁇ , a-difluoromethylamine, N, N-di (isopropyl) ⁇ a, a-difluoromethyltilamine, N, N-di (n-butyl) - ⁇ , ⁇ -difluoromethylamine, ⁇ , ⁇ -dimethyl-a, ⁇ -difluoroethylamine, N, ⁇ dimethyl- ⁇ , ⁇ -difluoropropylamine, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylpentafluoroethylamine, ⁇ , ⁇ dimethylcyano- ⁇ , ⁇ -difluoroethylamine, ⁇ , ⁇ -d
- the reaction between the fluoramine represented by the general formula (1) and the optically active diol represented by the general formula (2) can be carried out in a batch system, a semi-batch system, or a continuous system. Thermal reaction or reaction under irradiation of microwave and electromagnetic wave near Z or microwave I can do it.
- the reaction temperature is particularly preferably in the range of room temperature to 150 ° C., which is usually preferably carried out at 200 ° C. or lower.
- the reaction can be carried out by irradiating a microwave having a frequency in the range of 0.3 to 300 GHz, or an electromagnetic wave in the vicinity of a microwave of 1 GHz or less or 30 to 300 GHz.
- the electromagnetic wave can be applied continuously or intermittently while controlling the temperature.
- the amount of fluoramine used is preferably 1 mol or more per 1 mol of hydroxyl group of the target substrate (optically active diol), but the reaction is carried out in excess or stoichiometrically insufficient. May be.
- the reaction time is preferably in the range of 10 minutes to 360 minutes for a thermal reaction.
- the irradiation time is preferably in the range of 0.1 to 180 minutes, but irradiation can be carried out for a longer time.
- a solvent may be used for sufficient stirring and for preventing a rise in temperature.
- Preferred solvents are aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, aromatic halogenated hydrocarbons, nitriles, ethers and the like which are inert to the substrate, fluoroamine and products. These can be selected and used in combination as needed.
- the optically active fluoro compound obtained by the above method contains an ester bond as shown in the general formula (3). Accordingly, the optically active fluoroalcohol represented by the general formula (4) can be easily obtained by a hydrolysis reaction of the optically active fluoroalcohol compound.
- a method of hydrolyzing the optically active fluoro compound represented by the general formula (3) a known method, for example, a transesterification reaction, an acid, an alkali, a biocatalyst, or the like can be used.
- a three-necked flask (300 mL) was charged with 125 g (0.197 mol) of oxalyl chloride in a nitrogen atmosphere under a nitrogen atmosphere.
- the flask was ice-cooled, and 45 g (0.236 mol) of N, N-dimethylmethtolamide was added dropwise with stirring over 20 minutes.
- the temperature was maintained at the same temperature for 10 minutes, the content temperature was set to 50 ° C, and the reaction was carried out for 1 hour. Gas evolution was observed during the reaction, after which a white solid precipitated.
- Og 0.018 mol
- acetonitrile 5 Og in a 100 mL three-neck flask, spray 4.4 g of dried potassium fluoride (0.076 mol: Morita Chemicals) was charged and reacted at 80 ° C for 20 hours in a nitrogen atmosphere. After stopping the reaction, the temperature was returned to room temperature, and the mixture was filtered and washed in a glove box.
- fluorinating agent B N, N-dimethyl- a , a-difluoro (2-methoxy) benzylamine
- Heat generation start temperature Peak top Heat generation amount Heat generation start temperature Type of fluorinating agent (° C) (° C) (kJ / ⁇ ) (° c) Fluorinating agent A 21 0 280 0.34 1 80
- Example 1 [(2S, 4S) pentane 2,4-diol fluorination]
- (2S, 4S) -pentane 2,4-diol (lmmol), dioxane (lmL), fluorine fluoride A (lmmol) are added, and the mixture is stirred well. It was placed in a vessel (Sharp, 2.45 GHz, 500 W) and irradiated with microwaves for 10 minutes. After cooling, a fluorinating agent A (1 mmol) was further added, and irradiation with microwaves was performed again for 10 minutes.
- Example 1 instead of fluorinating agent A, 2,2-difluoro-1,3 dimethylimidazolidine (DFI; lmmol) was added to a microwave irradiator (Sharp, 2.45 GHz, 500 W). When microwave irradiation was started, a runaway reaction occurred, and the reaction solution scattered outside the container, so it was not possible to complete the reaction.
- DFI 2,2-difluoro-1,3 dimethylimidazolidine
- Example 7 [Fluorination of 1,2; 5,6-0-dicyclohexylidene-D-mantol] 1,2; 5,6-O-dicyclohexylidene in Teflon (registered trademark) PFA container D Add mantle (lmmol), nonane (ImL) and fluorinating agent A (2mmol), mix vigorously, and place in a microwave irradiator (Sharp, 2.45GHz, 500W) for 10 minutes Irradiated with microwaves. After cooling to room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether (40 mL, 3 times).
- (2S, 4R) -2- (3-methylbenzoyloxy) 4 fluor-opened pentane (lmmol) obtained by the method of Example 1 was mixed with 35% hydrochloric acid (ImL) and stirred overnight. After water was added to the reaction solution, the mixture was extracted with ether (40 mL, 3 times). After drying over magnesium sulfate, it was concentrated and separated and purified by silica gel column chromatography. The desired product (2S, 4R) -4 fluoropentanediol was obtained in a yield of 95%.
