WO2015166827A1 - 反応容器、並びに光学活性アンチ－１，２－ニトロアルカノール化合物の製造方法、及び製造装置 - Google Patents

反応容器、並びに光学活性アンチ－１，２－ニトロアルカノール化合物の製造方法、及び製造装置 Download PDF

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WO2015166827A1
WO2015166827A1 PCT/JP2015/061957 JP2015061957W WO2015166827A1 WO 2015166827 A1 WO2015166827 A1 WO 2015166827A1 JP 2015061957 W JP2015061957 W JP 2015061957W WO 2015166827 A1 WO2015166827 A1 WO 2015166827A1
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compound
optically active
nitroalkanol
active anti
reaction vessel
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PCT/JP2015/061957
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English (en)
French (fr)
Japanese (ja)
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柴崎　正勝
直哉 熊谷
和樹 橋本
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公益財団法人微生物化学研究会
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/32—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to acyclic carbon atoms and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • 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

Definitions

  • the present invention relates to a reaction vessel useful for a continuous and anti-selective catalytic asymmetric nitroaldol reaction, a method for producing an optically active anti-1,2-nitroalkanol compound using the same, and a production apparatus.
  • optically active anti-1,2-nitroalkanol compound is useful as a precursor of the optically active anti-1,2-aminoalcohol compound.
  • Optically active anti-1,2-aminoalcohol compounds are widely used as chiral building blocks with extremely high utility in the field of organic synthetic chemistry, particularly pharmaceutical synthetic chemistry.
  • optically active anti-1,2-aminoalcohol compounds are contained as basic units in pharmaceuticals such as ⁇ -agonists and many natural physiologically active compounds.
  • optically active anti-1,2-nitroalkanol compound itself is also useful as a raw material compound for pharmaceuticals.
  • a compound represented by the following structural formula (anacetrapib) which is considered as a CETP (cholesteryl ester transfer protein) inhibitor, can be synthesized from an optically active anti-1,2-nitroalkanol compound (for example, Non-patent document 1).
  • anacetrapib racemic optically active anti-1,2-nitroalkanol compound is used, and anacetrapib is obtained through optical resolution.
  • a method of reacting various aldehyde compounds with a nitroalkane compound in the presence of an optically active tetraaminophosphonium salt as a method for producing the optically active anti-1,2-nitroalkanol compound antiselectively by catalytic asymmetric reaction Is known (see, for example, Non-Patent Document 2).
  • this method needs to be performed at an extremely low temperature of ⁇ 78 ° C., and has a problem that it cannot be applied as an industrial production method.
  • the present inventors have proposed a method for producing an optically active anti-1,2-nitroalkanol compound in an anti-selective manner by catalytic asymmetric reaction and a catalyst used in the reaction (see Patent Document 1). .
  • various aldehyde compounds and nitroalkane compounds are used as catalysts using a heterogeneous metal complex complex in which a specific amide compound is coordinated to a lanthanoid such as neodymium and an alkali metal such as sodium. Nitroaldol reaction using By doing so, an optically active anti-1,2-nitroalkanol compound is synthesized with high anti-selectivity and extremely high asymmetric yield.
  • the nitroaldol reaction proceeds rapidly even under cooling of about ⁇ 40 ° C.
  • the catalyst since the catalyst uses a rare metal such as neodymium, it is desirable that the catalyst can be reused. However, in the present situation, the catalyst cannot be reused.
  • the present inventors further proposed a novel catalyst in which the catalyst is supported on a carbon structure such as a carbon nanotube, and a method for producing an optically active anti-1,2-nitroalkanol compound using the catalyst.
  • a novel catalyst in which the catalyst is supported on a carbon structure such as a carbon nanotube, and a method for producing an optically active anti-1,2-nitroalkanol compound using the catalyst.
  • the present invention provides a production method and production apparatus capable of synthesizing an optically active anti-1,2-nitroalkanol compound in a highly anti-selective and extremely high asymmetric yield in a continuous manner, and a production apparatus thereof.
