Method for producing ketone body of diacetone glucose and diacetone allose

Abstract

The purpose of the present disclosure is to provide a novel production method with which it is possible to produce a ketone body of diacetone glucose and diacetone allose in a relatively simple manner.　The present disclosure is a method for producing a solution containing a ketone body of diacetone glucose. The production method includes the following first to fourth steps.　The first step is a step for generating a first solution in which diacetone glucose is dissolved in an acetic acid ester.　The second step is a step in which a first aqueous solution containing an oxidizing agent is mixed with the first solution, and the diacetone glucose is oxidized into a ketone body thereof in the presence of an oxidation catalyst.　The third step is a step for separating a second solution after the oxidation reaction obtained in the second step into an organic solution and a second aqueous solution.　The fourth step is a step for obtaining the organic solution.

Description

Method for producing ketone bodies of diacetone glucose and diacetone allose

[0001] The present invention relates to a novel method for producing a ketone body of diacetone glucose and a novel method for producing diacetone allose.

[0002] Monosaccharides are broadly classified into aldoses with polyhydroxyl aldehyde structures, ketoses with polyhydroxyl ketone structures, and sugar alcohols obtained by reducing these aldoses. Monosaccharides are also classified by their abundance in nature. According to the International Rare Sugar Society's definition, rare sugars are "sugars that are rarely found in nature," and are monosaccharides found in low abundance in nature. Rare sugars generally result in low yields in organic chemical synthesis reactions. For this reason, many rare sugars have unknown properties, even among rare aldohexoses (hexose aldoses), including D-allose. D-allose is used in supplements because it is approximately 80% as sweet as sugar and contains almost no calories. D-allose is also known to inhibit cancer cell proliferation, and its use in the pharmaceutical field is anticipated.

[0003] As described in Non-Patent Document 1 (Carbohydrate Research 24 (1972), pp. 192-197), for example, D-allose can be produced from diacetone-D-glucose as a starting material via intermediates such as the ketone body of diacetone-D-glucose and diacetone allose. In the production of carbohydrates such as D-allose and its intermediates, a method for producing D-allose by biochemical carbohydrate conversion using enzymes, as described in Patent Document 1 (JP 2002-17392 A), for example, has the advantages of mild reaction conditions and a short reaction time. However, it requires the use of rare sugars as starting materials, which makes them expensive, requires specialized equipment for purification, and requires time-consuming and expensive maintenance of the production equipment.

[0004] D-Allose and its intermediates can also be produced by organic chemical methods, but organic chemical synthesis methods generally require harsh production conditions and result in low yields of the target carbohydrates, making them unsuitable for industrial production.

[0005] First, regarding the oxidation of the hydroxyl groups of carbohydrates to ketone groups, for example, Non-Patent Document 2 (Tetrahedron, 1987, 43, pp. 3095-3108) discloses oxidation by chromic acid oxidation. Because chromic acid is used as the oxidizing agent, the solvent is limited to halogen-based solvents, which are difficult to use from the viewpoint of environmental impact. Furthermore, this document uses an equivalent or more amount of hexavalent chromium (pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC)), a heavy metal. Tar-like by-products are generated in the reaction system, and the operation of removing them in post-treatment is complicated, making it difficult to scale up. Furthermore, because heavy metals are used, it is necessary to comply with regulations on residual metals. In Non-Patent Document 2, oxidation is carried out using a ruthenium catalyst. A catalytic amount of ruthenium tetroxide RuO ４ and potassium periodate KIO as an oxidizing agent. ４ In this document, the solvent used is chloroform, which is difficult to use from the viewpoint of environmental impact. Furthermore, since heavy metals are used, it is necessary to clear regulations on residual metals.

[0006] In Non-Patent Document 3 (Org. Proc. Res. Dev. 2004, 8, 5, pp. 777-780), oxidation is performed by Swern oxidation. The oxidation is carried out using DMSO as the solvent and an equivalent amount of acetic anhydride or oxalyl chloride. The yield of the final product from the entire process, including the reduction step, is low at approximately 60%. Furthermore, because the by-product dimethyl sulfide is a malodorous substance, strict odor control measures are essential. Furthermore, the solvent used, DMSO, is highly polar and has a high boiling point, making it difficult to remove by distillation. Extraction is only possible after dilution with a large amount of water, presenting significant challenges in post-processing operability. In Non-Patent Document 3, phosphorus pentoxide is used as the oxidizing agent during oxidation, improving the operability of the post-processing portion, thereby increasing the yield of the final product from the entire process, including the reduction step, to 73%. However, due to the use of phosphorus pentoxide, strict odor control measures are still required.

[0007] In Patent Document 2 (JP 2022-88661 A), alcohols are oxidized using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical). Specifically, a halogen-based solvent is used, N-bromosuccinimide (NBS) is used as an oxidizing agent, and a catalytic amount of TEMPO (5 mol%) is used for oxidation. The challenges here are reducing the amount of catalyst and separating by-products generated from the oxidizing agent.

[0008] In Patent Document 3 (WO 2019 / 224172), alcohols are oxidized using an acetate ester solvent, a 5% aqueous solution of sodium hypochlorite as an oxidizing agent, and a catalytic amount of TEMPO (5 mol%). The challenge here is also to reduce the amount of catalyst.

[0009] In Non-Patent Document 4 (Org. Lett. 2015, 17, pp. 828-831), a carbohydrate is oxidized to its ketone form using a halogenated solvent, a 5% aqueous solution of sodium hypochlorite as an oxidizing agent, and a catalytic amount of nor-AZADO (9-azanoradamantane-N-oxyl) (0.0051 mol%). The challenge here is to avoid the use of halogenated solvents.

[0010] Furthermore, organic chemical methods also have problems with reducing ketone bodies of carbohydrates. For example, Non-Patent Documents 1 and 4 disclose that NaBH is used as a reducing agent. ４ The reduction is carried out using a solvent such as methanol / THF, water / ethanol, water / DMSO, or water / methyl tert-butyl ether. While these methods use solvent combinations such as methanol / THF, water / ethanol, water / DMSO, and water / methyl tert-butyl ether, they all suffer from the drawback of time-consuming procedures and difficulty in controlling the reaction due to the intense foaming that occurs when the reducing agent is added to the reaction mixture. Furthermore, an excessive amount of reducing agent is required. Furthermore, only cyclohexane is used as the recrystallization solvent, which poses safety and environmental issues, and also results in poor recovery rates of the final product.

[0011] JP 2002-17392 A JP 2022-88661 A International Publication No. 2019 / 224172

[0012] Carbohydrate Research 24 (1972), pp. 192-197 Tetrahedron 1987, 43, pp. 3095-3108 Org. Proc. Res. Dev. 2004, 8, 5, pp. 777-780 Org. Lett. 2015, 17, pp. 828-831

[0013] As described above, conventional organic chemical methods for producing D-allose and its intermediates require harsh production conditions, produce low yields of the target carbohydrates, and have safety and environmental concerns, making them unsuitable for industrial production. On the other hand, methods for producing D-allose intermediates by enzymatic carbohydrate conversion are advantageous in terms of yield and efficiency, but have the difficult-to-solve problem of high cost. Therefore, it is desirable to provide an organic synthesis method that can produce D-allose intermediates safely, inexpensively, and with high purity and yield.

[0014] Therefore, an object of the present invention is to provide a novel production method that can relatively easily produce both the ketone body of diacetone glucose and diacetone allose.

[0015] The present disclosure includes the following aspects.

[0016] (Disclosure 1-1) Disclosure 1-1 is a method for producing a ketone body-containing solution of diacetone glucose. The production method of Disclosure 1-1 includes the following first to fourth steps. The first step is a step of producing a first solution by dissolving diacetone glucose in acetic acid ester. The second step is a step of mixing the first solution with a first aqueous solution containing an oxidizing agent and oxidizing the diacetone glucose to ketone bodies in the presence of an oxidation catalyst. The third step is a step of separating the second solution after the oxidation reaction obtained in the second step into an organic solution and a second aqueous solution. The fourth step is a step of obtaining the organic solution.

[0017] (Disclosure 1-2) Disclosure 1-2 relates to the production method of Disclosure 1-1, in which the acetate ester is ethyl acetate.

[0018] (Disclosure 1-3) Disclosure 1-3 relates to the manufacturing method of Disclosure 1-1 or Disclosure 1-2, in which the oxidizing agent is hypochlorous acid or a salt thereof, or molecular oxygen.

[0019] (Disclosure 1-4) Disclosure 1-4 is the manufacturing method according to any one of Disclosures 1-1 to 1-3, wherein the oxidizing agent is sodium hypochlorite.

[0020] (Disclosure No. 1-5) Disclosure No. 1-5 relates to the manufacturing method of Disclosure No. 1-4, wherein the sodium hypochlorite is a pentahydrate.

[0021] (Disclosure No. 1-6) Disclosure No. 1-6 relates to the manufacturing method according to any one of Disclosures No. 1-1 to No. 1-5, wherein the oxidation catalyst is an organic nitroxyl radical-based oxidation catalyst.

[0022] (Disclosure No. 1-7) Disclosure No. 1-7 is a manufacturing method according to any one of Disclosures No. 1-1 to No. 1-6, wherein the oxidation catalyst is nor-AZADO, 2-azaadamantane-N-oxyl (AZADO), 2-hydroxy-2-azaadamantane (AZADOL), [4-hydroxy-TEMPO + NaCl] / SiO ２ At least one selected from the group consisting of:

[0023] (Disclosure No. 1-8) Disclosure No. 1-8 relates to the production method according to any one of Disclosures No. 1-1 to No. 1-7, wherein the amount of the oxidation catalyst added is 0.001 mol % to 1 mol % with respect to the diacetone glucose.

[0024] (Disclosure No. 1-9) Disclosure No. 1-9 relates to the production method according to any one of Disclosures No. 1-1 to No. 1-8, wherein the organic solution contains a mixture of ketone bodies and hydrates of diacetone glucose, and the ratio of the ketone bodies to the hydrates is 3:1 to 7:1.

[0025] (Disclosure No. 1-10) Disclosure No. 1-10 is a method for producing ketone bodies from diacetone glucose, which are obtained by concentrating a ketone body-containing solution obtained by any one of the production methods of Disclosure No. 1-1 to Disclosure No. 1-9.

[0026] (Disclosure No. 1-11) Disclosure No. 1-11 is a method for producing diacetone allose. The production method of Disclosure No. 1-11 includes the following fifth and sixth steps. The fifth step is a step of suspending a reducing agent in a lower alcohol to produce a suspension. The sixth step is a step of mixing a ketone body-containing solution obtained by any one of the production methods of Disclosures No. 1-1 to No. 1-8 above with the suspension of the fifth step, and reducing the ketone body to diacetone allose.

[0027] (Disclosure No. 1-12) Disclosure No. 1-12 is a step in which, in the mixing step of the production method of Disclosure No. 1-11, a ketone body-containing solution obtained by any one of the production methods of Disclosures No. 1-1 to No. 1-8 is added dropwise to the suspension of Step 5 while stirring the suspension.

[0028] (Disclosure No. 1-13) Disclosure No. 1-13 is the production method according to Disclosure No. 1-11 or Disclosure No. 1-12, further comprising the following steps: a step of dissolving diacetone allose produced by the reduction reaction in a first organic solvent to produce a dissolved solution, and a step of mixing the dissolved solution with a heptane solution containing diacetone allose seed crystals to crystallize the diacetone allose.

[0029] (Disclosure No. 1-14) Disclosure No. 1-14 relates to the production method according to Disclosure No. 1-13, wherein the first organic solvent is selected from the group consisting of esters, ethers, hydrocarbons, ketones, alcohols, and cyano compounds.

[0030] (Disclosure No. 1-15) Disclosure No. 1-15 relates to the production method according to Disclosure No. 1-13 or Disclosure No. 1-14, wherein the first organic solvent is toluene or ethyl acetate.

[0031] (Disclosure No. 1-16) Disclosure No. 1-16 relates to the production method of any one of Disclosures No. 1-1 to No. 1-15, wherein the diacetone glucose is produced by a method including the following steps: a first dissolution step of mixing glucose, an aprotic polar solvent in which the glucose is soluble, and acetonide to produce a solution; a first reaction step of adding a Lewis acid or protonic acid catalyst that promotes the reaction between the glucose and the acetonide to the solution to produce a reaction solution; and a first neutralization step of neutralizing the reaction solution by adding a third aqueous solution containing a neutralizing agent to the reaction solution.

[0032] (Disclosure No. 1-17) Disclosure No. 1-17 is the manufacturing method according to Disclosure No. 1-16, wherein the catalyst is iron chloride or aluminum chloride, and in the first neutralization step, the third aqueous solution further contains a gelation inhibitor.

[0033] (Disclosure No. 1-18) Disclosure No. 1-18 relates to the production method according to Disclosure No. 1-16 or Disclosure No. 1-17, wherein the aprotic polar solvent is at least one selected from the group consisting of acetone, tetrahydrofuran, and ethyl acetate.

[0034] (Disclosure No. 1-19) Disclosure No. 1-19 relates to the production method according to any one of Disclosures No. 1-16 to No. 1-18, wherein the acetonide is at least one selected from the group consisting of acetone, dimethoxypropane, 2-methoxypropene, and 2-chloropropene.

[0035] (Disclosure No. 1-20) Disclosure No. 1-20 relates to the manufacturing method of any one of Disclosures No. 1-17 to No. 1-19, wherein the gelation inhibitor is Rochelle salt or trisodium citrate.

[0036] (Disclosure No. 1-21) Disclosure No. 1-21 relates to the manufacturing method according to any one of Disclosures No. 1-16 to No. 1-20, wherein the Lewis acid catalyst is iron chloride, iron chloride hexahydrate (FeCl ３ ・6H ２ O), zinc chloride, zinc chloride (ZnCl ２ ) and phosphoric acid (H ３ P.O. ４ ), aluminum chloride, magnesium sulfate, tetrabutylammonium tribromide ((n-Bu) ４ N ＋ Br ３ － ), montmorillonite, mordenite, titanosilicate (TS-1), and lanthanide fluorides such as ytterbium(III) trifluoromethanesulfonate (Yb(OTf)), scandium(III) trifluoromethanesulfonate (Sc(OTf)), lanthanum(III) trifluoromethanesulfonate (La(OTf)). ３ ), cerium(III) trifluoromethanesulfonate (Ce(OTf) ３ ), europium(III) trifluoromethanesulfonate (Eu(OTf) ３ ), and gadolinium(III) trifluoromethanesulfonate (Gd(OTf)3).

[0037] Disclosure No. 1-22 relates to the production method of any one of Disclosures No. 1-16 to No. 1-20, wherein the protonic acid catalyst is at least one selected from the group consisting of a combination of iodine and isopropanol, a compound represented by the following general formula (1), and silica gel-supported sulfuric acid. An example of the compound represented by the following general formula (1) is commercially available Amberlyst (registered trademark) 15.

[0038] (Disclosure No. 1-23) Disclosure No. 1-23 is the manufacturing method according to any one of Disclosures No. 1-16 to No. 1-22, wherein the neutralizing agent is at least one selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and aqueous ammonia.

[0039] (Disclosure No. 1-24) Disclosure No. 1-24 relates to the production method of any one of Disclosures No. 1-16 to No. 1-23, wherein solid glucose remains when the reaction solution is produced in the first reaction step, and the diacetone glucose is produced by a method further including the following steps: a separation step of performing solid-liquid separation of the remaining solid glucose and the reaction solution prior to the first neutralization step; a second dissolution step of mixing the separated solid glucose, an aprotic polar solvent in which the glucose is soluble, and acetonide to produce a solution; a second reaction step of adding a catalyst that promotes the reaction between glucose and acetonide to the solution produced in the second dissolution step to produce a reaction solution; and a second neutralization step of neutralizing the reaction solution by adding a third aqueous solution containing a gelation inhibitor and a neutralizing agent to the reaction solution.

[0040] (Disclosure No. 1-25) Disclosure No. 1-25 is the manufacturing method of Disclosure No. 1-24, wherein the catalyst is iron chloride or aluminum chloride, and in the first neutralization step, the third aqueous solution further contains a gelation inhibitor.

[0041] (Disclosure No. 1-26) Disclosure No. 1-26 is the manufacturing method according to Disclosure No. 1-24 or Disclosure No. 1-25, wherein the reaction solution produced in the first reaction step is a saturated solution.

[0042] (Disclosure No. 1-27) Disclosure No. 1-27 is the manufacturing method of any one of Disclosures No. 1-24 to No. 1-26, in which the first dissolving step, the first reacting step, the separating step, and the first neutralizing step are repeated before the second dissolving step.

[0043] (Disclosure No. 1-28) Disclosure No. 1-28 is the production method according to any one of Disclosures No. 1-24 to No. 1-27, wherein the second reaction step is a step of eliminating the remaining glucose.

[0044] (Disclosure No. 1-29) Disclosure No. 1-29 relates to the production method of any one of Disclosures No. 1-24 to No. 1-28, further comprising a solvent removal step. The solvent removal step removes the aprotic polar solvent from the reaction solution after the neutralization step. The aprotic polar solvent removed in the solvent removal step is used as the aprotic polar solvent in at least one of the first dissolving step and the second dissolving step.

[0045] (Disclosure No. 1-30) Disclosure No. 1-30 is the manufacturing method according to any one of Disclosures No. 1-24 to No. 1-29, further comprising a solvent removing step and a drying step. The solvent removing step removes the aprotic polar solvent from the reaction solution after the neutralization step. The drying step dries the organic matter after the aprotic polar solvent has been removed in the solvent removing step.

[0046] (Disclosure No. 1-31) Disclosure No. 1-31 is the production method according to any one of Disclosures No. 1-16 to No. 1-23, further comprising a removal step of removing water and / or the aprotic polar solvent from the reaction solution after the first neutralization step.

[0047] Disclosure No. 1-32 relates to the manufacturing method of Disclosure No. 1-31, wherein the removing step is carried out by utilizing the following reflux water removal reaction apparatus. The reflux water removal reaction apparatus includes a reaction tank for carrying out the first dissolving step, the first reacting step, and the first neutralizing step, a water separator provided with a membrane that is permeable to water vapor but not to the aprotic polar solvent, and that is connected to a vacuum pump and a cold trap, and a cooler.