- an optically active fluorinated compound having a protective group selectively introduced into the diol can be obtained with high optical purity and high purity. It can be easily produced in a high yield.
- an optically active fluorinated alcohol useful as a raw material for functional chemicals in addition to pharmaceuticals and agricultural chemicals can be obtained with high optical purity. It can be easily produced with high yield.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05719795A EP1721885A4 (en) | 2004-03-04 | 2005-03-02 | METHOD FOR PRODUCING OPTICALLY ACTIVE FLUOREM CHEMICALS |
JP2006510684A JP4752759B2 (ja) | 2004-03-04 | 2005-03-02 | 光学活性フルオロ化合物の製造方法 |
US10/591,698 US7307185B2 (en) | 2004-03-04 | 2005-03-02 | Process for producing optically active fluorochemical |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-061202 | 2004-03-04 | ||
JP2004061202 | 2004-03-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005085171A1 true WO2005085171A1 (ja) | 2005-09-15 |
Family
ID=34918047
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/003480 WO2005085171A1 (ja) | 2004-03-04 | 2005-03-02 | 光学活性フルオロ化合物の製造方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US7307185B2 (ja) |
EP (1) | EP1721885A4 (ja) |
JP (1) | JP4752759B2 (ja) |
CN (1) | CN100473638C (ja) |
WO (1) | WO2005085171A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2189466A3 (en) * | 2002-12-04 | 2010-09-08 | Mitsubishi Gas Chemical Company, Inc. | Method of fluorination by microwaves |
CN114539020B (zh) * | 2022-01-17 | 2023-12-08 | 南京迈诺威医药科技有限公司 | 一种1,5-二溴-3,3-二氟戊烷的制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01228927A (ja) * | 1988-03-10 | 1989-09-12 | Rikagaku Kenkyusho | γ−フルオロアルコールおよびその製造法 |
JPH03184929A (ja) * | 1989-12-15 | 1991-08-12 | Kanto Chem Co Inc | 光学活性フルオロアルコールおよびその製造方法 |
JPH04234333A (ja) * | 1990-07-25 | 1992-08-24 | Bayer Ag | β−フルオロアルコールの製造法 |
JPH11181022A (ja) | 1997-12-22 | 1999-07-06 | Mitsui Chem Inc | 含フルオロエチレン樹脂の製造方法 |
JP2003064034A (ja) | 2001-08-28 | 2003-03-05 | Mitsubishi Gas Chem Co Inc | フッ素化合物及び該フッ素化合物からなるフッ素化剤 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2189466A3 (en) * | 2002-12-04 | 2010-09-08 | Mitsubishi Gas Chemical Company, Inc. | Method of fluorination by microwaves |
-
2005
- 2005-03-02 JP JP2006510684A patent/JP4752759B2/ja not_active Expired - Fee Related
- 2005-03-02 CN CNB2005800070516A patent/CN100473638C/zh not_active Expired - Fee Related
- 2005-03-02 WO PCT/JP2005/003480 patent/WO2005085171A1/ja not_active Application Discontinuation
- 2005-03-02 EP EP05719795A patent/EP1721885A4/en not_active Withdrawn
- 2005-03-02 US US10/591,698 patent/US7307185B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01228927A (ja) * | 1988-03-10 | 1989-09-12 | Rikagaku Kenkyusho | γ−フルオロアルコールおよびその製造法 |
JPH03184929A (ja) * | 1989-12-15 | 1991-08-12 | Kanto Chem Co Inc | 光学活性フルオロアルコールおよびその製造方法 |
JPH04234333A (ja) * | 1990-07-25 | 1992-08-24 | Bayer Ag | β−フルオロアルコールの製造法 |
JPH11181022A (ja) | 1997-12-22 | 1999-07-06 | Mitsui Chem Inc | 含フルオロエチレン樹脂の製造方法 |
JP2003064034A (ja) | 2001-08-28 | 2003-03-05 | Mitsubishi Gas Chem Co Inc | フッ素化合物及び該フッ素化合物からなるフッ素化剤 |
Non-Patent Citations (7)
Title |
---|
CHEMISTRY & CHEMICAL INDUSTRY, vol. 55, no. 3, 2002, pages 259 - 262 |
FINE CHEMICAL, vol. 31, no. 10, 2002, pages 5 - 12 |
JOURNAL OF FLUORINE CHEMISTRY, vol. 16, 1980, pages 540 - 541 |
JOURNAL OF ORGANIC CHEMISTRY, vol. 40, no. 5, 1975, pages 574 - 578 |
JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS, vol. 2, no. 4, 1995, pages 861 - 866 |
See also references of EP1721885A4 |
TETRAHEDRON LETTERS, vol. 31, no. 49, 1990, pages 7209 - 7212 |
Also Published As
Publication number | Publication date |
---|---|
CN1930109A (zh) | 2007-03-14 |
US20070191631A1 (en) | 2007-08-16 |
EP1721885A1 (en) | 2006-11-15 |
EP1721885A4 (en) | 2008-02-27 |
CN100473638C (zh) | 2009-04-01 |
JP4752759B2 (ja) | 2011-08-17 |
US7307185B2 (en) | 2007-12-11 |
JPWO2005085171A1 (ja) | 2007-12-06 |
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