  • An object is to provide a reaction vessel.
  • the method for producing the optically active anti-1,2-nitroalkanol compound of the present invention comprises: A supply step of continuously supplying an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms to the reaction vessel; A reaction step of reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel to obtain an optically active anti-1,2-nitroalkanol compound; A discharge step of continuously discharging the optically active anti-1,2-nitroalkanol compound from the reaction vessel,
  • the reaction vessel includes a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure.
  • the apparatus for producing an optically active anti-1,2-nitroalkanol compound of the present invention comprises: Supply means for continuously supplying an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms to the reaction vessel; Reaction means for reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel; A discharge means for continuously discharging the optically active anti-1,2-nitroalkanol compound obtained by the reaction means from the reaction vessel;
  • the reaction vessel includes a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure.
  • the reaction vessel of the present invention is A reaction vessel used in any one of the method for producing the optically active anti-1,2-nitroalkanol compound of the present invention and the apparatus for producing the optically active anti-1,2-nitroalkanol compound of the present invention.
  • a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure is included.
  • the above-mentioned problems can be solved and the above-mentioned object can be achieved, and an optically active anti-1,2-nitroalkanol compound can be obtained with high antiselectivity and extremely high asymmetric yield. It is possible to provide a production method and a production apparatus that can be synthesized in a continuous manner, and a reaction vessel used for them.
  • FIG. 1 is a schematic diagram showing the reaction flow of Example 2.
  • FIG. 2 is a calibration curve of the amide type ligand 1.
  • FIG. 3 is a neodymium calibration curve.
  • FIG. 4 is a calibration curve for sodium.
  • the configuration in the chemical formulas and general formulas described in the present specification and claims represents an absolute configuration.
  • the “anti” configuration means that in the 1,2-nitroalkanol compound, a hydroxyl group and a nitro group are in an anti configuration.
  • the apparatus for producing an optically active anti-1,2-nitroalkanol compound of the present invention has at least supply means, reaction means, and discharge means, and further has other means as required.
  • the method for producing an optically active anti-1,2-nitroalkanol compound of the present invention includes at least a supply step, a reaction step, and a discharge step, and further includes other steps as necessary.
  • the reaction vessel of the present invention contains at least a catalyst. The reaction vessel is used in the method and apparatus for producing the optically active anti-1,2-nitroalkanol compound of the present invention.
  • Non-Patent Document 3 (Takanori Ogawa, Naoya Kumagai, and Masakatsu Shibasaki, Angew. Chem. Int. Ed. 2013, 52, 6196-6201) and Non-Patent Document 4 (Dulhak). and the catalyst proposed by Masakatsu Shibasaki, J. Org.
  • the catalytic active site and the support (carbon structure) are not covalently bound (note that In this regard, the present inventors have found that in the examples below, with dilute hydrochloric acid treatment, catalytic active site has been confirmed that easily desorbed from the carbon structure.).
  • the asymmetric synthesis reaction using a catalyst is performed in a continuous manner. Therefore, it is difficult for those skilled in the art to predict that the catalyst immobilized on the carbon structure can maintain the catalyst performance in the continuous asymmetric synthesis reaction. Therefore, those skilled in the art do not attempt to use the catalyst immobilized on the carbon structure in a continuous reaction.
  • the present inventors have conducted intensive studies, and as a result, even when the catalyst immobilized on the carbon structure was used in a continuous nitroaldol reaction, the catalytic active site was not detached from the carbon structure.
  • the present inventors have found that the catalyst performance of the catalyst immobilized on the carbon structure does not deteriorate, and have completed the present invention.
  • the method for producing the optically active anti-1,2-nitroalkanol compound can be suitably performed by the apparatus for producing the optically active anti-1,2-nitroalkanol compound, and the supplying step is preferably performed by the supplying means.