[0048] (Disclosure No. 1-33) Disclosure No. 1-33 relates to the manufacturing method of Disclosure No. 1-32, wherein the water separator is cylindrical with closed ends and is installed between the reaction vessel and the cooler. The inner tube of the water separator is connected to the vacuum pump via the cold trap. The water separator is provided with a membrane that is permeable to water vapor but not to the aprotic polar solvent. By operating the vacuum pump, the water vaporized from the reaction vessel passes through the water separator, the inside of which is placed in a negative pressure state, and is removed as water or ice into the cold trap. Meanwhile, the aprotic polar solvent vaporized from the reaction vessel is condensed in the cooler and returned to the reaction vessel, whereby it can be used as the aprotic polar solvent in the first dissolution step.

[0049] (Disclosure No. 1-34) Disclosure No. 1-34 relates to the manufacturing method according to Disclosure No. 1-32 or Disclosure No. 1-33, wherein the membrane is a zeolite membrane.

[0050] (Disclosure No. 1-35) Disclosure No. 1-35 relates to the manufacturing method of Disclosure No. 1-31, wherein the removing step is carried out by utilizing the following apparatus. The apparatus includes a reaction tank for carrying out the first dissolving step, the first reacting step, and the first neutralizing step, a pipe equipped with a cooling means, a vacuum pump, and a recovery vessel. Here, the reaction tank is fluidly connected to the vacuum pump and the recovery vessel via the pipe. The moisture and the aprotic polar solvent vaporized from the reaction tank are removed by being liquefied via the cooling means through the pipe, which is put into a negative pressure state by operating the vacuum pump.

[0051] Disclosure No. 1-36 relates to the manufacturing method of Disclosure No. 1-35, wherein the apparatus further includes a dropping funnel connected to the reaction vessel for adding an aprotic polar solvent. The aprotic polar solvent is mixed into the reaction vessel from the dropping funnel, and is used as the aprotic polar solvent in the first dissolution step.

[0052] (Disclosure No. 1-37) Disclosure No. 1-37 is the production method according to any one of Disclosures No. 1-24 to No. 1-30, further comprising a removal step of removing water and / or the aprotic polar solvent from the reaction solution after the first neutralization step and / or the second neutralization step.

[0053] Disclosure No. 1-38 relates to the manufacturing method of Disclosure No. 1-37, wherein the removing step is carried out by utilizing the following reflux water removal reaction apparatus. The reflux water removal reaction apparatus includes a reaction tank for carrying out the first and second dissolving steps, the first and second reacting steps, and the first and second neutralizing steps, a water separator provided with a membrane that is permeable to water vapor but not to the aprotic polar solvent, and that is connected to a vacuum pump and a cold trap, and a cooler.

[0054] (Disclosure No. 1-39) Disclosure No. 1-39 relates to the manufacturing method of Disclosure No. 1-38, wherein the water separator is cylindrical with closed ends and is installed between the reaction vessel and the cooler. The inner tube of the water separator is connected to the vacuum pump via the cold trap. The water separator is provided with a membrane that is permeable to water vapor but not to the aprotic polar solvent. The water vaporized from the reaction vessel in this manner is removed as water or ice into the cold trap through the water separator, the inside of which is placed under negative pressure by operating the vacuum pump. Meanwhile, the aprotic polar solvent vaporized from the reaction vessel is condensed in the cooler and returned to the reaction vessel, allowing it to be used as the aprotic polar solvent in at least one of the first dissolution step and the second dissolution step.

[0055] (Disclosure No. 1-40) Disclosure No. 1-40 relates to the manufacturing method according to Disclosure No. 1-38 or Disclosure No. 1-39, wherein the membrane is a zeolite membrane.

[0056] (Disclosure No. 1-41) Disclosure No. 1-41 relates to the manufacturing method of any one of Disclosures No. 1-38 to No. 1-40, wherein the removing step is carried out by utilizing the following apparatus. The apparatus includes a reaction vessel for carrying out the first and second dissolving steps, the first and second reacting steps, and the first and second neutralizing steps, a pipe equipped with a cooling means, a vacuum pump, and a recovery vessel. Here, the reaction vessel is fluidly connected to the vacuum pump and the recovery vessel via the pipe. The moisture and the aprotic polar solvent vaporized from the reaction vessel are removed by being liquefied via the cooling means through the pipe, which is brought to a negative pressure state by operating the vacuum pump.

[0057] Disclosure No. 1-42 relates to the manufacturing method of Disclosure No. 1-41, wherein the apparatus further includes a dropping funnel connected to the reaction vessel for adding an aprotic polar solvent. The aprotic polar solvent is dropped into the reaction vessel from the dropping funnel and is used as the aprotic polar solvent in at least one of the first dissolving step and the second dissolving step.

[0058] Disclosure No. 1-43 is a reflux dehydration reaction apparatus that includes a reaction tank containing a reaction solution, a water separator that is provided with a membrane that is permeable to water vapor but not to aprotic polar solvents and is connected to a vacuum pump and a cold trap, and a cooler.

[0059] (Disclosure No. 1-44) Disclosure No. 1-44 relates to the reflux water removal reaction apparatus of Disclosure No. 1-43, wherein the water separator is cylindrical with closed ends and is installed between the reaction vessel and the condenser. The inner pipe of the water separator is connected to the vacuum pump via the cold trap. The water separator is provided with a membrane that is permeable to water vapor but not to aprotic polar solvents. By operating the vacuum pump, the water vaporized from the reaction vessel in this manner passes through the water separator, the inside of which is placed in a negative pressure state, and is removed as water or ice into the cold trap. Meanwhile, the aprotic polar solvent vaporized from the reaction vessel is condensed in the condenser and returned to the reaction vessel.

[0060] (Disclosure No. 1-45) Disclosure No. 1-45 is the device according to Disclosure No. 1-43 or Disclosure No. 1-44, wherein the membrane is a zeolite membrane.

[0061] (Disclosure No. 1-46) Disclosure No. 1-46 is a solvent replacement apparatus. The apparatus includes a reaction tank containing a reaction solution, a pipe equipped with a cooling means, a vacuum pump, a collector, and a dropping funnel connected to the reaction tank and containing a solvent. Here, the reaction tank is fluidly connected to the vacuum pump and the collector via the pipe. The solvent vaporized from the reaction solution in the reaction tank is removed by passing through the pipe, which is placed in a negative pressure state by operating the vacuum pump, and being liquefied via the cooling means. The solvent in the dropping funnel is dropped into the reaction tank as the solvent for the reaction solution in the reaction tank, replacing the solvent of the reaction solution in the reaction tank.

[0062] (Disclosure 2-1) Disclosure 2-1 is a method for producing diacetone allose. The production method of Disclosure 2-1 includes the following first to third steps. The first step is a step of preparing a ketone body-containing solution in which ketone bodies of diacetone glucose are dissolved in an organic solvent. The second step is a step of suspending a reducing agent in a lower alcohol to produce a suspension. The third step is a step of adding the ketone body-containing solution from the first step dropwise to the suspension from the second step while stirring the suspension, thereby reducing the ketone bodies of diacetone glucose to diacetone allose.

[0063] (Disclosure 2-2) Disclosure 2-2 relates to the production method of Disclosure 2-1, in which the solution for dissolving the ketone body is acetic acid ester or tetrahydrofuran.

[0064] (Disclosure 2-3) Disclosure 2-3 relates to the production method according to Disclosure 2-1 or 2-2, in which the acetate ester is ethyl acetate.

[0065] (Disclosure No. 2-4) Disclosure No. 2-4 is the manufacturing method according to any one of Disclosures No. 2-1 to No. 2-3, wherein the reducing agent is sodium borohydride.

[0066] (Disclosure No. 2-5) Disclosure No. 2-5 is the production method according to any one of Disclosures No. 2-1 to No. 2-4, wherein the lower alcohol is ethanol.

[0067] (Disclosure No. 2-6) Disclosure No. 2-6 is the production method of No. 2-5, in which the ethanol is 98 to 100% by volume ethanol.

[0068] (Disclosure No. 2-7) Disclosure No. 2-7 is the production method according to any one of Disclosures No. 2-1 to No. 2-6, further comprising the following steps: a step of dissolving diacetone allose produced by the reduction reaction in Step No. 3 in a first organic solvent to produce a solution, and a step of mixing the solution with a heptane solution containing diacetone allose seed crystals to crystallize the diacetone allose.

[0069] (Disclosure No. 2-8) Disclosure No. 2-8 includes the following steps 1-1 to 1-4 in the first step in the manufacturing methods disclosed in Disclosures No. 2-1 to 2-7. Step 1-1 is a step of producing a 1-1 solution by dissolving diacetone glucose in acetic acid ester. Step 1-2 is a step of mixing a first aqueous solution containing an oxidizing agent with the solution from Step 1-1, and oxidizing the diacetone glucose to its ketone body in the presence of an oxidation catalyst. Step 1-3 is a step of separating the post-oxidation solution obtained in Step 1-2 into an organic solution and a second aqueous solution. Step 1-4 is a step of obtaining the organic solution.

[0070] (Disclosure No. 2-9) Disclosure No. 2-9 relates to the production method of Disclosure No. 2-8, in which the acetate ester is ethyl acetate.

[0071] (Disclosure No. 2-10) Disclosure No. 2-10 relates to the manufacturing method of Disclosure No. 2-8 or 2-9, wherein the oxidizing agent is sodium hypochlorite.

[0072] (Disclosure No. 2-11) Disclosure No. 2-11 relates to the manufacturing method of any one of Disclosures No. 2-8 to No. 2-10, wherein the sodium hypochlorite is a pentahydrate.

[0073] (Disclosure No. 2-12) Disclosure No. 2-12 relates to the manufacturing method according to any one of Disclosures No. 2-8 to No. 2-11, wherein the oxidation catalyst is an organic nitroxyl radical-based oxidation catalyst.

[0074] (Disclosure No. 2-13) Disclosure No. 2-13 is the manufacturing method according to any one of Disclosures No. 2-8 to No. 2-12, wherein the oxidation catalyst is nor-AZADO, AZADO, 2-hydroxy-2-azaadamantane (AZADOL), [4-hydroxy-TEMPO + NaCl] / SiO ２ At least one selected from the group consisting of:

[0075] (Disclosure No. 2-14) Disclosure No. 2-14 is the production method according to any one of Disclosures No. 2-8 to No. 2-13, wherein the amount of the oxidation catalyst added is 0.001 mol % to 1 mol % with respect to diacetone glucose.

[0076] Disclosure No. 2-15 relates to the manufacturing method of any one of Disclosures No. 2-8 to No. 2-14, wherein the organic solution contains a mixture of ketone bodies and hydrates of diacetone glucose, and the ratio of the ketone bodies to the hydrates is 3:1 to 7:1.

[0077] (Disclosure 3-1) Disclosure 3-1 is a method for producing diacetone allose. The production method of Disclosure 3-1 includes the following first to sixth steps. The first step is a step of producing a first solution by dissolving diacetone glucose in an acetate ester. The second step is a step of mixing the first solution with a first aqueous solution containing an oxidizing agent and oxidizing the diacetone glucose to its ketone body in the presence of an oxidation catalyst. The third step is a step of separating the second solution after the oxidation reaction obtained in the second step into an organic solution and a second aqueous solution. The fourth step is a step of obtaining the organic solution. The fifth step is a step of suspending a reducing agent in a lower alcohol to produce a suspension. The sixth step is a step of adding the organic solution obtained in the fourth step dropwise to the suspension of the fifth step while stirring the suspension, and reducing the ketone body of diacetone glucose to diacetone allose.

[0078] (Disclosure 3-2) Disclosure 3-2 relates to the production method of disclosure 3-1, in which the acetate ester is ethyl acetate.

[0079] (Disclosure 3-3) Disclosure 3-3 is the manufacturing method according to disclosure 3-1 or 3-2, wherein the oxidizing agent is sodium hypochlorite.

[0080] (Disclosure 3-4) Disclosure 3-4 is the manufacturing method according to any one of Disclosures 3-1 to 3-3, wherein the sodium hypochlorite is a pentahydrate.

[0081] (Disclosure No. 3-5) Disclosure No. 3-5 is the manufacturing method according to any one of Disclosures No. 3-1 to No. 3-4, wherein the oxidation catalyst is an organic nitroxyl radical-based oxidation catalyst.

[0082] (Disclosure No. 3-6) Disclosure No. 3-6 is a manufacturing method according to any one of the above-mentioned disclosures No. 3-1 to No. 3-5, wherein the oxidation catalyst is nor-AZADO, AZADO, 2-hydroxy-2-azaadamantane (AZADOL), [4-hydroxy-TEMPO + NaCl] / SiO ２ At least one selected from the group consisting of:

[0083] (Disclosure No. 3-7) Disclosure No. 3-7 relates to the production method according to any one of Disclosures No. 3-1 to No. 3-6, wherein the amount of the oxidation catalyst added is 0.001 mol % to 1 mol % with respect to diacetone glucose.

[0084] Disclosure No. 3-8 relates to the manufacturing method of any one of Disclosures No. 3-1 to No. 3-7, wherein the organic solution contains a mixture of ketone bodies and hydrates of diacetone glucose, and the ratio of the ketone bodies to the hydrates is 3:1 to 7:1.

[0085] (Disclosure No. 3-9) Disclosure No. 3-9 relates to the manufacturing method according to any one of Disclosures No. 3-1 to No. 3-8, wherein the reducing agent is sodium borohydride.

[0086] (Disclosure No. 3-10) Disclosure No. 3-10 relates to the production method according to any one of Disclosures No. 3-1 to No. 3-9, wherein the lower alcohol is ethanol.

[0087] (Disclosure No. 3-11) Disclosure No. 3-11 relates to the production method according to any one of Disclosures No. 3-1 to No. 3-10, wherein the ethanol is 98 to 100% by volume ethanol.

[0088] (Disclosure No. 3-12) Disclosure No. 3-12 relates to the production method of any one of Disclosures Nos. 3-1 to 3-11, further comprising the following steps: a step of dissolving diacetone allose produced by the reduction reaction of Step No. 6 in a first organic solvent to produce a solution, and a step of mixing the solution with a heptane solution containing seed crystals of diacetone allose to crystallize the diacetone allose.

[0089] According to the production method of the present invention, it is possible to produce each of the ketone body of diacetone glucose and diacetone allose in high yields relatively simply, safely, and under environmentally friendly conditions.

[0090] FIG. 1 is a flow diagram of a method for producing ketone bodies from diacetone glucose according to one embodiment of the present invention, up to the point at which a solution containing ketone bodies is obtained. FIG. 2 is a flow diagram of a method for producing diacetone allose according to another embodiment of the present invention, up to the point at which crystals of diacetone allose are obtained. FIG. 3 is a reflux dehydration reactor equipped with a reaction vessel containing a reaction solution, a water separator equipped with a zeolite membrane and connected to a vacuum pump and a cold trap, and a cooler. FIG. 4 is a dehydration reactor equipped with a reaction vessel, a pipe equipped with a cooling means, a vacuum pump, a recovery vessel, and a dropping funnel. FIG. 5 is a graph showing the relationship between the amount of water in the reaction solution measured with a Karl Fischer moisture meter and time. FIG. 6 is a flow diagram of a method for producing diacetone glucose according to yet another embodiment of the present invention, up to the point at which a solution containing diacetone glucose is obtained. FIG. 7 is a flow diagram of a method for producing diacetone glucose according to yet another embodiment of the present invention, up to the point at which a solution containing diacetone glucose is obtained. FIG. 8 is a flow diagram of a method for producing diacetone glucose according to yet another embodiment of the present invention, up to the point at which diacetone glucose is obtained. FIG. 9 is a flow diagram showing the process for obtaining diacetone glucose from a solution containing diacetone glucose and the process for obtaining diacetone allose from diacetone glucose. FIG. 10 is a diagram showing a synthesis scheme of an example. FIG. 11 is a flow diagram showing the process for producing allose from diacetone allose according to another embodiment of the present invention. FIG. 12 is a solvent-exchangeable reactor having a reactor connected to a vacuum pump and equipped with a dropping funnel for adding a volatile crystallization solvent, such as ethanol, and an opening for adding seed crystals. FIG. 13 is a reflux dehydration reactor having a reactor connected to both a vacuum pump and a condenser via a pipe equipped with a zeolite membrane tube. FIG. 14 is a dehydration reactor having a reactor connected to a vacuum pump and equipped with a dropping funnel for adding an aprotic polar solvent, such as acetone. FIG. 15 shows that when the acid catalyst is washed before use (Example 1b), the elution of impurities from the catalyst can be prevented and the purity of allose can be increased compared to when an unwashed acid catalyst is used (Comparative Example 1b). FIG. 16 shows the results of XRD of the solid D-allose obtained in Example 1b.FIG. 17 shows the NMR results of the solid D-allose obtained in Example 1b.

[0091] Hereinafter, preferred embodiments of the method for producing diacetone glucose ketone bodies and diacetone allose of the present invention will be described. In this specification, various numerical ranges mean ranges including the upper and lower limits unless otherwise specified.

[0092] <Production of a ketone body-containing solution from diacetone glucose> One embodiment of the present invention provides a method for producing a ketone body-containing solution from diacetone glucose, which includes the following steps: (1-1) Producing a first solution by dissolving diacetone glucose in acetic acid ester; (1-2) Mixing the first solution with a first aqueous solution containing an oxidizing agent, and oxidizing the diacetone glucose to ketone bodies in the presence of an oxidation catalyst; (1-3) Separating the second solution after the oxidation reaction obtained in step (1-2) into an organic solution and a second aqueous solution; (1-4) Obtaining the organic solution.

[0093] The ketone form of diacetone glucose ((3aR,5R,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[3,2-d][1,3]dioxol-6(3aH)-one) has the following structural formula:

[0094] The above method is a process of oxidizing diacetone glucose to produce its ketone body, as shown in the following chemical reaction formula.

[0095] In step (1-1), an acetic acid ester is used as a solvent for dissolving diacetone glucose. Examples of acetic acid esters include methyl acetate, ethyl acetate, butyl acetate, propyl acetate, and hexyl acetate. More specifically, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, and n-butyl acetate are mentioned. Ethyl acetate is particularly preferred in view of its ease of separation during extraction, the small amount of solvent required for dissolution, and its widespread use as a solvent. By using an acetic acid ester that is easy to handle from the standpoint of safety and the environment, it is possible to avoid the use of solvents that are difficult to handle, such as halogenated solvents.

[0096] The amount of acetic acid ester used as a solvent for dissolving diacetone glucose is not particularly limited, but can be, for example, in the range of 0.1 liter to 20 liters per mole of diacetone glucose. The amount of acetic acid ester used is preferably in the range of 0.5 liter to 2 liters.