  • the reaction step can be preferably performed by the reaction means
  • the discharge step can be preferably performed by the discharge means
  • the other steps are preferably performed by the other means. Can be done.
  • the production method is a production method in which a continuous and anti-selective catalytic asymmetric nitroaldol reaction is performed, and the supply step and the discharge step are performed simultaneously.
  • the supply means is not particularly limited as long as it is a means for continuously supplying an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms to the reaction vessel, and can be appropriately selected according to the purpose.
  • a mixing member for mixing the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms a first supply member for supplying the aldehyde compound to the mixing member, and the nitroalkane compound having 2 or more carbon atoms.
  • Examples thereof include a supply means including a second supply member that supplies the mixing member and a connection member that connects the mixing member to the reaction vessel.
  • the supply step is not particularly limited as long as it is a step of continuously supplying an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms to the reaction vessel, and can be appropriately selected according to the purpose. For example, it can be performed by the supply means.
  • the mixing member is not particularly limited as long as it is a member that mixes the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms, and can be appropriately selected according to the purpose.
  • the mixer include an ultrasonic mixer, an ultrasonic mixer, and a static mixer.
  • the pipe joint include a T-type joint and a Y-type joint.
  • the first supply member and the second supply member include a pump.
  • the first supply member may include a moisture removing member that removes moisture contained in the aldehyde compound.
  • the moisture removing member include a desiccant.
  • the desiccant include molecular sieves.
  • the first supply member may include an impurity removal member that removes acidic impurities contained in the aldehyde compound. Examples of the impurity removing member include dry sodium bicarbonate.
  • the concentration of the aldehyde compound in the first supply member is not particularly limited. However, it is preferably 0.01M to 0.5M, more preferably 0.05M to 0.15M from the viewpoint of adjusting to an optimum flow rate.
  • the concentration can be adjusted with an organic solvent. Examples of the organic solvent include tetrahydrofuran, cyclopentyl methyl ether, diethyl ether, dichloromethane, ethyl acetate, and the like.
  • the amount of the liquid containing the aldehyde compound in the first supply member is not particularly limited and can be appropriately selected according to the purpose. 25 mL / hour to 300 mL / hour is preferable with respect to 1 mmol (neodymium standard) of the catalyst used, and 50 mL / hour to 100 mL / hour is more preferable.
  • the concentration of the nitroalkane compound having 2 or more carbon atoms in the second supply member (in other words, the concentration of the nitroalkane compound having 2 or more carbon atoms before being mixed with the aldehyde compound in the supplying step).
  • concentration can be adjusted with an organic solvent.
  • the organic solvent include tetrahydrofuran, cyclopentyl methyl ether, diethyl ether, dichloromethane, ethyl acetate, and the like.
  • the amount of the liquid containing the nitroalkane compound having 2 or more carbon atoms in the second supply member is not particularly limited and can be appropriately selected according to the purpose. In view of the above, 25 mL / hour to 300 mL / hour is preferable and 50 mL / hour to 100 mL / hour is more preferable with respect to 1 mmol (neodymium standard) of the catalyst used.
  • the aldehyde compound is not particularly limited as long as it is a compound having an aldehyde group, and can be appropriately selected according to the purpose. Examples thereof include aromatic aldehyde compounds and aliphatic aldehyde compounds.
  • the aliphatic group of the aliphatic aldehyde compound may have an aromatic ring.
  • the aldehyde compound may have a substituent. Examples of the substituent include an alkoxy group, a carboxyl group, a hydroxyl group, and a halogen atom.
  • the substituent may be protected by a protecting group.
  • the protecting group is not particularly limited and may be appropriately selected depending on the purpose. See, for example, Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. You can refer to such books.
  • Examples of the aromatic aldehyde compound include benzaldehyde, halogenobenzaldehyde, alkoxybenzaldehyde, alkylbenzaldehyde, naphthylaldehyde, and the like.
  • Examples of the halogenobenzaldehyde include chlorbenzaldehyde, iodobenzaldehyde, bromobenzaldehyde, and the like. Two or more halogen atoms may be substituted on the benzene ring.
  • Examples of the alkoxybenzaldehyde include methoxybenzaldehyde and ethoxybenzaldehyde.
  • Examples of the alkyl benzaldehyde include methyl benzaldehyde and ethyl benzaldehyde.
  • Examples of the aliphatic aldehyde compound include alkyl aldehyde and aralkyl aldehyde.
  • Examples of the alkyl aldehyde include butyraldehyde and cyclopropyl aldehyde.
  • Examples of the aralkyl aldehyde include 3-phenylpropanal, phenethyl aldehyde, and benzyl aldehyde.
  • the nitroalkane compound having 2 or more carbon atoms is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the nitroalkane compound having 2 or more carbon atoms may have a substituent in the alkyl group constituting the main chain. Examples of the substituent include an alkoxy group, a carboxyl group, a hydroxyl group, and a halogen atom.
  • the substituent may be protected by a protecting group.
  • the protecting group is not particularly limited and may be appropriately selected depending on the purpose. See, for example, Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. You can refer to such books.
  • the nitroalkane compound having 2 or more carbon atoms may contain an arbitrary number of double bonds or triple bonds in the alkyl chain.
  • the nitroalkane compound having 2 or more carbon atoms is preferably a compound represented by the following general formula (2), more preferably nitroethane.
  • R 2 represents an alkyl group having 1 to 20 carbon atoms which may have a substituent. Examples of the substituent include the above-described substituents.
  • the nitroalkane compound having 2 or more carbon atoms may be the same as or different from the nitroalkane compound used in preparing the catalyst.
  • the mixing ratio when mixing the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms is not particularly limited and can be appropriately selected according to the purpose.
  • the nitroalkane compound having 2 or more carbon atoms is preferably from 2 mol to 20 mol, more preferably from 3 mol to 10 mol, relative to 1 mol of the aldehyde compound.
  • the reaction means is not particularly limited as long as it is a means for reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel, and can be appropriately selected according to the purpose.
  • it has the said reaction container and a cooling member.
  • the reaction step is a step in which an optically active anti-1,2-nitroalkanol compound is obtained by reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel.
  • an optically active anti-1,2-nitroalkanol compound is obtained by reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel.
  • reaction step is performed after the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms are mixed in the supplying step.
  • reaction vessel contains a catalyst.
  • the inner diameter of the reaction vessel is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 2 mm to 20 mm, and more preferably 4 mm to 8 mm. The range of these inner diameters is a particularly preferable range when 0.024 mmol (neodymium standard) catalyst is used.
  • the length of the reaction vessel is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 20 mm to 200 mm, and more preferably 30 mm to 100 mm. These length ranges are particularly preferable when 0.024 mmol (neodymium standard) catalyst is used.
  • the reaction vessel may be, for example, a reaction port for supplying the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms to the reaction vessel, and the optically active anti-1,2-nitroalkanol compound.
  • a discharge port for discharging from the container. It is preferable that the discharge port has a discharge preventing member for preventing the catalyst from being discharged. Examples of the discharge preventing member include a filter.
  • the catalyst is obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure.
  • the catalyst is a complex of different metal complexes in which a compound represented by the following structural formula (1) is coordinated to neodymium (Nd) and sodium (Na).
  • the catalyst contains a compound represented by the following structural formula (1).
  • the nitroalkane compound may have a substituent in the alkyl group constituting the main chain.
  • the substituent include an alkoxy group, a carboxyl group, a hydroxyl group, and a halogen atom.
  • the substituent may be protected by a protecting group.
  • the protecting group is not particularly limited and may be appropriately selected depending on the purpose. See, for example, Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. You can refer to such books.
  • the nitroalkane compound may contain an arbitrary number of double bonds or triple bonds in the alkyl chain.
  • nitroalkane compound a compound represented by the following general formula (1) is preferable, and nitroethane is more preferable.