[0097] The starting material, diacetone glucose, can be produced, for example, by a process comprising the following steps (1) to (6): (1) reacting α-D-glucose with acetone in the presence of a Lewis acid at a temperature in the range of 80 to 120°C and under a pressure of at least 2.5 bar; (2) distilling off components that are volatile under these conditions, and replacing the distillate with acetone until about 5 / 3 of the initial reaction volume has been replaced with acetone; (3) then distilling the reaction mixture under reduced pressure at a temperature in the range of 30 to 70°C and mixing it with an aqueous solution of a base; (4) distilling the reaction mixture under reduced pressure at a temperature in the range of 0 to 70°C, extracting with an organic extractant, and distilling off the extract; (5) combining the residue with an organic precipitant and heating to a temperature in the range of 65 to 80°C; (6) isolating the resulting crystals upon cooling as 1,2-5,6-diacetone-D-glucose.

[0098] Alternatively, diacetone glucose may be produced by a method comprising the following steps (1) to (4): (1) reacting α-D-glucose with diketene in acetone in the presence of a Lewis acid or a Bronsted acid at a temperature in the range of 60 to 120°C; (2) after the reaction is complete, the reaction mixture is cooled, and any solid components are removed. Then, an aqueous solution of an alkaline reactive compound is added to the solution and mixed until the pH is in the range of 6 to 8; (3) distilling off the acetone, and extracting the residue with a water-immiscible organic extractant; (4) evaporating the extractant, and recrystallizing the residue from an organic solvent to isolate the resulting 1,2-5,6-diacetone-D-glucose.

[0099] Alternatively, diacetone glucose can also be produced by a method comprising the following dissolving step, reacting step, and neutralizing step: a dissolving step of mixing glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide to produce a solution, a reacting step of adding a Lewis acid catalyst that promotes the reaction between glucose and acetonide to the solution to produce a reaction solution, and a neutralizing step of adding an aqueous solution containing a gelation inhibitor and a neutralizing agent to the reaction solution to neutralize it.

[0100] When iron chloride, aluminum chloride, or the like is used as a catalyst for the Lewis acid used in the reaction step, gelation tends to occur easily, and therefore it is particularly advantageous to add a gelation inhibitor in the neutralization step. However, in another embodiment of the present invention, the addition of a gelation inhibitor is not necessary. Furthermore, in yet another embodiment of the present invention, a protonic acid may be used as a catalyst for the acetonidation reaction in place of some or all of the Lewis acid described above.

[0101] The aprotic polar solvent referred to here is preferably at least one solvent selected from the group consisting of acetone, tetrahydrofuran, and ethyl acetate. Among these, it is particularly preferable to use acetone, which is also an acetonide. When acetone is used as both the aprotic polar solvent and the acetonide, there is no need to provide separate storage tanks for the aprotic polar solvent and the acetonide, which further facilitates avoiding the expansion of the production equipment.

[0102] To obtain diacetone glucose from glucose, glucopyranose undergoes an equilibrium reaction to become glucofuranose via acyclic glucose, and then two diol structures must react with one molecule of acetone each in the presence of an acid catalyst. This reaction produces two molecules of acetonide and two molecules of water. The water produced is trapped in the initial stage of the reaction by reacting with acetone in the presence of an acid catalyst to form 1,1-dihydroxypropane. More specifically, to convert glucose to diacetone glucose, the six-membered ring glucose in the crystal or aqueous solution first becomes linear and then recyclizes to form a five-membered ring glucose. The five-membered ring glucose reacts with two molecules of acetone to form the five-membered ring diacetone glucose, releasing two molecules of water. The resulting water molecules are thought to increase the solubility of glucose in acetone. However, they also accelerate the reverse reaction from diacetone glucose to five-membered ring glucose. Because this reverse reaction plays a large role, the rate of diacetone glucose production is thought to gradually decrease as the amount of water in acetone increases as the reaction progresses.

[0103] Furthermore, when a large amount of water is produced as the reaction progresses, the water that cannot be trapped as 1,1-dihydroxypropane reacts with diacetone glucose, and it is thought that this leads to an equilibrium reaction with a reaction that returns to glucose and acetone through a reverse reaction. In order to shift this equilibrium reaction in the direction of increasing the amount of diacetone glucose produced, it is necessary to increase the amount of acetone unless a dehydrating agent or the like is used. In particular, glucose has the property of being difficult to dissolve in acetone, and simply converting it into acetonide using an acid catalyst is not enough to produce a large amount of diacetone glucose, making industrial mass production difficult. In other words, industrial mass production of diacetone glucose requires a large amount of acetone to dissolve glucose, which poses the problem of the need for large production facilities such as tanks and reaction vessels for storing it.

[0104] Therefore, this method for producing diacetone glucose from glucose may further include a step of removing water and / or an aprotic polar solvent from the solution containing diacetone glucose during the reaction step. This removing step may also be performed on the reaction solution after the neutralization step. Therefore, this method for producing diacetone glucose from glucose may further include a step of removing water and / or an aprotic polar solvent from the reaction solution after the neutralization step.

[0105] When acetone is used as the aprotic polar solvent, the solvent removal step can be performed using a reflux dehydration reactor, such as that shown in FIG. 3, which has a reaction vessel equipped with a tube formed of a membrane, such as a zeolite membrane, that is permeable to water vapor but not to the aprotic polar solvent. Specifically, the apparatus shown in FIG. 3 includes a reaction vessel (3) containing a reaction liquid / acetone solution, a water separator equipped with a membrane, such as a zeolite membrane (4), that is permeable to water vapor but not to the aprotic polar solvent, and connected to a vacuum pump (8) and a cold trap (9), and a cooler (5). The interior of the water separator is connected to the cold trap and vacuum pump via a tube. This reflux dehydration reactor can separate and recover organic solvents, such as acetone, from water, allowing the organic solvent to be reused. The principle is as follows.

[0106] Acetone and water do not form an azeotropic mixture, making it difficult to remove water by conventional azeotropic distillation. However, heating produces a mixture of acetone vapor and water vapor, and the device shown in Figure 3 can be used to remove water from this vapor.

[0107] When the reaction vessel is heated in the apparatus shown in Figure 3, the water produced in the reaction system rises as vapor together with acetone, is cooled in the upper condenser, and then refluxes. A tube made of a zeolite membrane is installed between the reaction vessel and the condenser. Zeolite membranes have minute pores specific to their structure, allowing only water to pass through selectively. Therefore, only the vaporized water passes through the zeolite membrane and moves into the negatively pressurized interior, where it is cooled in a cold trap and removed as water or ice. Meanwhile, acetone, which cannot pass through the zeolite membrane, is cooled in the upper condenser and returns to the reaction vessel. This process continues throughout the reaction, allowing efficient removal of only the water produced in the reaction system and maintaining a low water content in the solution in the reaction vessel.

[0108] The lower limit of the water content of the solution in the reaction tank is preferably 0.1% by mass or more, more preferably 0.3% by mass or more, and even more preferably 0.5% by mass or more, and the upper limit of the water content of the solution in the reaction tank is preferably 1% by mass or less, more preferably 0.8% by mass or less, and even more preferably 0.5% by mass or less.

[0109] The zeolite membrane is also placed in the position of the rectification tower, and functions as a rectification tower. This creates a water vapor concentration gradient, with the water vapor concentration higher at the bottom and lower at the top. This allows the effective surface area of ​​the zeolite membrane to be used to the maximum extent possible to remove water.

[0110] The heating temperature of the reaction tank is not particularly limited, but from the viewpoint of suppressing coloration of the product, it is preferably 20° C. to 80° C., more preferably 30° C. to 70° C., and even more preferably 50° C. to 60° C. A temperature control jacket may be installed in the reflux dehydration reaction apparatus to control the temperature inside the apparatus.

[0111] The pressure inside the reflux dehydration reactor is not particularly limited, but the pressure inside the tube formed of the zeolite membrane is preferably 2 hPa to 30 hPa, more preferably 4 hPa to 15 hPa, and even more preferably 6 hPa to 8 hPa. On the other hand, the pressure outside the tube made of the zeolite membrane is preferably 200 hPa to 1000 hPa, more preferably 300 to 800 hPa, and even more preferably 400 hPa to 500 hPa, from the viewpoint of reflux at a preferred reaction temperature.

[0112] Alternatively, this solvent removal step can be performed using a solvent replacement device, such as that shown in Figure 4, which includes a reaction vessel (10) containing the reaction solution, a pipe equipped with a cooling means, a vacuum pump, a recovery vessel (14), and a dropping funnel (11) connected to the reaction vessel for adding an aprotic polar solvent, such as acetone. Water is removed by distillation through the pipe, which is placed under negative pressure by operating the vacuum pump, while at the same time the aprotic polar solvent is dropped from the dropping funnel into the reaction vessel to replenish the reaction solution, thereby performing solvent replacement and preventing an increase in the amount of water in the aprotic polar solvent.

[0113] The diacetone glucose used as a starting material may be concentrated and crystallized into a solid. Alternatively, for example, when diacetone glucose is produced by the above-mentioned dissolution step, reaction step, and neutralization step, after this neutralization step, an aprotic polar solvent is added to the neutralized solution, the organic solution is separated, and the separated organic solution is optionally concentrated. This solution in which diacetone glucose is dissolved in an aprotic polar solvent may be used as the first solution in this embodiment without performing the concentration and crystallization steps into a solid. The residue obtained by adding an aprotic polar solvent to the neutralized solution is again subjected to the above-mentioned dissolution step, reaction step, and neutralization step to obtain an organic solution in which diacetone glucose is dissolved, thereby increasing the recovery rate of diacetone glucose.

[0114] (Oxidizing Agent) The oxidizing agent used in the oxidation of diacetone glucose is not particularly limited, and examples thereof include hypochlorous acid, hypobromite, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, and hydrates thereof, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, trichloroisocyanuric acid, iodobenzene diacetate, gaseous oxygen, sodium chlorite, potassium chlorite, calcium chlorite, metachlorobenzoic acid (mCPBA), hydrogen peroxide, and potassium hydrogen persulfate-potassium hydrogen sulfate-potassium sulfate double salt (2KHSO5-KHSO4-K2SO4). Furthermore, the oxidizing agent may be, for example, hypochlorite, high-grade bleaching powder (effective chlorine concentration of 60% or more), aqueous sodium hypochlorite solution (effective chlorine concentration of 5% or more), sodium hypochlorite pentahydrate, hypobromous acid, or molecular oxygen. The high-grade bleaching powder may be calcium hypochlorite or a mixture of calcium chloride and calcium hypochlorite.

[0115] Hypochlorous acid or its salts are preferred. Particularly preferred are sodium hypochlorite and its hydrates. Sodium hypochlorite is advantageous in that it can be easily removed by reacting with, for example, sodium thiosulfate to form NaCl. The sodium hypochlorite hydrate may be, for example, monohydrate, di-pentahydrate, pentahydrate, or hexahydrate, with pentahydrate being preferred. The use of sodium hypochlorite pentahydrate is advantageous in that it can increase the concentration of the aqueous solution and reduce the amount of the aqueous layer. In addition, it is easy to use in terms of crystalline solubility, melting point, storage stability, etc.

[0116] High-grade bleaching powder is also preferred because it has a high available chlorine concentration (60% or more), is relatively inexpensive, and has low hygroscopicity, allowing it to withstand long-term storage.

[0117] Molecular oxygen can be supplied as, for example, air, pure oxygen gas, or an oxygen-enriched mixed gas, although air is particularly advantageous from the standpoint of ease of operation and economy.

[0118] The amount of the oxidizing agent is not particularly limited, but may be, for example, 1 to 3 moles, preferably 1 to 1.1 moles, per mole of diacetone glucose.

[0119] The oxidizing agent is preferably added all at once or in small amounts gradually, for example dropwise, to a solution of acetic acid ester in which diacetone glucose has been dissolved.

[0120] The use of the above oxidizing agent in combination with acetate as a solvent avoids problems in the prior art, such as the use of heavy metals as oxidizing agents.

[0121] The oxidation of diacetone glucose is carried out in the presence of a catalyst. The catalyst to be used is not particularly limited, and examples thereof include organic nitroxyl radical oxidation catalysts, such as 2-azaadamantane-N-oxyl (AZADO), 9-azanoradamantane-N-oxyl (nor-AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 1,5-dimethyl-9-azanoradamantane-N-oxyl (DMN-AZADO), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), silica gel-supported TEMPO, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-hydroxy-TEMPO), and [4-hydroxy-TEMPO + NaCl] / SiO ２, 4-amino-TEMPO, 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-phenoxy-TEMPO, 4-acetoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-methacrylate-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, 4-paratoluenesulfonyloxy-TEMPO, 4-oxo-TEMPO, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxy, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxy "2,2,6,6-tetramethylpiperidine nitroxyl radical compounds" such as 4-oxo-2,2,6,6-tetramethylpiperidin-1-oxy, 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxy, 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxy, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-oxy, and 4-(benzoyloxy)-2,2,6,6-tetramethylpiperidin-1-oxy, as well as di-tert-butyl nitroxide radicals; Examples of suitable nitroxides include diphenyl nitroxide, bis(4-methoxyphenyl) nitroxide, phenyl(tert-butyl) nitroxide, 2-naphthyl(tert-butyl) nitroxide, 2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3,3,5,5-tetramethyl-4-morpholinyloxy, 9-azabicyclo[3,3,1]nonane-N-oxyl (ABNO), and 2-hydroxy-2-azaadamantane (AZADOL).

[0122] Considering the efficiency of oxidation, nor-AZADO, AZADO, and 4-hydroxy-TEMPO are particularly preferred. 2-Hydroxy-2-azaadamantane (AZADOL) is also preferred. Considering safety, nor-AZADO is the most preferred. When 4-hydroxy-TEMPO is used, the ratio of [4-hydroxy-TEMPO + NaCl] / SiO ２ It is preferable to use the system as follows.

[0123] The amount of the oxidation catalyst added is not particularly limited, but may be, for example, 0.001 to 1 mol %, preferably 0.001 to 0.1 mol %, more preferably 0.001 to 0.01 mol %, and even more preferably 0.001 to 0.005 mol % relative to diacetone glucose, depending on the combination of the oxidizing agent and acetate ester.

[0124] By using the catalyst in combination with the oxidizing agent and the acetic acid ester as a solvent, the use of halogenated solvents and DMSO can be avoided, which is extremely advantageous in terms of safety and the environment. Furthermore, the amount of catalyst used can be significantly reduced, the yield of the oxidation reaction can be significantly improved, and costs can be significantly reduced. Furthermore, problems associated with conventional techniques, such as the difficulty of processing operations caused by the use of large amounts of water and solvents, the generation of large amounts of by-products, and low reaction yields, can be avoided. As a result, the production method of this embodiment has the advantage of contributing to environmental conservation and achieving the Sustainable Development Goals (SDGs) adopted at the United Nations Summit.

[0125] The reaction temperature, reaction pressure, and reaction time in the oxidation reaction step are not particularly limited as long as they are conditions under which the oxidation reaction of diacetone glucose to ketone bodies can proceed. Examples of reaction temperatures include 0 to 60°C. The reaction temperature may be 10 to 40°C. Examples of reaction pressures include pressures of 0.1 MPa to 0.5 MPa. Examples of reaction times include 1 hour to 24 hours.

[0126] The oxidation reaction process proceeds by mixing the oxidizing agent with a solution of diacetone glucose acetate dissolved in an aqueous solution. This aqueous solution may be prepared by dissolving the oxidizing agent in water or another suitable aqueous medium in which the oxidizing agent can be dissolved. In this process, the oxidation reaction occurs in a mixed solution in a suspension state of the organic solution and the aqueous solution. Because the oxidizing agent and catalyst are distributed in the aqueous solution, they can be easily and safely removed by removing the aqueous solution after the reaction is complete. This is extremely advantageous considering that removing the oxidizing agent and catalyst used in the oxidation reaction process usually requires difficult and complicated procedures. For example, if a reducing agent is used in a subsequent process, the reducing agent and the oxidizing agent may come together, creating an extremely dangerous situation. Furthermore, if the oxidizing agent remains in the aqueous solution and is subsequently subjected to a concentration process by heating, this can also lead to an extremely dangerous situation. The easy and safe removal of the oxidizing agent and catalyst facilitates scale-up. Furthermore, the oxidizing agent and / or catalyst in the separated aqueous solution can be easily recovered and reused as needed.

[0127] Furthermore, since the ketone bodies obtained by the oxidation of diacetone glucose are distributed in the organic solution, the organic solution containing the ketone bodies to be recovered can be separated from the aqueous solution and simply washed with, for example, a small amount of sodium bicarbonate water, facilitating the scale-up of the production equipment. If necessary, the washed organic solution may be further extracted with acetic ester several times, for example, about 2 to 5 times, to improve the purity of the ketone bodies.

[0128] The organic solution and the aqueous solution can be separated by a method commonly used in chemical synthesis, such as leaving the solution to stand in a separatory funnel, stopping stirring in a reaction vessel and leaving the solution to stand, centrifuging in a centrifuge, or using a superhydrophobic filter (phase separator).

[0129] The organic solution can also be obtained by a method commonly used in chemical synthesis, such as draining from a separatory funnel or a reaction vessel using gravity, pumping by applying pressure to a reaction vessel, or suctioning using a suction pump.

[0130] The step of separating the organic solution from the aqueous solution and the step of obtaining the organic solution essentially mean, in other words, extracting the organic solution from the second solution after the oxidation reaction obtained in the step of subjecting the ketone body to an oxidation reaction.

[0131] It was found that the ketone body and the hydrate existed as a mixture in the organic solution, and the ketone body:hydrate ratio was found to be about 3:1 to 7:1 in one embodiment, and about 3:1 to 5:1 in another embodiment.

[0132] The hydrate ((3aR,5R,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxole-6,6(5H)-diol) has the following structure:

[0133] The organic solution containing the ketone body and its hydrate (hereinafter also simply referred to as "ketone body") can be used as a starting material for the next step, production of diacetone allose, in the solution state. It has also been found that the ketone body is stable even when stored in an acetate ester, for example, ethyl acetate, at room temperature for 2 days or more.

[0134] If necessary, the organic solution containing the ketone body can be concentrated to obtain the ketone body as a dry solid. The concentration method is not particularly limited as long as it does not impair the effects of the present invention, and may be, for example, reduced pressure, drying, or filtration. The solid ketone body can be stored at room temperature for a long period of time, for example, several weeks to several years.