  • R 1 represents an alkyl group having 1 to 20 carbon atoms which may have a substituent. Examples of the substituent include the above-described substituents.
  • the amount of the nitroalkane compound relative to the compound represented by the structural formula (1) when preparing the catalyst is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the amount of the compound represented by 1) is preferably 300 parts by mass to 1,000 parts by mass, and more preferably 400 parts by mass to 500 parts by mass with respect to 100 parts by mass of the compound represented by 1).
  • the neodymium-containing compound is particularly limited as long as it is a compound that contains neodymium (Nd) and can provide neodymium coordinated by the compound represented by the structural formula (1) when the catalyst is formed.
  • Nd neodymium
  • NdO OCH (CH 3 ) 2
  • the amount of the neodymium-containing compound relative to the compound represented by the structural formula (1) when preparing the catalyst is not particularly limited and may be appropriately selected depending on the intended purpose. 0.4 mol to 1.6 mol in terms of neodymium is preferable, and 0.8 mol to 1.2 mol is more preferable with respect to 1 mol of the compound represented by 1).
  • the sodium-containing compound is not particularly limited as long as it contains sodium (Na) and can provide sodium coordinated by the compound represented by the structural formula (1) when the catalyst is formed. And can be appropriately selected depending on the purpose, and examples thereof include sodium bis (trimethylsilyl) amide.
  • the amount of the sodium-containing compound with respect to the compound represented by the structural formula (1) when preparing the catalyst is not particularly limited and may be appropriately selected depending on the intended purpose. 1.2 mol to 2.8 mol in terms of sodium is preferable, and 1.8 mol to 2.2 mol is more preferable with respect to 1 mol of the compound represented by 1).
  • Carbon structure-- The carbon structure is not particularly limited as long as it is a structure formed by an unsaturated six-membered ring network of carbon, and can be appropriately selected according to the purpose.
  • carbon nanotube, carbon nanohorn, graphene Etc Among these, carbon nanotubes are preferable.
  • the carbon nanotube may be a single wall nanotube (SWNT) having a single-layer structure or a multi-wall nanotube (MWNT) having a multilayer structure, but MWNT is preferable.
  • SWNT single wall nanotube
  • MWNT multi-wall nanotube
  • the carbon structure may be a commercial product.
  • Examples of commercially available carbon nanotubes include Baytubes (registered trademark) C70P and C150P manufactured by Bayer MaterialScience.
  • the amount of the carbon structure with respect to the compound represented by the structural formula (1) in preparing the catalyst is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the amount is preferably 50 parts by mass to 400 parts by mass and more preferably 100 parts by mass to 200 parts by mass with respect to 100 parts by mass of the compound represented by 1).
  • the amount is within the more preferable range, it is advantageous in that the reaction yield is excellent.
  • the catalyst may be prepared by mixing the compound represented by the structural formula (1), the nitroalkane compound, the neodymium-containing compound, the sodium-containing compound, and the carbon structure.
  • the compound represented by the structural formula (1) there is no restriction
  • Method A (method A) --- In this method, the treatment A1 in which the compound represented by the structural formula (1), the neodymium-containing compound, the sodium-containing compound, and the carbon structure are mixed, and the treatment A1 are further performed.
  • Method B (method B) --- In this method, the treatment B1 in which the compound represented by the structural formula (1), the neodymium-containing compound, the sodium-containing compound, and the nitroalkane compound are mixed, and the treatment B1 are further performed.
  • method A is preferable because it is excellent in reaction yield.
  • the compound represented by the structural formula (1), the neodymium-containing compound, and the sodium-containing compound are mixed in the presence of a solvent to obtain a cloudy suspension.
  • the solvent include tetrahydrofuran.
  • the carbon structure is added to the obtained suspension. If it does so, it will be in the state where the cloudy suspension and the black deposit (carbon structure) coexist.
  • the nitroalkane compound is added thereto and aging is performed. By doing so, the catalyst can be obtained. In this method, a black catalyst is obtained and is not clouded. This is considered because the complex is uniformly dispersed in the carbon structure.
  • the compound represented by the structural formula (1), the neodymium-containing compound, and the sodium-containing compound are mixed in the presence of a solvent to obtain a cloudy suspension.
  • the solvent include tetrahydrofuran.
  • the nitroalkane compound is added to the resulting suspension.
  • the carbon structure is added thereto, and aging is performed. By doing so, the catalyst can be obtained.
  • the resulting catalyst is observed to be black and cloudy due to the carbon structure. Since white turbidity is observed, the dispersion state of the complex in the carbon structure is considered to be lower than that of Method A.
  • the catalyst is solidified using the carbon structure, it is possible to prevent the catalyst from being discharged out of the reaction vessel on the liquid flow in the reaction vessel.
  • a catalytic active site is bonded to the carbon structure by a bond other than a covalent bond. Even in such a state, when the catalyst is subjected to the production method of the present invention (continuous reaction), the catalyst active site and the carbon structure are caused by the flow of the liquid in the reaction vessel. Are not separated and can be used in the production method of the present invention.
  • the amount of the catalyst in the reaction vessel is not particularly limited and may be appropriately selected depending on the purpose. From the viewpoint of reaction rate, the amount of the aldehyde compound supplied to the reaction vessel per hour The amount is preferably 10 mol% to 100 mol%, more preferably 15 mol% to 30 mol%, in terms of neodymium.
  • the temperature of the reaction in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably ⁇ 70 ° C. to ⁇ 30 ° C., more preferably ⁇ 60 ° C. to ⁇ 40 ° C.
  • the discharging means is not particularly limited as long as it is a means for continuously discharging the optically active anti-1,2-nitroalkanol compound obtained by the reaction means from the reaction vessel. You can choose.
  • the discharging step is not particularly limited as long as it is a step of continuously discharging the optically active anti-1,2-nitroalkanol compound from the reaction vessel, and can be appropriately selected according to the purpose. For example, it can be performed by the discharging means.
  • the discharge can be performed, for example, using the supply means and the flow of liquid in the supply process.
  • the optically active anti-1,2-nitroalkanol compound can be isolated by concentrating the discharged liquid.
  • the reaction can be carried out even if the amount of catalyst in the reaction is reduced to about 1/6 as compared with the batch reaction. Moreover, according to the present invention, the stereoselectivity in the reaction is equivalent to that in the batch type. Moreover, since this invention performs reaction by a continuous type, a reaction container can be made small. Therefore, the volume that requires temperature control is reduced, and temperature control is facilitated. In addition, according to the present invention, since the catalyst discharged from the reaction vessel does not contain the catalyst, the product can be isolated by distilling off the solvent in the solution under reduced pressure.
  • THF represents “tetrahydrofuran”.
  • NaHMDS represents “sodium bis (trimethylsilyl) amide”.
  • O i Pr represents an “isopropyloxy group”.
  • Example 1 Preparation of catalyst and reaction vessel> A magnetic stir bar was placed in a test tube with a 20 mL thread and dried in a vacuum. After allowing to cool, amide type ligand 1 (9.0 mg, 0.024 mmol) was added and vacuum dried at room temperature for about 15 minutes. After substituting with Ar gas, dry THF (0.7 mL) and Nd 5 O (O i Pr) 13 (0.2 M in THF: 120 ⁇ L, 0.024 mmol) were sequentially added dropwise with a syringe under ice cooling, and at room temperature. Stir for 15 minutes.
  • Celite (50 g) was suspended in THF (100 mL), filtered under reduced pressure, and further filtered through Celite with THF (100 mL). The obtained celite was dried under reduced pressure at 100 ° C. and 0.9 kPa for 8 hours to obtain dry celite. After adding dry celite (350 mg) to a 20 mL eggplant flask and adding THF (1 mL), the black suspension 1 was transferred while washing with 1 mL of THF to obtain a black suspension 2.