[0135] The diacetone glucose ketone bodies thus obtained can be used, for example, in the production of functional foods and pharmaceutical products.

[0136] <Production of diacetone allose from ketone bodies of diacetone glucose> Another embodiment of the present invention further provides a method for producing diacetone allose from ketone bodies of diacetone glucose. The method includes the following steps: (2-1) preparing a ketone body-containing solution in which ketone bodies of diacetone glucose are dissolved in an organic solvent; (2-2) suspending a reducing agent in a lower alcohol to form a suspension; (2-3) mixing the ketone body-containing solution obtained in step (2-1) above with the suspension obtained in step (2-2) above, and reducing the ketone bodies to diacetone allose.

[0137] There is no particular rule as to the order in which the steps (2-1) and (2-2) are carried out.

[0138] The above method is a process of reducing the ketone body of diacetone glucose to produce diacetone allose, as shown in the chemical reaction formula below.

[0139] The ketone bodies in the step (2-1) are preferably ketone bodies obtained from diacetone glucose in the steps (1-1) to (1-4) of the method for producing ketone bodies. More preferably, the organic solution containing the ketone bodies obtained in the step (1-4) is used as the ketone body-containing solution in the step (2-1) in which the ketone bodies are dissolved in an organic solvent, thereby enabling continuous production of ketone bodies and diacetone allose.

[0140] Ketone bodies have a problem in that they become less soluble in a solvent when concentrated and crystallized into a solid state. If the ketone bodies can be used in the step (2-1) in the effectively dissolved state, the loss of the ketone bodies can be avoided, and the yield of the final product can be increased.

[0141] Alternatively, the ketone body-containing solution in step (2-1) above may be a solution obtained by dissolving a solid ketone body in a suitable organic solvent. Examples of organic solvents that can be used include esters, such as acetates (e.g., methyl acetate, ethyl acetate, isopropyl acetate, etc.), and ethyl formate; ethers, such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, diisopropyl ether, dipropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, and 1,2-dimethoxyethane; hydrocarbons, such as hexane, heptane, cyclohexane, benzene, and toluene; ketones, such as acetone and 2-butanone; alcohols, such as methanol, ethanol, 2-propanol, 1-propanol, n-butanol, and tert-butanol; and cyano compounds, such as acetonitrile and propionitrile. Preferred are acetates, tetrahydrofuran, and ethanol, particularly preferred are acetates, and most preferred is ethyl acetate.

[0142] The reducing agent in the above step (2-2) is not particularly limited, and examples thereof include sodium borohydride (NaBH ４ ) or lithium aluminum hydride (LiAlH ４ ) is used. Particularly preferred is NaBH ４ is.

[0143] In a preferred embodiment, the mixing of the ketone body-containing solution in (2-3) with the suspension in (2-2) is carried out by adding the ketone body-containing solution dropwise to the suspension of the reducing agent while stirring the suspension.

[0144] When a reducing agent is added dropwise to a solution containing ketone bodies, the reducing agent must be in a solution state. ４Reducing agents such as ketone body-containing ...

[0145] A lower alcohol can be used as the solvent for suspending the reducing agent. As the lower alcohol, an alcohol having 1 to 5 carbon atoms is preferred, an alcohol having 2 to 4 carbon atoms is more preferred, and an alcohol having 2 to 3 carbon atoms is even more preferred. As the lower alcohol, for example, methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, and tert-butanol can be used. Ethanol is particularly preferred. The concentration of the lower alcohol must have a low water content to prevent decomposition and foaming of the ketone body-containing solution, and is preferably 71% by volume or more, more preferably 96% by volume or more, and most preferably 98% by volume or more. 100% by volume ethanol is particularly preferred.

[0146] The solution containing diacetone allose obtained by the reduction reaction may be washed with saturated saline, for example, and subjected to several extraction steps using the organic solvent. The extracted organic solution containing diacetone allose may be concentrated as needed. The concentration method is not particularly limited as long as it does not impair the effects of the present invention, and may be, for example, reduced pressure, drying, or filtration.

[0147] <Crystallization of diacetone allose> The diacetone allose obtained as described above can be crystallized by a method including the following steps: The diacetone allose produced by the reduction reaction described above is dissolved in a first organic solvent to produce a dissolved solution, which is then mixed with a heptane solution containing diacetone allose seed crystals to crystallize the diacetone allose.

[0148] The first organic solvent is not particularly limited, and examples thereof include esters, such as acetates such as methyl acetate, ethyl acetate, and isopropyl acetate, and ethyl formate; ethers, such as tetrahydrofuran, methyl tert-butyl ether, diethyl ether, diisopropyl ether, dipropyl ether, and cyclopentyl methyl ether; hydrocarbons, such as toluene, heptane, cyclohexane, and benzene; ketones, such as acetone and 2-butanone; alcohols, such as methanol, ethanol, 2-propanol, and 1-propanol; and cyano compounds, such as acetonitrile and propionitrile. Preferred are toluene, acetates, tetrahydrofuran, methyl tert-butyl ether, and acetone, particularly preferred are toluene and ethyl acetate, and most preferred is toluene.

[0149] The method for mixing the above-mentioned dissolved solution with the heptane solution containing the diacetone allose seed crystals is not particularly limited, and examples thereof include dropwise addition.

[0150] The diacetone allose thus obtained can be used, for example, in the production of functional foods and pharmaceutical products.

[0151] <Method for Producing Allose> Yet another embodiment of the present invention is a method for producing allose, in which allose is produced by deprotecting the diacetone allose obtained by the above-mentioned embodiment using an ion exchange resin as a catalyst. Specifically, the method for producing allose of this embodiment includes a dissolving step of dissolving diacetone allose in a solvent to produce a solution, and a reaction step of adding an ion exchange resin to the solution and mixing them to produce allose by an ion exchange reaction.

[0152] In this embodiment, the solvent used in the dissolving step is not particularly limited as long as it can dissolve diacetone allose. An example of the solvent used in the dissolving step is tetrahydrofuran.

[0153] In this embodiment, the ion exchange resin used in the reaction step is not particularly limited as long as it can produce allose. Examples of the ion exchange resin used in the reaction step include compounds represented by the following general formula (2). An example of the compound represented by the following general formula (2) is the commercially available "AMBERLITE" (registered trademark).

[0154] In the reaction step, an ion exchange resin is added to a solution in which diacetone allose has been dissolved and mixed, and as shown in the following chemical reaction formula, the protecting group (acetonide) of diacetone allose is deprotected by reacting with water using the ion exchange resin as a catalyst, thereby producing allose. Here, the ion exchange resin is preferably washed with water or an organic solvent before the reaction.

[0155]

[0156] Allose can be obtained by a deprotection reaction using the acidity of an ion exchange resin as a catalyst. A specific example of allose is D-allose. The allose obtained in this manner, particularly D-allose, can be used in products in the fields of functional foods and pharmaceuticals.

[0157] The methods for producing ketone bodies of diacetone glucose, diacetone allose, and D-allose of the present invention are not limited to the above-mentioned embodiments or the examples described below, and can be appropriately combined, substituted, modified, etc. within the scope of the purpose and intent of the present invention.

[0158] <Other Steps Related to the Present Invention> Hereinafter, still another embodiment related to the present invention will be described in detail.

[0159] <Method for Producing Diacetone Glucose and Diacetone Allose, Which is Yet Another Embodiment of the Present Invention> Yet another embodiment of the present invention relates to a novel method for producing each of diacetone glucose and diacetone allose.

[0160] (Background of the Present Embodiment) In recent years, diacetone-D-glucose has been used as an intermediate for nucleic acid medicines, antiviral drugs, antibiotics, and the like. Diacetone-D-glucose can be used to produce D-allose, as disclosed in the non-patent document, Carbohydrate Research, 24 (1972), pp. 192-197. D-Allose is a type of monosaccharide classified as a hexose or aldose, and is a type of "rare sugar" that is rarely found in nature. D-Allose has a sweetness intensity of about 80% of that of sugar and contains almost no calories, and is therefore used in supplements and the like. D-Allose is also known to have the effect of inhibiting the proliferation of cancer cells, and its use in the pharmaceutical field is expected.

[0161] Diacetone glucose used for producing such D-allose can be produced by dissolving glucose in acetone and acetonidating it with an acid catalyst, as disclosed in, for example, Japanese Patent Application Laid-Open Nos. 6-157574 and 6-234785.

[0162] However, in order to simply produce diacetone glucose with higher purity and higher yield, the methods disclosed in the above patent documents are not sufficient and further improvements are required.

[0163] (Problem to be Solved by the Present Embodiment) Therefore, an object of the present embodiment is to provide a novel production method that can produce diacetone glucose relatively easily.

[0164] (Means for solving the problems of the present embodiment) The present disclosure includes the following aspects.

[0165] (Disclosure 1a) Disclosure 1a is a method for producing diacetone glucose. The production method of Disclosure 1a includes the following first dissolution step, first reaction step, and neutralization step. The first dissolution step is a step of mixing glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide to produce a solution. The first reaction step is a step of adding a Lewis acid catalyst that promotes the reaction between glucose and acetonide to the solution to produce a reaction solution. The neutralization step is a step of neutralizing the reaction solution by adding a gelation inhibitor and a neutralizer.

[0166] (Disclosure 2a) Disclosure 2a is the production method according to Disclosure 1a, wherein the aprotic polar solvent is at least one selected from the group consisting of acetone, tetrahydrofuran, and ethyl acetate.

[0167] (Disclosure 3a) Disclosure 3a relates to the production method according to Disclosure 1a or Disclosure 2a, wherein the acetonide is at least one selected from the group consisting of acetone, dimethoxypropane, 2-methoxypropene, and 2-chloropropene.

[0168] (Disclosure 4a) Disclosure 4a is the manufacturing method according to any one of Disclosures 1a to 3a, wherein the gelation inhibitor is Rochelle salt or trisodium citrate.

[0169] (Disclosure of No. 5a) Disclosure of No. 5a is the manufacturing method according to any one of the disclosures of No. 1a to No. 4a, wherein the Lewis acid catalyst is iron chloride, iron chloride hexahydrate (FeCl ３ ・6H ２ O), zinc chloride, zinc chloride (ZnCl ２ ) and phosphoric acid (H ３ P.O. ４ ), aluminum chloride, magnesium sulfate, tetrabutylammonium bromide ((n-Bu) ４ N ＋ Br ３ － ), montmorillonite, mordenite, and lanthanide fluoride.

[0170] (Disclosure 6a) Disclosure 6a is the manufacturing method according to any one of Disclosures 1a to 5a, wherein the neutralizing agent is at least one selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and aqueous ammonia.

[0171] (Disclosure 7a) Disclosure 7a relates to any one of the manufacturing methods of Disclosures 1a to 6a, wherein solid glucose remains in the first reaction step when the reaction solution is produced. Disclosure 7 further includes the following separation step, second dissolution step, and second reaction step. The separation step is a step of performing solid-liquid separation of the remaining solid glucose and the reaction solution prior to the neutralization step. The second dissolution step is a step of mixing the separated solid glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide to produce a solution. The second reaction step is a step of adding a catalyst that promotes the reaction between glucose and acetonide to the solution produced in the second dissolution step to produce a reaction solution.

[0172] (Disclosure 8a) Disclosure 8a is the manufacturing method according to disclosure 7a, wherein the reaction solution produced in the first reaction step is a saturated solution.

[0173] (Disclosure 9a) Disclosure 9a relates to the manufacturing method of disclosure 7a or disclosure 8a, wherein the first dissolving step, the first reaction step, and the separation step are repeated before the second dissolving step.

[0174] (Disclosure 10a) Disclosure 10a is the production method according to disclosure 9a, wherein the second reaction step is a step of eliminating the remaining glucose.

[0175] Disclosure 11a relates to the manufacturing method of any one of Disclosures 7a to 10a, further comprising a solvent removal step. The solvent removal step removes the aprotic polar solvent from the reaction solution after the neutralization step. The aprotic polar solvent removed in the solvent removal step is used as the aprotic polar solvent in at least one of the first dissolving step and the second dissolving step.

[0176] Disclosure 12a: The disclosure 12a relates to any one of the manufacturing methods of disclosures 7a to 11a, including a solvent removal step and a drying step. The solvent removal step removes the aprotic polar solvent from the reaction solution after the neutralization step. The drying step dries the organic matter after the aprotic polar solvent has been removed in the solvent removal step.

[0177] (Disclosure of No. 13a) Disclosure of No. 13a is a method for producing diacetone allose. The production method of Disclosure of No. 13a produces diacetone allose by oxidizing and reducing the diacetone glucose obtained by the production method of Disclosure of No. 12a.

[0178] (Effects of this embodiment) According to the production method of this embodiment, diacetone glucose can be produced relatively easily.

[0179] (Specific Modes for Carrying Out the Present Embodiment) Preferred specific embodiments of the methods for producing diacetone glucose and diacetone allose according to the present embodiment will be described below. In this specification, various numerical ranges mean ranges including the upper and lower limits unless otherwise specified.

[0180] The glucose used to produce diacetone glucose is easily soluble in water. The solubility of glucose in water is, for example, about 91 g / 100 mL at 25°C. On the other hand, glucose is poorly soluble in acetone. The solubility of glucose in acetone is only 0.0037 mol / L.

[0181] To obtain diacetone glucose from glucose, glucopyranose undergoes an equilibrium reaction to become glucofuranose via acyclic glucose, and then two diol structures must react with one molecule of acetone each in the presence of an acid catalyst. This reaction produces two molecules of acetonide and two molecules of water. The water produced is trapped in the initial stage of the reaction by reacting with acetone in the presence of an acid catalyst to form 1,1-dihydroxypropane. More specifically, to convert glucose to diacetone glucose, the six-membered ring glucose in the crystal or aqueous solution first becomes linear and then recyclizes to form a five-membered ring glucose. The five-membered ring glucose reacts with two molecules of acetone to form the five-membered ring diacetone glucose, releasing two molecules of water. The resulting water molecules are thought to increase the solubility of glucose in acetone. However, they also accelerate the reverse reaction from diacetone glucose to five-membered ring glucose. Because this reverse reaction plays a large role, the rate of diacetone glucose production is thought to gradually decrease as the amount of water in acetone increases as the reaction progresses. 5 is a graph showing the relationship between the amount of water in the reaction solution measured with a Karl Fischer moisture meter and time. The lower limit of the water content in the reaction solution is 0.1% or more, more preferably 0.3% or more, and even more preferably 0.5% or more. The upper limit of the water content in the reaction solution is 1% or less, more preferably 0.8% or less, and even more preferably 0.5% or less.

[0182] However, as shown in Figure 5, when a large amount of water is produced as the reaction progresses, the water that cannot be trapped as 1,1-dihydroxypropane reacts with diacetone glucose, and it is thought that an equilibrium reaction occurs with the reaction that returns to glucose and acetone through a reverse reaction. In order to shift this equilibrium reaction in the direction of increasing the amount of diacetone glucose produced, it is necessary to increase the amount of acetone unless a dehydrating agent or the like is used. In particular, glucose has the property of being difficult to dissolve in acetone, and simply converting it into acetonide using an acid catalyst is not enough to produce large amounts of diacetone glucose, making industrial mass production difficult. In other words, industrial mass production of diacetone glucose requires a large amount of acetone to dissolve glucose, which poses the problem of large production facilities such as tanks and reaction vessels for storing it.

[0183] In addition, since an acid catalyst is used in the reaction of glucose with acetonide, there is a problem that the reaction solution after the reaction is difficult to handle. In view of these problems, a new production method that can relatively easily produce diacetone glucose is desired.

[0184] Therefore, the present inventors have conducted extensive research focusing on the difficulty of handling the reaction solution, and as a result have discovered a novel method in which glucose and acetonide are reacted using a Lewis acid catalyst, and then a gelation inhibitor and a neutralizing agent are added to the reaction solution to neutralize it.

[0185] The present embodiment has been completed based on the above findings, and includes the following specific embodiments.

[0186] First, a preferred embodiment of the method for producing diacetone glucose of the present invention will be described in detail with reference to the drawings. Fig. 6 is a flow chart showing the process for producing diacetone glucose according to this embodiment up to obtaining a solution containing diacetone glucose.

[0187] <Method for Producing Diacetone Glucose> This embodiment is a method for producing diacetone glucose. The production method of this embodiment is a production method including a first dissolving step, a first reaction step, a separation step, a neutralization step, a second dissolving step, and a second reaction step, as shown in Fig. 6 .

[0188] In the first dissolution step, glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide are mixed to produce a solution. In the first reaction step, a Lewis acid catalyst that promotes the reaction between glucose and acetonide is added to this solution to produce a reaction solution. The first dissolution step and the first reaction step may be carried out as separate steps, or may be carried out simultaneously. In other words, the Lewis acid catalyst may be added before stirring the glucose, the aprotic polar solvent, and the acetonide. Alternatively, the Lewis acid catalyst may be added all at once. The Lewis acid catalyst may be added not only all at once, but also in multiple portions to reduce heat generation associated with the addition of the catalyst.

[0189] In the neutralization step, a gelation inhibitor and a neutralizing agent are added to the reaction solution after the first reaction step to neutralize the reaction solution. However, if solid glucose remains in the reaction solution produced in the first reaction step, a separation step is carried out prior to the neutralization step. The solid glucose is unreacted glucose that is not dissolved in the reaction solution.

[0190] In the neutralization step, the Lewis acid in the reaction solution is neutralized with a neutralizing agent, thereby making the reaction solution easier to handle. Furthermore, when the reaction solution is neutralized with a neutralizing agent, it tends to gel. In this embodiment, a gelation inhibitor is added to the reaction solution, thereby reducing the viscosity of the aqueous layer and making it possible to extract diacetone glucose relatively easily. In the production method of this embodiment, diacetone glucose can be produced relatively easily by carrying out such a neutralization step.

[0191] In the separation step performed prior to the neutralization step, the solid glucose remaining in the reaction solution after the first reaction step is separated from the reaction solution by solid-liquid separation. The separated solid glucose is then subjected to the second dissolution step.

[0192] In the second dissolution step, solid glucose separated as a solid component, an aprotic polar solvent in which the glucose dissolves, and acetonide are mixed to produce a solution. In the second reaction step, a Lewis acid catalyst that promotes the reaction between glucose and acetonide is added to the solution produced in the second dissolution step to produce a reaction solution. The reaction solution obtained in the second reaction step is a solution containing diacetone glucose. The second dissolution step and the second reaction step may be carried out as separate steps, or may be carried out simultaneously. In other words, the Lewis acid catalyst may be added before stirring the glucose, the aprotic polar solvent, and the acetonide.