  • the black suspension 2 was packed in a column (diameter: 4.6 mm ⁇ length: 100 mm, manufactured by SUS) using THF (1 mL) to prepare a reaction vessel containing a catalyst.
  • Example 2 As shown in FIG. 1, a production apparatus having a first pump 1, a second pump 2, a mixer 3, a connecting member 4, and a catalyst column 5 was produced, and 1- (3-methoxyphenyl) -2-nitro A continuous synthesis of propan-1-ol was performed. Specifically, it is as follows.
  • Dry sodium bicarbonate (2.7 g) and dry molecular sieve (1.7 g, 3A, powder) were packed in columns (diameter 10 mm x length 30 mm, manufactured by SUS), respectively, and the first pump 1 (LC-A20 Manufactured by Shimadzu Corporation), a column 1A containing molecular sieves, and a column 1B containing sodium hydrogen carbonate were connected in series to obtain a first supply member. Then, it was degassed by flowing dry THF (1 mL per minute, 5 minutes).
  • a catalyst column 5 (reaction vessel prepared in Example 1) was installed downstream of the first supply member via a mixing member (mixer 3, HELIX type, SUS316, manufactured by YMC) and a connecting member 4.
  • a THF solution of 3-methoxybenzaldehyde (0.107M) is 1.5 mL / hour using the first pump 1, and a THF solution (1.07M) of nitroethane is 1.5 mL / hour using the second pump 2.
  • the liquid was sent.
  • the samples were collected from the 3rd to 24th hours and concentrated to obtain 1- (3-methoxyphenyl) -2-nitropropan-1-ol (677 mg, 3.2 mmol, yield 95%).
  • the anti / cin ratio measured using chiral HPLC (high performance liquid chromatography) was 96/4, and the optical purity was 93% ee.
  • the catalyst rotation number (TON) per mole equivalent of neodymium used for the catalyst was 133.
  • 1M hydrochloric acid 8 mL
  • ethyl acetate 10 mL
  • the obtained solution was analyzed under the conditions described later using an MP-AES spectrometer (manufactured by Agilent), and the contents of neodymium and sodium were calculated (neodymium: 0.021 mmol, sodium: 0.038 mmol).
  • the organic layer at the time of the liquid separation operation was concentrated, transferred to a 10 mL volumetric flask using acetonitrile to make 10 mL, and then HPLC measurement was performed under the above conditions to calculate the content of amide type ligand 1 (0 .019 mmol).
  • neodymium, sodium, and amide type ligand 1 were calculated for the removed supernatant (A) (neodymium: 0.005 mmol, sodium: 0.010 mmol, amide type ligand 1: 0.004 mmol).
  • the sum of the leakage amount of neodymium, sodium and amide type ligands from the catalyst and the supernatant (A) is almost equal to the amount used for the preparation of the catalyst, and this catalyst can be easily removed from the carbon structure with dilute hydrochloric acid. Desorption was confirmed.
  • HPLC LC-2000Plus, manufactured by JASCO Corporation
  • Mobile phase A 0.1% by volume trifluoroacetic acid aqueous solution
  • Mobile phase B 0.1% by volume trifluoroacetic acid acetonitrile solution
  • sample measurement- A sample to be quantified (sample prepared in the above-mentioned “confirmation of catalyst release by acid treatment”) was placed in a 10 mL volumetric flask, and acetonitrile was added to make 10 mL. Measurement was performed under the above HPLC conditions, and 1 amount of amide type ligand was calculated from the calibration curve.
  • neodymium standard stock solution (Nd1000, 1004 mg / L, manufactured by Kanto Chemical Co., Inc.), 1.0 mL, 0.75 mL, 0.50 mL, 0.25, 0 mL to 4 50 mL volumetric flasks, respectively, and add 1M hydrochloric acid.