[0193] In the production method of this embodiment, a small amount of aprotic polar solvent is used in the first dissolution step and the first reaction step, so that solid glucose remains in the reaction solution. While using such a small amount of aprotic polar solvent is not essential in this embodiment, using such a small amount of aprotic polar solvent eliminates the need for a large-capacity storage tank or reaction vessel, thereby avoiding the expansion of the production equipment. Furthermore, the solid glucose remaining in the reaction solution is separated into solid and liquid in a separation step and recovered as a solid component. Meanwhile, the liquid component is recovered as a solution containing diacetone glucose.

[0194] Furthermore, in the production method of the present embodiment, the recovered solid glucose is used in the second dissolution step and the second reaction step to produce a solution containing diacetone glucose, and by combining this with the solution recovered in the separation step, diacetone glucose can be obtained in high yield.

[0195] Therefore, according to the production method of this embodiment, diacetone glucose can be produced relatively easily, and diacetone glucose can be produced in high yield without requiring large-scale production equipment.

[0196] In addition, the production method of this embodiment can improve the productivity of products containing diacetone glucose or compounds produced using the same, and therefore has the advantage of contributing to the achievement of the SDGs adopted at the United Nations Summit.

[0197] Hereinafter, various steps of the manufacturing method of this embodiment will be described in detail.

[0198] [First dissolution step] The first dissolution step is a step of mixing glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide to generate a solution. In the first dissolution step, glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide are placed in a reaction vessel equipped with an optional stirring device and mixed by stirring to generate a solution. As will be described later, the aprotic polar solvent and the acetonide may be the same substance. For example, the aprotic polar solvent and the acetonide may be the same substance, acetone.

[0199] In the first dissolution step, it is preferable to use a small amount of aprotic polar solvent so that solid glucose remains in the reaction solution produced in the subsequent first reaction step. Using a small amount of aprotic polar solvent eliminates the need for a large-capacity storage tank or reaction vessel, and can avoid the expansion of the production equipment. In consideration of mass productivity, it is preferable that 85% to 95% of the initial glucose remain in a single reaction, and more preferably 87% to 93% of the initial glucose remain in a single reaction.

[0200] (Glucose) In this embodiment, the glucose is not particularly limited. Glucose may be not only D-glucose but also L-glucose. When D-glucose is used as glucose, the obtained diacetone glucose becomes diacetone-D-glucose. When L-glucose is used as glucose, the obtained diacetone glucose becomes diacetone-L-glucose. Furthermore, deuterated glucose and glucose 13C isotope may be used.

[0201] (Aprotic Polar Solvent) In this embodiment, the aprotic polar solvent is not particularly limited as long as it can dissolve glucose. The aprotic polar solvent is preferably at least one solvent selected from the group consisting of acetone, tetrahydrofuran, and ethyl acetate, in order to more reliably obtain the effects of the present invention. Among these, it is particularly preferable to use acetone, which is also an acetonide. When acetone is used as both the aprotic polar solvent and the acetonide, there is no need to provide separate storage tanks for the aprotic polar solvent and the acetonide, which further facilitates avoiding the expansion of the production equipment.

[0202] (Acetonide) In the present embodiment, the acetonide is not particularly limited as long as it can acetonide glucose in the presence of a catalyst described below. The acetonide is preferably at least one acetonide selected from the group consisting of acetone, dimethoxypropane, 2-methoxypropene, and 2-chloropropene, in order to more reliably obtain the effects of the present embodiment. Among these, it is particularly preferable to use acetone, which is also an aprotic polar solvent, in order to more easily avoid the expansion of the production equipment.

[0203] The temperature and pressure conditions in the first dissolution step are not particularly limited as long as they are conditions that allow the above-mentioned solution to be produced. An example of the temperature condition is a temperature of 15°C to 40°C. An example of the pressure condition is atmospheric pressure.

[0204] The solution produced in the first dissolution step is then subjected to the next first reaction step.

[0205] [First Reaction Step] The first reaction step is a step of adding a Lewis acid catalyst that promotes the reaction between glucose and acetonide to the solution produced in the first dissolution step to produce a reaction solution. In the first reaction step, the Lewis acid catalyst is added to the solution produced in the first dissolution step in the reaction vessel, and glucose and acetonide are reacted.

[0206] This reaction proceeds by stirring the solution in a reaction vessel to which a Lewis acid catalyst has been added, and as shown in the following chemical reaction formula, glucose in the solution is acetonidized to produce diacetone glucose. Note that the following chemical reaction formula is an example in which iron chloride is used as the Lewis acid catalyst. The first dissolution step and the first reaction step may be carried out at different times, or the first dissolution step and the first reaction step may be carried out simultaneously. In other words, the Lewis acid catalyst may be added before stirring the acetone and glucose.

[0207]

[0208] (Catalyst) In this embodiment, the catalyst used in the acetonidation reaction is a Lewis acid. Examples of the Lewis acid include iron chloride, iron chloride hexahydrate (FeCl ３ ・6H ２ O), zinc chloride, zinc chloride (ZnCl ２ ) and phosphoric acid (H ３ P.O. ４ ), aluminum chloride, magnesium sulfate, tetrabutylammonium bromide ((n-Bu) ４ N ＋ Br ３ － ), montmorillonite, mordenite, titanosilicate (TS-1), such as ytterbium(III) trifluoromethanesulfonate (Yb(OTf)), scandium(III) trifluoromethanesulfonate (Sc(OTf)), lanthanum(III) trifluoromethanesulfonate (La(OTf) ３ ), cerium(III) trifluoromethanesulfonate (Ce(OTf) ３ ), europium(III) trifluoromethanesulfonate (Eu(OTf) ３At least one catalyst selected from the group consisting of iron chloride (III), fluorine-containing ammonium salt (FMA), and gadolinium(III) trifluoromethanesulfonate (Gd(OTf)). For example, when iron chloride is used as the Lewis acid, specific examples of the iron chloride include anhydrous iron(III) chloride and ferric chloride (hydrate). When ferric chloride (hydrate) is used, the amount of iron chloride can be reduced more than when using ferric chloride (anhydrous), making it possible to further reduce the occurrence of coloration due to impurities. Furthermore, when iron chloride or aluminum chloride is used as a catalyst, gelation tends to occur easily. However, the production method of the present embodiment is particularly advantageous when using such iron chloride or aluminum chloride because a gelation inhibitor is added in the neutralization step.

[0209] In yet another embodiment of the present invention, a protonic acid may be used as a catalyst for the acetonidation reaction in place of part or all of the Lewis acid. Examples of protonic acids include a combination of iodine and isopropanol, Amberlyst (registered trademark) 15 (a catalytic ion exchange resin manufactured by Angene Chemical Co.), Amberlite (registered trademark), and silica gel-supported sulfuric acid. When these protonic acids are used as catalysts for the acetonidation reaction, diacetone glucose can also be obtained in high yield.

[0210] If the amount of catalyst is too small, the reaction will not proceed smoothly, and if the amount is too large, the catalyst will react rapidly with acetone, tending to produce a large amount of impurities. Therefore, the catalyst concentration is preferably 0.100 to 1.000 molar equivalents, more preferably 0.2 to 0.900 molar equivalents, and even more preferably 0.3 to 0.7 molar equivalents.

[0211] Incidentally, the reaction solution can be catalyzed by inorganic or organic acids. However, inorganic or organic acids are strongly acidic and easily react with acetone. Therefore, when inorganic or organic acids are used, impurities are likely to be generated, and the product produced by the reaction may become discolored. A colored product may suffer from deterioration in properties due to impurities. Furthermore, if the product becomes discolored, there is a risk of a decrease in yield when diacetone glucose is recrystallized. In this embodiment, the reaction solution is catalyzed by a Lewis acid, so that D-diacetone glucose with a higher purity can be produced in a good yield, and discoloration due to the impurities described above is unlikely to occur.

[0212] The reaction temperature, reaction pressure, and reaction time in the first reaction step are not particularly limited as long as the conditions allow the above-mentioned acetonidation reaction to proceed. Examples of the reaction temperature include room temperature to 60°C. The reaction temperature may be 20°C to 55°C. Examples of the reaction pressure include a pressure of 0.1 MPa to 0.5 MPa. Examples of the reaction time include 1 hour to 24 hours.

[0213] Then, when the stirring in the reaction vessel is stopped and the reaction of the first reaction step is completed, a reaction solution of diacetone glucose, the reaction product, is produced. At this time, when a small amount of aprotic polar solvent as described above is used, solid glucose remains in the reaction solution. That is, the remaining solid glucose settles in the reaction solution as an unreacted solid component, and a solution containing diacetone glucose exists as a supernatant. When a small amount of aprotic polar solvent as described above is used, the reaction solution produced in the first reaction step becomes a saturated solution. In the production method of this embodiment, even if the amount of solvent is small enough to make the reaction solution a saturated solution, diacetone glucose can be obtained in a higher yield by using the remaining undissolved glucose in the second dissolution step and the second reaction step.

[0214] When solid glucose remains in the reaction solution produced in the first reaction step, the reaction solution is subjected to the subsequent separation step. In the separation step, the solid glucose remaining in the reaction solution and a solution containing diacetone glucose are separated into solid and liquid. On the other hand, when no solid glucose remains in the reaction solution, the reaction solution is subjected to the neutralization step as is.

[0215] [Separation step] The separation step is a step of performing solid-liquid separation between the solid glucose remaining in the reaction solution and the reaction solution, as shown in Fig. 6. In the separation step, the solution containing diacetone glucose present in the upper part of the reaction tank is removed by filtration, discharged by a pump, or discharged by pressure feeding, thereby separating the solid glucose remaining as a solid component from the reaction solution.

[0216] In the separation step, the means for performing solid-liquid separation of the solid glucose and the reaction solution is not particularly limited. As the means for solid-liquid separation, it is preferable to use a means for discharging the solution containing diacetone glucose present in the upper part of the reaction tank by a pump or a means for discharging by pressure, in order to more easily avoid enlargement of the production equipment.

[0217] In the separation step, the solid glucose remaining in the reaction solution is recovered as a solid component, while the liquid component of the reaction solution is subjected to a neutralization step.

[0218] [Neutralization step] The reaction solution in which no solid glucose remains after the first reaction step, or the reaction solution in which the solid glucose has been separated into solid and liquid in the separation step, contains the Lewis acid used as a catalyst. In the neutralization step, in order to make the reaction solution easier to handle, it is preferable to neutralize the Lewis acid contained in the reaction solution with a neutralizing agent.

[0219] Examples of neutralizing agents that can be used in this embodiment include sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and aqueous ammonia. The neutralizing agent may be used in the form of a neutralizing solution. A specific example of an optimal neutralizing solution is a solution in which 2.6 g of trisodium citrate and 2.2 g of NaCl are dissolved in 26 mL of saturated aqueous sodium bicarbonate solution for neutralizing 1 g of iron chloride.

[0220] When a reaction solution is neutralized with a neutralizing agent, it tends to gel. When the reaction solution gels, it becomes difficult to separate the organic layer containing diacetone glucose from the solution, and mass productivity tends to decrease significantly. However, in this embodiment, a gelation inhibitor is added to the reaction solution, which suppresses gelation of the reaction solution and reduces the viscosity of the aqueous layer, making it possible to extract diacetone glucose relatively easily.

[0221] Examples of gelation inhibitors that can be used in this embodiment include Rochelle salt (sodium and potassium tartrate) and trisodium citrate. The amount of gelation inhibitor added is preferably 10% by mass or more and 100% by mass or less, more preferably 20% by mass or more and 70% by mass or less, and even more preferably 30% by mass or more and 50% by mass or less.

[0222] On the other hand, the solid glucose recovered as a solid component is subjected to the next second dissolution step.

[0223] [Second dissolution step] The second dissolution step is a step of producing a solution by mixing the recovered solid glucose, an aprotic polar solvent in which the glucose dissolves, and acetonide. In the second dissolution step, similar to the first step described above, the recovered solid glucose, the aprotic polar solvent in which the glucose dissolves, and acetonide are placed in a reaction vessel equipped with an optional stirring device, and mixed by stirring to produce a solution.

[0224] The aprotic polar solvent and acetonide used in the second dissolution step, as well as the temperature and reaction conditions in the second dissolution step, are the same as those in the first dissolution step described above, and therefore a description thereof will be omitted.

[0225] [Second Reaction Step] In the second reaction step, a Lewis acid catalyst that promotes the reaction between glucose and acetonide is added to the solution produced in the second dissolution step to produce a reaction solution. In the second reaction step, similar to the first reaction step described above, a Lewis acid catalyst is added to the solution produced in the reaction vessel in the second dissolution step to react glucose with acetonide. This reaction, similar to the first reaction step described above, proceeds by stirring the solution in the reaction vessel to which the Lewis acid catalyst has been added, and the glucose in the solution is converted into acetonide to produce diacetone glucose. The second dissolution step and the second reaction step may be carried out at different times, or may be carried out simultaneously. In other words, the Lewis acid catalyst may be added before stirring the acetone and glucose.

[0226] The catalyst used in the second reaction step, and the reaction temperature, reaction pressure, and reaction time in the second reaction step are the same as those in the first reaction step described above, and therefore, description thereof will be omitted.

[0227] Then, when the stirring in the reaction tank is stopped and the reaction of the second reaction step is completed, a reaction solution of diacetone glucose, the reaction product, is produced. It is preferable that no glucose remains in this reaction solution, or even if glucose remains, it is so small that it does not require repeated reaction and is essentially absent. In particular, it is preferable that the second reaction step is a step in which the glucose remaining in the reaction solution is completely eliminated. When the glucose in the reaction solution is completely eliminated by the second reaction step, the reaction product diacetone glucose can be obtained in a higher yield. If diacetone glucose can be obtained in this way in a high yield, the amount of aprotic polar solvent used in the first dissolution step and the first reaction step can be minimized, which makes it even easier to avoid the expansion of the production equipment.

[0228] The reaction solution produced in the second reaction step may be a saturated solution or an unsaturated solution.

[0229] Furthermore, the reaction solution produced in the second reaction step may be subjected to a neutralization step, similar to the reaction solution produced in the first reaction step described above. By subjecting the reaction solution to the neutralization step, it becomes possible to relatively easily extract diacetone glucose from the reaction solution produced in the second reaction step.

[0230] (Solution containing diacetone glucose) The reaction solution produced in the second reaction step is recovered as a solution containing diacetone glucose. Then, by combining it with the solution containing diacetone glucose recovered in the above-mentioned separation step, a solution containing diacetone glucose can be obtained in a higher yield. Furthermore, as a result, diacetone glucose can also be obtained in a high yield.

[0231] The solution containing diacetone glucose may be used for the production of diacetone glucose, which will be described later. Furthermore, the solution containing diacetone glucose may be used for the production of other products using diacetone glucose as an intermediate, such as diacetone allose, which will be described later.

[0232] The method for producing diacetone glucose of this embodiment is not limited to the aspect of the embodiment shown in Fig. 6. Here, Fig. 7 is a flow diagram of the method for producing diacetone glucose according to yet another embodiment of the present invention up to obtaining a solution containing diacetone glucose.

[0233] The embodiment shown in FIG. 7 is similar to the embodiment shown in FIG. 7 described above, except that the first dissolution step, the first reaction step, and the separation step are repeated before the second dissolution step. In this embodiment, as shown in FIG. 7, by repeating each step from the first dissolution step to the separation step, i.e., by having a repeating step, unreacted glucose is reduced as much as possible before the second dissolution step. As a result, it is possible to obtain diacetone glucose in a higher yield, since no glucose remains, or even if glucose remains, it can be reduced as much as possible in the reaction solution finally produced in the second reaction step. Therefore, the production method of this embodiment can obtain diacetone glucose in a high yield by performing the repeating step described above, even if the amount of aprotic polar solvent used is further reduced, and it is easier to avoid the expansion of the production equipment.

[0234] Furthermore, in this embodiment, it is preferable that the amount of unreacted glucose is reduced as much as possible by the above-mentioned repeating step before the second dissolution step, and that no glucose remains in the reaction solution obtained in the subsequent second reaction step. That is, it is preferable that the second reaction step is a step in which the glucose remaining in the reaction solution is completely eliminated. When the glucose in the reaction solution is completely eliminated by the second reaction step, diacetone glucose can be obtained in a higher yield. If diacetone glucose can be obtained in a high yield, the amount of aprotic polar solvent used in the first dissolution step and the first reaction step can be reduced, making it easier to avoid the expansion of the production equipment.

[0235] In this embodiment, the number of times each step from the first dissolution step to the separation step is repeated is not particularly limited, and may be appropriately set in consideration of the amount of unreacted glucose remaining in the reaction solution and productivity. The number of repetitions is, for example, 1 to 15 times.

[0236] In this embodiment, other than the repetition step, the details are the same as those of the embodiment shown in Fig. 6. In this embodiment, the steps from the first dissolving step to the separation step are repeated, and the second dissolving step and the second reaction step can be carried out continuously.

[0237] [Solvent Removal Step] The method for producing diacetone glucose according to yet another embodiment of the present invention further comprises a solvent removal step of removing the aprotic polar solvent from the solution containing diacetone glucose after the second reaction step. Here, Fig. 8 is a flow chart of the method for producing diacetone glucose according to yet another embodiment of the present invention up to obtaining diacetone glucose.

[0238] The manufacturing method of the embodiment shown in Fig. 8 further includes a solvent removal step of removing the aprotic polar solvent from the solution containing diacetone glucose produced in the second reaction step and the solution containing diacetone glucose separated in the separation step and subjected to the neutralization step. In this embodiment, the method includes a solvent reuse step of using the aprotic polar solvent removed in the solvent removal step as the aprotic polar solvent in at least one of the first dissolving step and the second dissolving step, as shown in Fig. 8.

[0239] By including such a solvent recycling step, the production method of this embodiment can efficiently utilize the aprotic polar solvent. Furthermore, the production method of this embodiment does not require the installation of a solvent recovery tank or a treatment facility for the recovered solvent, which makes it easier to avoid the expansion of the production equipment.

[0240] In the solvent removal step, the means for removing the aprotic polar solvent from the solution containing diacetone glucose is not particularly limited as long as it does not impair the effects of this embodiment, and examples thereof include vacuum concentration means and filtration means.

[0241] The organic matter after the solvent removal step is optionally washed and then dried in the drying step, thereby obtaining diacetone glucose.

[0242] Next, preferred embodiments of the process for obtaining diacetone glucose from a solution containing diacetone glucose obtained by the production method of each of the above embodiments and the process for producing diacetone allose from diacetone glucose will be described in detail with reference to the drawings. Here, Fig. 9 is a flow diagram of the process for obtaining diacetone glucose from a solution containing diacetone glucose and the process for obtaining diacetone allose from diacetone glucose.

[0243] <Process for Obtaining Diacetone Glucose from a Solution Containing Diacetone Glucose> As shown in FIG. 9 , the process for obtaining diacetone glucose from a solution containing diacetone glucose obtained by the manufacturing method of each of the above embodiments includes a solvent removal process for removing the aprotic polar solvent from the solution containing diacetone glucose, and a drying process for drying the organic matter after the aprotic polar solvent has been removed.

[0244] The solvent removal step in this embodiment is the same as that in the embodiment shown in FIG. 8, and therefore a description thereof will be omitted.

[0245] The drying step is a step of drying the organic matter after the removal of the aprotic polar solvent in the solvent removal step under any drying conditions, such as 20° C. to 60° C. for 1 hour to 20 hours, preferably 20° C. to 50° C. for 3 hours to 15 hours, and more preferably 25° C. to 40° C. for 5 hours to 10 hours.

[0246] The drying means used in the drying step is not particularly limited as long as it does not impair the effects of this embodiment, and examples thereof include means using a desiccant or a dryer. The drying temperature, drying time, and drying atmosphere in the drying step are also not particularly limited as long as they do not impair the effects of this embodiment, and each condition may be appropriately set depending on the amount of solvent remaining in the organic substance and the desired drying state.

[0247] Diacetone glucose can be obtained by going through the above solvent removal step and drying step. Specific examples of diacetone glucose include diacetone-D-glucose and diacetone-L-glucose. The diacetone glucose obtained in this manner may be used to produce other products. For example, the diacetone glucose obtained may be used to produce diacetone allose as described below.

[0248] <Method for Producing Diacetone Allose> Diacetone glucose obtained by the above-described embodiment may be subjected to a method for producing diacetone allose, which further includes an oxidation step and a reduction step as shown in Fig. 9. That is, yet another embodiment of the present invention is a method for producing diacetone allose, in which diacetone allose is produced by oxidizing and reducing diacetone glucose.

[0249] The oxidation step and reduction step in the method for producing diacetone allose of this embodiment will be described below.

[0250] [Oxidation Step] In this embodiment, the oxidation step is a step of oxidizing diacetone glucose to produce its ketone body, as shown in the following chemical reaction formula.

[0251]

[0252] (Oxidizing Agent) The oxidizing agent used in the oxidation step is not particularly limited, and examples thereof include hypochlorous acid and hypochlorites. Specific examples include hypochlorous acid, hypobromite, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, and hydrates thereof, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, trichloroisocyanuric acid, iodobenzene diacetate, gaseous oxygen, sodium chlorite, potassium chlorite, calcium chlorite, metachlorobenzoic acid (mCPBA), hydrogen peroxide, and a double salt of potassium hydrogen persulfate, potassium hydrogen sulfate, and potassium sulfate (2KHSO5.KHSO4.K2SO4). Furthermore, the oxidizing agent may be, for example, high-grade bleaching powder (effective chlorine concentration of 60% or more), a sodium hypochlorite aqueous solution (effective chlorine concentration of 5% or more), sodium hypochlorite pentahydrate, or air.

[0253] (Oxidation Catalyst) An oxidation catalyst may be used together with the oxidizing agent. Examples of the oxidation catalyst include organic nitroxyl radical-based oxidation catalysts, such as 2-azaadamantane-N-oxyl (AZADO), 9-azanoradamantane-N-oxyl (nor-AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 1,5-dimethyl-9-azanoradamantane-N-oxyl (DMN-AZADO), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), silica gel-supported TEMPO, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-hydroxy-TEMPO), and [4-hydroxy-TEMPO + NaCl] / SiO ２, 4-amino-TEMPO, 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-phenoxy-TEMPO, 4-acetoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-methacrylate-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, 4-paratoluenesulfonyloxy-TEMPO, 4-oxo-TEMPO, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxy, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxy "2,2,6,6-tetramethylpiperidine nitroxyl radical compounds" such as 4-oxo-2,2,6,6-tetramethylpiperidin-1-oxy, 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxy, 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxy, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-oxy, and 4-(benzoyloxy)-2,2,6,6-tetramethylpiperidin-1-oxy, as well as di-tert-butyl nitroxide radicals; Examples of suitable nitroxides include diphenyl nitroxide, bis(4-methoxyphenyl) nitroxide, phenyl(tert-butyl) nitroxide, 2-naphthyl(tert-butyl) nitroxide, 2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3,3,5,5-tetramethyl-4-morpholinyloxy, 9-azabicyclo[3,3,1]nonane-N-oxyl (ABNO), and 2-hydroxy-2-azaadamantane (AZADOL).

[0254] Other oxidation conditions may be appropriately set depending on the oxidizing agent used, so that ketone bodies of diacetone glucose are produced.

[0255] The ketone body of diacetone glucose produced by the oxidation step is subjected to the subsequent reduction step.

[0256] [Reduction Step] In this embodiment, the reduction step is a step of reducing the ketone body of diacetone glucose to produce diacetone allose, as shown in the following chemical reaction formula.

[0257]

[0258] The reducing agent used in the reduction step is not particularly limited, and examples thereof include sodium borohydride (NaBH ４ ) and lithium aluminum hydride (LiAlH ４ ) are listed.

[0259] Other reduction conditions may be appropriately set according to the reducing agent used so as to produce diacetone allose.

[0260] Diacetone allose can be obtained through the above oxidation and reduction steps. A specific example of diacetone allose is diacetone-D-allose. The diacetone allose obtained in this manner may be further subjected to the production of other products. For example, the obtained diacetone allose may be subjected to the production of allose as described below.

[0261] <Method for Producing Allose> Yet another embodiment of the present invention is a method for producing allose, in which allose is produced by deprotecting the diacetone allose obtained by the above-mentioned embodiment using an ion exchange resin as a catalyst. Specifically, the method for producing allose of this embodiment includes a dissolving step of dissolving diacetone allose in a solvent to produce a solution, and a reaction step of adding an ion exchange resin to the solution and mixing them to produce allose by an ion exchange reaction.

[0262] In this embodiment, the solvent used in the dissolving step is not particularly limited as long as it can dissolve diacetone allose. An example of the solvent used in the dissolving step is tetrahydrofuran.

[0263] In this embodiment, the ion exchange resin used in the reaction step is not particularly limited as long as it can produce allose. An example of the ion exchange resin used in the reaction step is commercially available "AMBERLITE" (registered trademark).

[0264] In the reaction step, an ion exchange resin is added to a solution in which diacetone allose has been dissolved and mixed, and as shown in the chemical reaction formula below, the protecting group (acetonide) of diacetone allose is deprotected by reacting with water using the ion exchange resin as a catalyst, thereby producing allose.

[0265]

[0266] Allose can be obtained by a deprotection reaction using the acidity of an ion exchange resin as a catalyst. A specific example of allose is D-allose. The allose obtained in this manner, particularly D-allose, can be used in products in the fields of functional foods and pharmaceuticals.

[0267] The methods for producing diacetone glucose and diacetone allose of this embodiment are not limited to the specific embodiments described above or the examples described below, and can be appropriately combined, substituted, modified, etc. within the scope that does not deviate from the purpose and intent of this embodiment.

[0268] Next, still another embodiment of the present invention will be described in detail.

[0269] <Method for Producing Allose, Yet Another Embodiment of the Present Invention> This embodiment relates to a method for producing allose.

[0270] (Background of the Present Embodiment) Monosaccharides are broadly classified into aldoses with a polyhydroxyl aldehyde structure, ketoses with a polyhydroxyl ketone structure, and sugar alcohols obtained by reducing these aldoses. Monosaccharides are also classified based on their abundance in nature. According to the International Rare Sugar Society's definition, rare sugars are "sugars that are rarely found in nature," and are monosaccharides that are found in small amounts in nature. Rare sugars generally result in low yields in synthetic reactions using organic chemical synthesis methods. For this reason, many rare sugars have unknown properties, and even rare aldohexose (hexose aldose) sugars, including D-allose, currently have many unknown properties. D-allose has approximately 80% the sweetness of sugar and is virtually calorie-free, making it suitable for use in supplements and other applications. D-allose is also known to inhibit the proliferation of cancer cells, and its potential use in the pharmaceutical field is anticipated.

[0271] D-allose can be produced from diacetone-D-glucose as a starting material, as described in the aforementioned non-patent document (Carbohydrate Research 24 (1972), pp. 192-197). D-allose can be produced from the starting material via intermediates such as the ketone body of diacetone-D-glucose and diacetone allose.

[0272] In the production of carbohydrates such as D-allose and its intermediates, D-allose can also be produced by biochemical methods such as carbohydrate conversion using enzymes, as described in, for example, Japanese Patent Application Laid-Open No. 2002-17392. Enzymatic methods for producing D-allose have the advantages of mild reaction conditions and short reaction times. However, enzymatic methods for producing D-allose tend to be expensive because they require the use of rare sugars as raw materials and enzymes. Furthermore, enzymatic methods for producing D-allose have the drawback of requiring specialized equipment for purification and the time and expense required for maintenance of the production equipment.

[0273] In the above-mentioned non-patent literature, D-allose is produced from diacetone allose by adding an ion exchange resin to an aqueous suspension of diacetone allose under stirring, followed by cooling to crystallize D-allose. However, this method has the problem of being unable to obtain D-allose containing metastable crystals. There is no known industrial method for producing D-allose containing metastable crystals using a relatively simple method.

[0274] Furthermore, it has been known that when a solid acid catalyst such as an acidic cation exchange resin is used as a catalyst, the acid component is released from the acidic cation exchange resin, resulting in the generation of impurities. For example, in the patent document, JP-A-9-176069, in order to solve this problem, in a method for producing bisphenols from raw materials containing a carbonyl compound and a phenol using a strongly acidic cation exchange resin, the acidic cation exchange resin is washed with water and then with phenol before being used as a catalyst.

[0275] Furthermore, in the patent document JP 2004-250619 A, the water content of a strongly acidic cation exchange resin is adjusted in order to provide a resin that leaches out less inorganic and organic acids. Neither document discloses any problems that arise when a strongly acidic cation exchange resin is used as an acid catalyst in the production of D-allose.

[0276] Diacetone glucose used to produce D-allose is disclosed in, for example, Japanese Patent Application Laid-Open Nos. 6-157574 and 6-234785.

[0277] As described above, there is no known method for industrially producing metastable crystal-containing D-allose using a relatively simple method. Furthermore, there are no known problems associated with using a strongly acidic cation exchange resin as an acid catalyst in the production of D-allose.

[0278] Therefore, an object of this embodiment is to provide a novel production method that can relatively easily produce metastable D-allose from diacetone allose.

[0279] (Means for solving the problems of the present embodiment) The present disclosure includes the following aspects.

[0280] (Disclosure 1b) Disclosure 1b is a method for producing allose. The production method 1b includes the following steps 1 to 4. Step 1 is a heating step in which a first solution in which diacetone allose is dissolved is mixed with an acid catalyst and heated to produce a second solution containing allose. Step 2 is an admixing step in which a volatile crystallization solvent in which the solubility of the allose is lower than that of the first solution is admixed with the second solution. Step 3 is a concentration step in which a third solution in which the crystallization solvent has been admixed by the admixing step is concentrated. Step 4 is a crystallization step in which the allose is crystallized from the third solution after the concentration step.

[0281] (Disclosure 2b) Disclosure 2b is the manufacturing method of Disclosure 1b, further comprising a separation step of separating the acid catalyst from the second solution heated in the heating step.

[0282] (Disclosure 3b) Disclosure 3b is the manufacturing method of Disclosure 1b or Disclosure 2b, which includes a second concentration step between the concentration step and the crystallization step, in which the crystallization solvent is added to the concentrated third solution and then the solution is further concentrated.

[0283] (Disclosure 4b) Disclosure 4b relates to any one of the manufacturing methods according to Disclosures 1b to 3b, which further includes a pre-concentration step of concentrating the second solution between the heating step and the mixing step.

[0284] (Disclosure of 5b) Disclosure of 5b is a manufacturing method according to any one of the manufacturing methods according to Disclosures 1b to 4b, wherein the concentrating step, the pre-concentrating step and / or the second concentrating step is a step of concentrating at least the second solution or the third solution under reduced pressure until the Brix value is 20 to 80.

[0285] (Disclosure 6b) Disclosure 6b is the manufacturing method of any one of the manufacturing methods of disclosures 1b to 5b, wherein the crystallization step comprises heating the third solution to a temperature of 40°C to 110°C.

[0286] Disclosure 7b is the manufacturing method of any one of Disclosures 1b to 6b, wherein the first solution is an aqueous solution in the concentrating step, and the concentrating step includes mixing the crystallization solvent and removing water from the aqueous solution.

[0287] (Disclosure 8b) Disclosure 8b is the production method according to any one of the production methods according to Disclosures 1b to 7b, wherein the crystallization solvent contains ethanol.

[0288] (Disclosure 9b) Disclosure 9b relates to the production method according to Disclosure 2b, wherein the acid catalyst is a solid acid catalyst, and the solid acid catalyst is subjected to solid-liquid separation in the separation step.

[0289] (Disclosure 10b) Disclosure 10b relates to the production method according to disclosure 9b, wherein the solid acid catalyst is at least one selected from the group consisting of a strongly acidic cation exchange resin, a zeolite, and an alumina.

[0290] (Disclosure 11b) Disclosure 11b is the manufacturing method according to disclosure 9b, wherein the solid acid catalyst is washed in advance with components of the first solution.

[0291] (Disclosure 12b) Disclosure 12b is the manufacturing method according to any one of disclosures 1b to 10b, wherein the first solution contains water or water and tetrahydrofuran.

[0292] (Effects of this embodiment) According to the production method of this embodiment, allose containing metastable crystals can be produced from diacetone allose relatively easily.

[0293] (Specific Mode for Carrying Out the Present Embodiment) A preferred specific embodiment of the method for producing allose of the present embodiment will be described below. Note that, in this specification, various numerical ranges mean ranges including the preferred upper and lower limit values ​​unless otherwise specified.

[0294] <Production of allose from diacetone allose> Allose is a type of monosaccharide classified as a hexose or aldose, and is the epimer at the 3-position of glucose. Allose is soluble in water but insoluble in methanol. In particular, D-allose is a type of monosaccharide classified as a hexose or aldose, and is a type of "rare sugar" that is rarely found in nature. It has been confirmed that the method of this embodiment can be applied to the production of not only D-allose but also L-allose.

[0295] D-allose and L-allose each have the following structure:

[0296] This embodiment provides a method for producing allose from diacetone allose, comprising the following steps: (1) a heating step of mixing and heating a first solution in which diacetone allose is dissolved with an acid catalyst to produce a second solution containing allose; (2) optionally, a separation step of separating the acid catalyst from the second solution heated in the heating step; (3) optionally, a preconcentration step of concentrating the second solution between the heating step and the mixing step; (4) an mixing step of mixing a volatile crystallization solvent in which the solubility of allose is lower than that of the first solution into the second solution; (5) a concentration step of concentrating a third solution mixed with the crystallization solvent in the mixing step; and (6) a crystallization step of crystallizing the allose from the third solution after the concentration step. (7) Optionally, between the concentration step and the crystallization step, a second concentration step is performed in which the crystallization solvent is added to the concentrated third solution, followed by further concentration.

[0297] (Heating Step) In the heating step of the present embodiment, the first solution in which diacetone allose is dissolved and the acid catalyst are mixed and heated to produce a second solution containing allose.

[0298] In the heating step, the protecting group (acetonide) of diacetone allose is deprotected by reaction with water using, for example, the acidity of an ion exchange resin as a catalyst, to produce allose. Specifically, when allose is in the D-form, D-allose is produced from diacetone-D-allose as shown in the following chemical reaction formula:

[0299]

[0300] In this embodiment, the solvent for dissolving diacetone allose to produce the first solution for the heating step is not particularly limited as long as it can dissolve diacetone allose. Examples of preferred solvents include water, tetrahydrofuran (THF), acetonitrile, ethyl acetate, and methyl ethyl ketone. At least one of water and THF is particularly preferred as the solvent for dissolving diacetone allose.

[0301] In this embodiment, the ion exchange resin used as the solid acid catalyst in the reaction step is not particularly limited as long as it is capable of producing allose, and may be, for example, a gel or porous type. Examples include strongly acidic cation exchange resins, such as sulfonic acid-based cation exchange resins, styrene-divinylbenzene copolymers, perfluoroethylene copolymers, phenol-formaldehyde polymers, zeolites, alumina, and titanosilicate (TS-1). The acid catalyst is preferably a solid catalyst for ease of separation. The amount of catalyst added is not particularly limited, but the amount of acid catalyst used per gram of diacetone allose may be 100% by mass to 300% by mass, preferably 100% by mass to 200% by mass, on a wet basis. Ion exchange using an acid catalyst is preferably carried out in the presence of water.

[0302] The heating temperature is not particularly limited as long as it is a temperature that promotes the ion exchange of diacetone allose with an acid catalyst, and may be, for example, in the range of 30 to 75° C., preferably 40 to 60° C. The heating time is also not particularly limited, and may be, for example, about 30 minutes to 10 hours, preferably 1 to 6 hours, and more preferably 2 to 4 hours.

[0303] (Separation Step) The separation step is an optional step, and is preferably employed to separate and remove an acid catalyst to prevent contamination with an ion exchange resin used as an acid catalyst in a subsequent step. The separation means is not particularly limited and may be a conventional means such as a filter or a centrifugal separation. Preferably, the separation step is followed by a desalting step using an ion exchange resin and / or a removal step of organic matter using activated carbon. If the crude product contains impurities such as ionic substances or water-soluble organic matter, they may remain without being removed by crystallization. Therefore, by providing a desalting step and / or a removal step using activated carbon before crystallization, it is possible to remove ionic impurities in the desalting step and organic matter in advance using activated carbon.