  • a standard solution of 20 ppm, 15 ppm, 10 ppm, 5 ppm, and 0 ppm on a mass basis was prepared.
  • Each standard solution was analyzed with an Agilent 4100 MP-AES spectrometer (manufactured by Agilent), and a calibration curve of neodymium was prepared.
  • a calibration curve is shown in FIG.
  • Table 2 shows the intensity at each concentration.
  • the measurement conditions of Agilent 4100 MP-AES are shown below. ⁇ Measurement condition ⁇ Nebulizer pressure: 180 kPa to 240 kPa Reading time: 3 seconds Repeat count: 3 Stabilization time: 15 seconds Background correction: Auto
  • sample measurement The sample to be quantified (the sample prepared in the above-mentioned “confirmation of catalyst release by acid treatment”) is analyzed with the Agilent 4100 MP-AES spectrometer (manufactured by Agilent) under the above measurement conditions, and from the calibration curve of neodymium and sodium. Each content was calculated.
  • the production method, production apparatus, and reaction vessel of the present invention can synthesize optically active anti-1,2-nitroalkanol compounds in a continuous manner with high anti-selectivity and extremely high asymmetric yield. It can be suitably used in a method for producing an optically active anti-1,2-nitroalkanol compound useful as a raw material compound for pharmaceuticals.
  • the reaction vessel includes a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure.
  • ⁇ 2> The method for producing an optically active anti-1,2-nitroalkanol compound according to ⁇ 1>, wherein the nitroalkane compound in the catalyst is a compound represented by the following general formula (1).
  • R 1 represents an alkyl group having 1 to 20 carbon atoms which may have a substituent.
  • ⁇ 3> The method for producing an optically active anti-1,2-nitroalkanol compound according to any one of ⁇ 1> to ⁇ 2>, wherein the nitroalkane compound in the catalyst is nitroethane.
  • ⁇ 4> The method for producing an optically active anti-1,2-nitroalkanol compound according to any one of ⁇ 1> to ⁇ 3>, wherein the carbon structure is a carbon nanotube.
  • ⁇ 5> The method for producing an optically active anti-1,2-nitroalkanol compound according to any one of ⁇ 1> to ⁇ 4>, wherein the neodymium-containing compound is Nd 5 O (OCH (CH 3 ) 2 ) 13 It is.
  • ⁇ 6> The method for producing an optically active anti-1,2-nitroalkanol compound according to any one of ⁇ 1> to ⁇ 5>, wherein the sodium-containing compound is sodium bis (trimethylsilyl) amide.
  • Supply means for continuously supplying the aldehyde compound and the nitroalkane compound having 2 or more carbon atoms to the reaction vessel;
  • Reaction means for reacting the aldehyde compound with the nitroalkane compound having 2 or more carbon atoms in the reaction vessel;
  • a discharge means for continuously discharging the optically active anti-1,2-nitroalkanol compound obtained by the reaction means from the reaction vessel;
  • the reaction vessel includes a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure.
  • a reaction vessel used in any of the compound production apparatuses A reaction vessel comprising a catalyst obtained by mixing a compound represented by the following structural formula (1), a nitroalkane compound, a neodymium-containing compound, a sodium-containing compound, and a carbon structure. . ⁇ 9>
  • a reaction vessel supplies an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms to the reaction vessel, and an optically active anti-1,2-nitroalkanol compound is discharged from the reaction vessel. It is a reaction container as described in said ⁇ 8> which has a discharge port to do.

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Publication number Priority date Publication date Assignee Title
WO2017090569A1 (ja) * 2015-11-24 2017-06-01 公益財団法人微生物化学研究会 触媒、及びその製造方法、並びに光学活性アンチ－１，２－ニトロアルカノール化合物の製造方法
US10413892B2 (en) 2015-11-24 2019-09-17 Microbial Chemistry Research Foundation Catalyst, production method therefor, and method for producing optically active anti-1, 2-nitroalkanol compound

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