[0304] (Preconcentration Step) The preconcentration step is a step of concentrating the second solution between the heating step and the mixing step. The concentration may be performed to reduce the total volume of the solution and to avoid increasing the viscosity, for example, until the Brix value reaches 20 to 80, preferably 30 to 70, and more preferably 40 to 60. The concentration method is not particularly limited as long as it does not impair the effects of this embodiment, and may be, for example, reduced pressure, drying, or filtration.

[0305] (Mixing Step - Concentrating Step - Crystallization Step) In this embodiment, the mixing step is a step of mixing a volatile crystallization solvent in which the solubility of the allose is lower than that of the first solution into the second solution.

[0306] In this embodiment, the volatile crystallization solvent having a lower solubility of allose than the first solution may be any solvent capable of suppressing the dissolution of allose and crystallizing allose. The volatile crystallization solvent is preferably a water-soluble solvent that can be easily removed by evaporation under reduced pressure or heating due to its volatility. Examples of the crystallization solvent include volatile solvents that have a lower solubility of allose than the first solution at room temperature, with the difference in solubility being 100 g / L to 2000 g / L, preferably 300 g / L to 1500 g / L, and more preferably 700 g / L to 1300 g / L at room temperature. For example, when the first solution is water, specific examples of the volatile crystallization solvent include lower alcohols such as ethanol, n-propanol, and isopropanol. The solubility of allose in water at room temperature is approximately 1000 g / L, while the solubility of allose in ethanol at room temperature is 1.62 g / L.

[0307] The concentration step is a step of concentrating the third solution into which the crystallization solvent has been mixed in the mixing step. The concentration step allows for slow cooling by mixing the crystallization solvent. Preferably, seed crystals are added to the concentration step. Generally, using seed crystals is preferable in terms of controlling the crystal form. On the other hand, if there is a possibility that the crystals may change from a metastable form to a stable form, the seed crystals used may be contaminated with even a trace amount of stable crystals, and it may be better not to add seed crystals. The concentration may be performed, for example, until the Brix value reaches 20 to 80, preferably 30 to 70, and more preferably 40 to 60. The concentration method is not particularly limited as long as it does not impair the effects of this embodiment, and may be, for example, reduced pressure, drying, or filtration.

[0308] In the allose production method of this embodiment, the above-mentioned concentration step using a volatile crystallization solvent without adding water is provided, thereby increasing the concentration rate and the allose recovery rate, for example, to 80% or more, further 90% or more, even 96% or more, and even close to 100%. Allose is easily crystallized by adding a volatile crystallization solvent, such as ethanol. Allose itself has very low solubility in a volatile crystallization solvent, making recovery easy and increasing the recovery rate. In particular, in the allose production method of this embodiment, by repeatedly gradually replacing the solution with a volatile crystallization solvent, the water content can be reduced compared to when an aqueous allose solution is added to a volatile crystallization solvent, thereby significantly increasing the allose recovery rate. Furthermore, in the allose production method of this embodiment, water forms an azeotrope when the volatile crystallization solvent (ethanol) is removed by distillation or the like, and therefore, anhydrous allose crystals are more likely to be formed as the concentration of the volatile crystallization solvent increases. Furthermore, allose becomes hydrated crystals when there is a lot of water, so a drying step is required. However, azeotropy allows the production of anhydrous allose crystals without the need for a drying step, which is more efficient.

[0309] In the embodiment of the method for producing allose, a second concentration step may preferably be provided between the concentration step and the crystallization step, in which the crystallization solvent is added to the concentrated third solution and then the solution is further concentrated.

[0310] The second concentration step may be repeated multiple times, thereby increasing the amount of allose crystallized. The concentration may be performed, for example, until the Brix value reaches 20 to 80, preferably 30 to 70, and more preferably 40 to 60. The concentration method is not particularly limited as long as it does not impair the effects of this embodiment, and may be, for example, reduced pressure, drying, or filtration.

[0311] When the first solution is an aqueous solution, the concentration step and / or the second concentration step can involve the addition of the crystallization solvent and the removal of water from the aqueous solution. The addition of the crystallization solvent and the removal of water from the aqueous solution can be performed simultaneously or alternately. Preferably, the addition of the crystallization solvent and the removal of water from the aqueous solution are performed using a reaction vessel (15b) optionally connected to a vacuum pump and equipped with a dropping funnel (16b) for adding a volatile crystallization solvent, as shown in FIG. 12 . The reaction vessel (15b) may further have an opening (20b) for adding seed crystals, if necessary. By using this apparatus, solvent substitution can be performed by dropping a volatile crystallization solvent while recovering and removing water by distillation in a recovery vessel (19b), preferably under reduced pressure (18b), thereby improving the efficiency of the crystallization step.

[0312] The crystallization step is a step of crystallizing the allose from the third solution after the concentration step. According to this embodiment, allose containing metastable crystals can be produced relatively easily from diacetone allose. Metastable crystals of diacetone allose can also be converted to stable crystals depending on the storage conditions. Allose containing metastable crystals may be, for example, metastable allose alone, or may contain both metastable and stable allose. The conditions for the crystallization step are not particularly limited, as long as they allow crystals to emerge from a volatile crystallization solvent, such as ethanol. For example, the temperature range during concentration under which allose crystals precipitate is preferably 40°C to 110°C, more preferably 50°C to 100°C, and even more preferably 60°C to 90°C.

[0313] Generally, crystals can be obtained by crystallization at a lower temperature. In the case of a method of crystallization by simply lowering the temperature, allose crystals tend to adhere to the walls of the reaction vessel, which cools first, making stirring and subsequent removal of the allose crystals difficult. On the other hand, in the preferred method for producing allose of this embodiment, concentration and ethanol substitution are carried out at a predetermined temperature, for example, 40°C to 110°C, and since the wall temperature of the reaction vessel is high, allose crystals emerge within the solution without adhering to the wall of the reaction vessel. As a result, the method for producing D-allose of this embodiment has the advantage that allose crystals do not adhere to the walls of the reaction vessel, making stirring and removal of D-allose crystals easy.

[0314] Furthermore, in the method for producing allose of this embodiment, by performing a step of washing the solid acid catalyst in advance with the solution to be used, it is possible to produce allose with fewer impurities and high purity.

[0315] In the method for producing allose of this embodiment, a step of pre-washing the solid acid catalyst with the solution to be used allows the production of allose with fewer impurities and higher purity. The pre-washing step for the acid catalyst can be carried out by preparing a solvent, such as tetrahydrofuran (THF), used to dissolve water and diacetone allose in the strongly acidic cation exchange resin, adding a small amount of water to the strongly acidic cation exchange resin, stirring for an appropriate period of time, and then filtering through a funnel to remove the water. Thereafter, the strongly acidic cation exchange resin filtered onto filter paper may be washed by alternately pouring water and THF at room temperature while suctioning. The solid acid catalyst is used in the reaction only after visually confirming that the filtrate is not colored after washing.

[0316] However, even after washing the strongly acidic cation exchange resin, the produced allose solution may be weakly acidic. This is thought to be because, when diacetone allose is contaminated with a trace amount of inorganic matter (e.g., inorganic salts such as sodium sulfate), the cations of the inorganic matter are exchanged for protons by the strongly acidic cation exchange resin in the allose production process, resulting in an acidic substance (e.g., sulfuric acid).

[0317] Therefore, it is preferable to convert the anions of acidic substances into water by exchanging them with hydroxy ions using an anion exchange resin before crystallization of allose. In other words, since the process for producing allose from diacetone allose of this embodiment is the final process in which the purity of allose is desired to be further improved, it is preferable to have a removal step of removing water-soluble ionic substances (inorganic salts) using an anion exchange resin or both an anion exchange resin and a cation exchange resin before recrystallization, and an adsorption step of adsorbing fat-soluble organic compounds with activated carbon.

[0318] In the production process of this embodiment, the removal step and the adsorption step may be carried out simultaneously or separately. Furthermore, by including the removal step and the adsorption step in the production process of this embodiment, the purity of allose can be further improved. Even if the anion exchange resin contains impurities derived from the raw materials of the anion exchange resin, these can be removed by activated carbon in the adsorption step, but it is more preferable to wash the anion exchange resin with the solution to be used beforehand.

[0319] In this embodiment, the starting material diacetone allose may be produced, for example, starting from glucose, via diacetone glucose and its ketone body.

[0320] <Production of diacetone glucose from glucose> Diacetone glucose can be produced from glucose, for example, by dissolving glucose in acetone and acetonidating it with an acid catalyst. The chemical reaction formula for producing diacetone-D-glucose from D-glucose is shown below.

[0321]

[0322] Briefly, diacetone glucose can be produced by a process comprising the following steps (1) to (6): (1) reacting α-D-glucose with acetone in the presence of a Lewis acid at a temperature in the range of 80 to 120°C under a pressure of at least 2.5 bar; (2) distilling off components that are volatile under these conditions and replacing the distillate with acetone until about 5 / 3 of the initial reaction volume has been replaced with acetone; (3) the reaction mixture is then distilled off under reduced pressure at a temperature in the range of 30 to 70°C and mixed with an aqueous solution of a base; (4) the reaction mixture is distilled off under reduced pressure at a temperature in the range of 30 to 70°C, extracted with an organic extractant, and the extract is distilled off; (5) the residue is combined with an organic precipitant and heated to a temperature in the range of 65 to 80°C; (6) the crystals that form on cooling are isolated as 1,2-5,6-diacetone-D-glucose.

[0323] Diacetone glucose can also be produced by a process comprising the following steps (1) to (4): (1) reacting α-D-glucose with diketene in acetone in the presence of a Lewis acid or a Brönsted acid at a temperature in the range of 60 to 120°C; (2) after completion of the reaction, the reaction mixture is cooled, and then any solid components are removed. Then, an aqueous solution of an alkaline reactive compound is added to the solution and mixed until the pH is in the range of 6 to 8; (3) distilling off the acetone, and extracting the residue with a water-immiscible organic extractant; (4) evaporating the extractant, and recrystallizing the residue from an organic solvent to isolate the resulting 1,2-5,6-diacetone-D-glucose.

[0324] Alternatively, diacetone glucose can also be produced by a method including the following dissolving step, reacting step, and neutralizing step: a dissolving step of mixing glucose, an aprotic polar solvent in which the glucose is soluble, and acetonide to produce a solution, a reacting step of adding a Lewis acid catalyst that promotes the reaction between glucose and acetonide to the solution to produce a reaction solution, and a neutralizing step of adding a gelation inhibitor and a neutralizing agent to the reaction solution to neutralize it.

[0325] The aprotic polar solvent referred to here is preferably at least one solvent selected from the group consisting of acetone, tetrahydrofuran, and ethyl acetate, and particularly preferably acetone, which is also an acetonidation reagent. When acetone is used as both the aprotic polar solvent and the acetonidation reagent, there is no need to provide separate storage tanks for the aprotic polar solvent and the acetonidation reagent, which further facilitates avoiding the expansion of the production equipment.

[0326] To obtain diacetone glucose from glucose, glucopyranose undergoes an equilibrium reaction to become glucofuranose via acyclic glucose, and then two diol structures must react with one molecule of acetone each in the presence of an acid catalyst. This reaction produces two molecules of acetonide and two molecules of water. The water produced is trapped in the initial stage of the reaction by reacting with acetone in the presence of an acid catalyst to form 1,1-dihydroxypropane. More specifically, to convert glucose to diacetone glucose, the six-membered ring glucose in the crystal or aqueous solution first becomes linear and then recyclizes to form a five-membered ring glucose. The five-membered ring glucose reacts with two molecules of acetone to form the five-membered ring diacetone glucose, releasing two molecules of water. The resulting water molecules are thought to increase the solubility of glucose in acetone. However, they also accelerate the reverse reaction from diacetone glucose to five-membered ring glucose. Because this reverse reaction plays a large role, the rate of diacetone glucose production is thought to gradually decrease as the amount of water in acetone increases as the reaction progresses.

[0327] Furthermore, if a large amount of water is produced as the reaction progresses, the water that cannot be trapped as 1,1-dihydroxypropane will react with diacetone glucose, resulting in an equilibrium reaction with a reaction that returns to glucose and acetone through a reverse reaction. In order to shift this equilibrium reaction in the direction of increasing the amount of diacetone glucose produced, it is necessary to increase the amount of acetone unless a dehydrating agent or the like is used. In particular, glucose has the property of being difficult to dissolve in acetone, and simply converting it into acetonide using an acid catalyst cannot produce large amounts of diacetone glucose, making industrial mass production difficult. In other words, industrial mass production of diacetone glucose requires a large amount of acetone to dissolve glucose, which poses the problem of the expansion of production equipment such as tanks and reaction vessels for storing it. Therefore, this method for producing diacetone glucose from glucose optionally further includes a step of removing an aprotic polar solvent from the solution containing diacetone glucose during the reaction step.

[0328] When acetone, for example, is used as the aprotic polar solvent, the solvent removal step can be performed using a reflux dehydration reactor, such as that shown in Figure 13, which has a reaction vessel connected to both a vacuum pump (8b) and a cooler (5b) via a pipe equipped with a tube formed of a zeolite membrane. This allows water and an organic solvent such as acetone to be separated and recovered, making it possible to reuse the organic solvent. The principle is as follows.

[0329] Acetone and water do not form an azeotrope, but pseudo-azeotropic distillation does occur. When the reaction vessel is heated in the oil bath (2b) in the apparatus shown in Figure 13, the water produced in the reaction system rises as vapor together with acetone, is cooled in the upper condenser (5b), and refluxes.

[0330] A tube made of a zeolite membrane (4b) is installed between the reaction vessel and the cooler (5b). The zeolite membrane (4b) has minute pores specific to its structure, allowing only water to selectively pass through. When a mixture of vaporized acetone and water is brought into contact with the zeolite membrane (4b) while the inside of the zeolite membrane (4b) is under negative pressure using a vacuum pump (8b) connected to the end of the tube, only the vaporized water passes through the negatively pressurized zeolite membrane, is cooled in a cold trap (9b), and is removed as water or ice.

[0331] On the other hand, acetone that cannot pass through the zeolite membrane is cooled by the cooler above and returned to the reactor for reuse. By continuing this process, only the water in the reaction system can be removed, and the reaction can be completed without solvent exchange.

[0332] Alternatively, this solvent removal step can use a reaction vessel (10b) connected to a vacuum pump and equipped with a dropping funnel (11b) for adding an aprotic polar solvent, for example, acetone, as shown in Figure 14. By using this apparatus, water is removed by distillation under reduced pressure (13b) and recovered in a recovery vessel (14b), while at the same time the aprotic polar solvent is dropped from the dropping funnel (11b) into the reaction vessel (10b) to replenish the reaction solution, thereby performing solvent replacement and preventing an increase in the amount of water in the aprotic polar solvent.

[0333] Furthermore, as a starting material, diacetone glucose that has been concentrated and crystallized into a solid state after the above-mentioned steps may be used, or a solution in which diacetone glucose is dissolved in an aprotic polar solvent may be used as the first solution without carrying out the steps of concentration and crystallization into a solid state.

[0334] <Production of ketone bodies from diacetone glucose> Ketone bodies can be produced by oxidizing diacetone glucose. The chemical reaction is shown below.

[0335]

[0336] (Oxidizing Agent) The oxidizing agent used in the oxidation step is not particularly limited, and examples thereof include hypochlorous acid and hypochlorites. Specific examples include hypochlorous acid, hypobromite, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, and hydrates thereof, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, trichloroisocyanuric acid, iodobenzene diacetate, gaseous oxygen, sodium chlorite, potassium chlorite, calcium chlorite, metachlorobenzoic acid (mCPBA), hydrogen peroxide, and a double salt of potassium hydrogen persulfate, potassium hydrogen sulfate, and potassium sulfate (2KHSO5.KHSO4.K2SO4). Furthermore, the oxidizing agent may be, for example, high-grade bleaching powder (effective chlorine concentration of 60% or more), a sodium hypochlorite aqueous solution (effective chlorine concentration of 5% or more), sodium hypochlorite pentahydrate, or air.

[0337] (Oxidation Catalyst) An oxidation catalyst may be used together with the oxidizing agent. Examples of the oxidation catalyst include organic nitroxyl radical-based oxidation catalysts, such as 2-azaadamantane-N-oxyl (AZADO), 9-azanoradamantane-N-oxyl (nor-AZADO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 1,5-dimethyl-9-azanoradamantane-N-oxyl (DMN-AZADO), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), silica gel-supported TEMPO, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-hydroxy-TEMPO), and [4-hydroxy-TEMPO + NaCl] / SiO ２, 4-amino-TEMPO, 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-phenoxy-TEMPO, 4-acetoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-methacrylate-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, 4-paratoluenesulfonyloxy-TEMPO, 4-oxo-TEMPO, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxy, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxy "2,2,6,6-tetramethylpiperidine nitroxyl radical compounds" such as 4-oxo-2,2,6,6-tetramethylpiperidin-1-oxy, 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxy, 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxy, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-oxy, and 4-(benzoyloxy)-2,2,6,6-tetramethylpiperidin-1-oxy, as well as di-tert-butyl nitroxide radicals; Examples of suitable nitroxides include diphenyl nitroxide, bis(4-methoxyphenyl) nitroxide, phenyl(tert-butyl) nitroxide, 2-naphthyl(tert-butyl) nitroxide, 2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-oxy, 3,3,5,5-tetramethyl-4-morpholinyloxy, 9-azabicyclo[3,3,1]nonane-N-oxyl (ABNO), and 2-hydroxy-2-azaadamantane (AZADOL).

[0338] Other oxidation conditions may be appropriately set depending on the oxidizing agent used, so that ketone bodies of diacetone glucose are produced.

[0339] The ketone body of diacetone glucose produced by the oxidation step is subjected to the subsequent reduction step.

[0340] <Production of diacetone allose from ketone bodies> Diacetone allose can be produced by reducing ketone bodies. The chemical reaction formula is shown below.

[0341]

[0342] The reducing agent used in the reduction step is not particularly limited, and examples thereof include sodium borohydride (NaBH ４ ) and lithium aluminum hydride (LiAlH ４ ) are listed.

[0343] Other reduction conditions may be appropriately set according to the reducing agent used so as to produce diacetone allose.

[0344] Diacetone allose can be obtained through the above oxidation and reduction steps. A specific example of diacetone allose is diacetone-D-allose. The diacetone allose obtained in this manner may be further subjected to the production of other products. For example, the obtained diacetone allose may be subjected to the production of allose as described below.

[0345] The method for producing D-allose in this embodiment is not limited to the specific embodiments described above or the examples described below, and appropriate combinations, substitutions, modifications, etc. are possible within the scope that does not deviate from the purpose and intent of this embodiment.

[0346] EXAMPLES The present invention will be explained in more detail below by way of examples and comparative examples, but the present invention is not limited to these examples.

[0347] Example 1 (Synthesis Example 1) <Production of a ketone body from diacetone glucose (Synthesis Example 1-1)> Diacetone glucose (Compound 1) (1 g) and ethyl acetate (4.2 mL) were placed in a 50 mL flask and stirred at room temperature to dissolve (Step 1). Saturated aqueous sodium bicarbonate solution (1.8 mL) and potassium bromide (46 mg) were added, and the mixture was cooled in an ice bath. To the cooled mixture, nor-AZADO (0.03 mg) was added as an ethyl acetate solution, and then aqueous sodium hypochlorite solution (4.2 mL, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise, followed by stirring at room temperature for 1 hour (Step 2). Saturated aqueous sodium thiosulfate solution (1.2 mL) was added to the reaction solution and stirred (Step 3), followed by extraction four times with ethyl acetate (4 mL) (Step 4). The organic solutions were mixed and washed with saturated saline (2 mL), and then anhydrous sodium sulfate (5 g) was added for drying. The drying agent was filtered off, and the obtained filtrate was concentrated under reduced pressure to obtain a crude product (Compound 2), which was a ketone form of diacetone glucose, as a colorless solid.

[0348] Preparation of Diacetone Allose from Ketone Bodies (Synthesis Example 1-2) Compound 2 prepared as described above was dissolved in tetrahydrofuran (1.56 L). A 2-L flask was charged with 100% ethanol (0.52 L) and cooled to 10°C in an ice bath. Sodium tetrahydroborate (26.607 g) was added to prepare a suspension (Step 5). The prepared tetrahydrofuran solution was added dropwise over approximately 1 hour while stirring the suspension with a mechanical stirrer, followed by stirring at 5°C to 10°C for 1 hour (Step 6). After adding 5% aqueous ammonium chloride solution (1.65 L), the reaction mixture was extracted four times with ethyl acetate (0.3 L). The extracted organic solutions were mixed and washed with saturated saline (0.3 L). Anhydrous sodium sulfate (300 g) was added to the organic solution, and the mixture was dried for 16 hours. The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (450.79 g). The resulting crude product was dissolved in toluene (0.35 L) while heating, and seed crystals were added to n-heptane (1.75 L) stirred with a mechanical stirrer in an ice bath. The toluene solution was then slowly added dropwise, and the mixture was stirred in the ice bath for 1 hour. The resulting crystals were collected by filtration and washed with n-heptane (0.3 L), yielding diacetone allose, Compound 3 (382.48 g), as a colorless solid. (Total yield of Synthesis Example 1: 67.3%)

[0349] Example 2 (Synthesis Example 2) <Production of Ketone Body from Diacetone Glucose (Synthesis Example 2-1)> Diacetone glucose (Compound 1) (5 g) was added to ethyl acetate (22 mL) and stirred at room temperature to dissolve (Step 1). Potassium bromide (229 mg) and saturated sodium bicarbonate (9 mL) were added to the ethyl acetate solution, and the mixture was cooled in an ice bath. Nor-AZADO (0.1 mg) was added to the cooled mixture, and then an aqueous sodium hypochlorite solution (21 mL, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise, followed by stirring at 0°C for 1 hour (Step 2). After 1 hour, stirring was stopped, and a saturated aqueous sodium thiosulfate solution (6 mL) was added (Step 3), followed by extraction four times with ethyl acetate (10 mL) (Step 4). The organic solutions were mixed, washed with saturated brine, and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the mixture was concentrated to about half its original volume under reduced pressure to obtain an ethyl acetate solution (about 30 mL) of a crude product (compound 2), which was a ketone form of diacetone glucose.

[0350] After storing the ethyl acetate solution of the crude product at room temperature for 2 days, the TLC of the crude product was checked, and it was confirmed that no impurities had been produced, compared with the TLC before storage.

[0351] <Preparation of diacetone allose from ketone bodies (Synthesis Example 2-2)> Sodium tetrahydroborate (254 mg) was added to 100% ethanol (5 mL) cooled in an ice bath to prepare a suspension (Step 5). An ethyl acetate solution (approximately 30 mL) of compound 2 prepared as described above was added dropwise to the prepared ethanol suspension, followed by stirring at 5 to 10°C for 1 hour (Step 6). The reaction mixture was added to saturated saline, and the mixture was extracted four times with ethyl acetate (10 mL). The extracted organic solutions were mixed and washed with saturated saline (10 mL), and then dried by adding anhydrous sodium sulfate. The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (4.534 g). The resulting crude product was dissolved in toluene (3 mL) with heating, and seed crystals were added to n-heptane (20 mL) stirred in an ice bath. The toluene solution was then slowly added dropwise, and the mixture was stirred in the ice bath for 1 hour. The resulting crystals were collected by filtration and washed with ice-cold n-heptane to obtain diacetone allose, Compound 3 (3.403 g), as a colorless solid (total yield of Synthesis Example 2: 68%).

[0352] (NMR analysis) When the integral values ​​of the NMR of the proton on the carbon at position 1 (anomeric carbon) of the crude product obtained in Synthesis Example 2 were compared, the ratio of ketone body to hydrate was 3.5:1. The conditions for NMR analysis were as follows: NMR apparatus: AV400N ( １ Measurements were performed using a 1H resonance frequency (400 MHz) (Bruker Corporation). A 90°C pulse was accumulated 16 times at 14 μs. The sample was dissolved in chloroform-d, 99.8% (containing 0.05 vol% TMS) (Fujifilm Wako Pure Chemical Industries) to a concentration of 10 mg / mL, and the solution was added to a 5 mm diameter sample tube. １ H-NMR measurements were performed, and the NMR spectra were obtained by Fourier transformation using Bruker Top Spin software.

[0353] Example 3 (Synthesis Example 3) <Production of Ketone Form from Diacetone Glucose> Diacetone glucose (Compound 1) (1 g) was added to ethyl acetate (4 mL) and stirred at room temperature to dissolve (Step 1). Potassium bromide (46 mg) and saturated sodium bicarbonate (3.6 mL) were added to the ethyl acetate solution, and the mixture was cooled in an ice bath. Nor-AZADO (0.03 mg) was added to the cooled mixture, followed by N-chlorosuccinimide (770 mg, Tokyo Chemical Industry Co., Ltd.) and stirring at 0°C for 2 hours (Step 2). After 2 hours, stirring was stopped, and saturated aqueous sodium thiosulfate solution (3 mL) was added (Step 3). Extraction was performed four times with ethyl acetate (4 mL) (Step 4). The organic solutions were mixed, washed with saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude product (891 mg) that was a ketone form of diacetone glucose.

[0354] As in Synthesis Example 2, the crude product obtained in Synthesis Example 3 was compared for the integral values ​​of the proton on the carbon at position 1 (anomeric carbon) by NMR, and the ratio of ketone body to hydrate was found to be 6.9:1.

[0355] Example 4 <Effect of Alcohol Concentration in the Production of Diacetone Allose from Ketone Bodies> In the same manner as in Synthesis Example 1-2, different concentrations of methanol, ethanol, isopropanol, n-butanol, and t-butanol were used as the solvent for suspending the reducing agent sodium tetrahydroborate, and the effect of the alcohol concentration on foaming was compared.

[0356] As a result, as shown in the table below, foaming was observed in all alcohol concentrations except 100% by volume. Methanol also reacted with NaBH4 to generate hydrogen gas, and foaming was observed even at a concentration of 100% by volume. A more detailed analysis of 91-99% by volume using ethanol revealed no foaming at 98 and 99% by volume, slight foaming at 96 and 97% by volume, and foaming at 95% by volume or less.

[0357]

[0358] In the above table, "◯" means "no foaming", "Δ" means "some foaming observed", and "×" means "foaming observed".

[0359] Example 5 <Comparison of Solvents in Crystallization of Diacetone Allose> Using crude diacetone allose obtained in the middle of Synthesis Example 2-2, the degree of crystallization in each of the following solvents was compared.

[0360] A solution of crude diacetone allose (630 mg) in toluene (1 mL) was added to heptane (15 mL) and seed crystals to crystallize, resulting in 529 mg of diacetone allose crystals (recovery rate: 84%).

[0361] A solution of crude diacetone allose (630 mg) in ethyl acetate (1 mL) was added to heptane (15 mL) and seed crystals to crystallize, resulting in 518 mg of diacetone allose crystals (recovery rate: 82%).

[0362] A solution of crude diacetone allose (630 mg) in methyl tert-butyl ether (3 mL) was added to heptane (15 mL) and seed crystals to crystallize, resulting in 487 mg of diacetone allose crystals (recovery rate: 77%).

[0363] A solution of crude diacetone allose (630 mg) in acetone (0.5 mL) was added to heptane (15 mL) and seed crystals to crystallize, resulting in 462 mg of diacetone allose crystals (recovery rate: 73%).

[0364] A solution of crude diacetone allose (630 mg) in tetrahydrofuran (1 mL) was added to heptane (15 mL) and seed crystals to crystallize, resulting in 471 mg of diacetone allose crystals (recovery rate: 75%).

[0365] Example 6 (Scale-up Example 1) <Production of ketone body from diacetone glucose (Synthesis Example 3-1)> Diacetone glucose (Compound 1) (568.18 g) was added to ethyl acetate (2.4 L) and stirred at room temperature for 30 minutes using a mechanical stirrer to dissolve (Step 1). Water (1 L), potassium bromide (25.978 g), and sodium bicarbonate (150 g) were added, and the mixture was cooled to 5°C in an ice bath. After adding nor-AZADO (0.057 g), an aqueous sodium hypochlorite solution (2.045 L, Wako Pure Chemical Industries, available chlorine concentration: 5% or more) was added dropwise over approximately 2 hours, and the mixture was further stirred at room temperature for 1 hour (Step 2).

[0366] Stirring was stopped, the organic solution was separated, and the aqueous layer was extracted four times with ethyl acetate (0.3 L) (Steps 3 and 4). The organic solutions were combined and washed with saturated brine (0.3 L), and then anhydrous sodium sulfate (300 g) was added and dried for 16 hours. The desiccant was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (Compound 2) (518.998 g, crude product), a ketone form of diacetone glucose, as a colorless solid.

[0367] <Production of diacetone allose from ketone body (Synthesis Example 3-2)> To sodium tetrahydroborate (26.607 g), ice-cooled ethanol (0.52 L) was added to prepare a suspension at 10°C (Step 5). Separately, Compound 2 produced in Step 2 was dissolved in tetrahydrofuran (1.56 L).

[0368] To the sodium tetrahydroborate suspension, a tetrahydrofuran solution of Compound 2 was added dropwise over approximately 1 hour while stirring under ice cooling (Step 6). The mixture was then stirred at 5°C to 10°C for 1 hour. After adding 5% aqueous ammonium chloride solution (1.65 L), the reaction mixture was extracted four times with ethyl acetate (0.3 L). The extracted organic solutions were mixed and washed with saturated brine (0.3 L), and then anhydrous sodium sulfate (300 g) was added to the organic solution, followed by drying for 16 hours. The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (450.79 g) of diacetone allose.

[0369] The obtained crude product was dissolved in toluene (0.35 L) while heating. n-Heptane (1.75 L) was cooled by stirring with a mechanical stirrer in an ice bath. After adding seed crystals, the above toluene solution was slowly added dropwise. The mixture was stirred in the ice bath for another hour to precipitate crystals.

[0370] The resulting crystals were collected by filtration and washed with n-heptane (0.3 L) to obtain diacetone allose, Compound 3 (382.48 g), as a colorless solid (total yield of Synthesis Example 3: 67.3%).

[0371] Example 7 (Scale-up Example 2) <Production of Ketone Body from Diacetone Glucose (Synthesis Example 4-1)> Diacetone glucose (Compound 1) (568.18 g) and ethyl acetate (2.4 L) were placed in a 10 L flask and stirred at room temperature for 30 minutes using a mechanical stirrer to dissolve (Step 1). Water (1 L), potassium bromide (25.978 g), and sodium bicarbonate (150 g) were added, and the mixture was cooled to 5°C in an ice bath. Nor-AZADO (0.057 g) was added to the cooled mixture, and then an aqueous sodium hypochlorite solution (2.045 L, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise over approximately 2 hours, followed by stirring at room temperature for 1 hour (Step 2). After 1 hour, stirring was stopped, the organic solution was removed (Step 3), and the aqueous layer was extracted four times with ethyl acetate (0.3 L) (Step 4). The organic solutions were mixed and washed with saturated saline (0.3 L), and then anhydrous sodium sulfate (300 g) was added and dried for 16 hours. The desiccant was filtered off, and the mixture was concentrated under reduced pressure to obtain a crude ethyl acetate solution of diacetone glucose ketone. The solution was stored at room temperature.

[0372] Preparation of diacetone allose from ketone bodies (Synthesis Example 4-2) Ethanol (0.52 L) was placed in a 2 L flask and cooled to 10°C in an ice bath. Sodium tetrahydroborate (26.607 g) was added to prepare a suspension (Step 5). While stirring the suspension with a mechanical stirrer, the ethyl acetate solution prepared in the above step was added dropwise over approximately 1 hour, followed by stirring at 5°C to 10°C for 1 hour (Step 6). After adding 5% aqueous ammonium chloride solution (1.65 L), the reaction mixture was extracted four times with ethyl acetate (0.3 L). The extracted organic solutions were mixed and washed with saturated saline (0.3 L). Anhydrous sodium sulfate (300 g) was added to the organic solution, and the mixture was dried for 16 hours. The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (450.79 g). The resulting crude product was dissolved in toluene (0.35 L) while heating, and seed crystals were added to n-heptane (1.75 L) stirred with a mechanical stirrer in an ice bath. The toluene solution was then slowly added dropwise, and the mixture was stirred in the ice bath for 1 hour. The resulting crystals were collected by filtration and washed with n-heptane (0.3 L), yielding compound 3 (382.48 g), which was diacetone allose, as a colorless solid. (Total yield of Synthesis Example 4: 67.3%)

[0373] Example 8 (Synthesis Example 5-1) <Step 1: Production of diacetone-D-glucose> (50 g scale production of D-glucose, four consecutive reactions) Acetone (0.5 L, Wako Pure Chemical Industries, Grade 1) and glucose (50 g, Wako Pure Chemical Industries, Special Grade, unground) were placed in a 1 L three-neck flask, and the atmosphere inside the vessel was replaced with argon gas. Then, anhydrous iron(III) chloride (3.6 g, 0.08 equivalents, Aldrich) was added in approximately four portions with stirring at room temperature (first dissolution step). The mixture was stirred in an oil bath at 50°C for 3 hours (first reaction step). After 3 hours, the solid unreacted D-glucose and reaction solution 1 were separated. Reaction solution 1 was then slowly added to a neutralizing aqueous solution (third aqueous solution) prepared by mixing saturated aqueous sodium bicarbonate (0.9 L) as a neutralizing agent, trisodium citrate (90 g) as a gelation inhibitor, and table salt (75 g) to neutralize the solution (first neutralization step). The separated organic solution was concentrated under reduced pressure (water bath temperature: 40° C., vacuum degree: 100 to 150 hPa), and the residual solution was mixed again with the aqueous solution for neutralization.

[0374] The aqueous neutralization solution to which the reaction solution had been added was stored at room temperature until the reaction was completely completed.

[0375] Acetone (0.5 L, Wako Pure Chemical Industries, Ltd. Grade 1) was added to the solid unreacted glucose remaining in the reaction vessel, and anhydrous iron(III) chloride (3.6 g, 0.08 equivalents, Aldrich) was added in approximately four portions while stirring at room temperature. The mixture was stirred in an oil bath at 50°C for 1.5 hours, followed by 16 hours of stirring at room temperature. After 16 hours, the solid unreacted D-glucose and reaction solution 2 were separated, and reaction solution 2 was slowly added to a neutralization solution for neutralization. The separated organic solution was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was mixed again with the neutralization solution. Acetone (0.5 L, Wako Pure Chemical Industries, Ltd. Grade 1) was added to the solid unreacted D-glucose remaining in the reaction vessel, and anhydrous iron(III) chloride (3.6 g, 0.08 equivalents, Aldrich) was added in approximately four portions while stirring at room temperature. The mixture was stirred in an oil bath at 50°C for 3 hours. After 3 hours, the solid unreacted D-glucose and reaction solution 3 were separated, and reaction solution 3 was slowly added to the aqueous solution for neutralization to neutralize it. The separated organic solution was concentrated under reduced pressure (water bath temperature: 40°C, degree of vacuum: 100 to 150 hPa), and the residual solution was mixed again with the aqueous solution for neutralization.

[0376] Acetone (0.5 L, Wako Pure Chemical Industries, Grade 1) was added to the solid, unreacted D-glucose remaining in the reaction vessel. Anhydrous iron(III) chloride (3.6 g, 0.08 equivalents, Aldrich) was added in approximately four portions while stirring at room temperature, and the mixture was stirred in an oil bath at 50°C for 2 hours. After 2 hours, visual inspection confirmed that no solid D-glucose remained, and the resulting reaction solution 4 was slowly added to the neutralization aqueous solution for neutralization. The separated organic solution was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was mixed with the neutralization aqueous solution again. The neutralization aqueous solution was transferred to a separatory funnel and extracted four times with ethyl acetate (0.25 L). All organic solutions were mixed, and the combined organic solution was washed twice with saturated brine (0.2 L), followed by the addition of anhydrous sodium sulfate (80 g, Wako Pure Chemical Industries, Special Grade) and storage at room temperature for 3 days. After 3 days, the drying agent was filtered off to obtain a colorless ethyl acetate solution of Compound 1 (crude product), which was diacetone glucose.

[0377] Synthesis Example 5-2 Step 2: Production of Ketone Body of Diacetone-D-Glucose The ethyl acetate solution of Compound 1 (crude product) obtained in Step 1 (Step 1) was concentrated under reduced pressure to remove approximately 1.5 L of solvent. Saturated aqueous sodium bicarbonate solution (142 mL) and potassium bromide (3.303 g, Wako Pure Chemical Industries, Ltd.) were added to the concentrated ethyl acetate solution (approximately 0.3 L), and the mixture was then ice-cooled. Nor-AZADO (5 mg) was added to the mixture, and aqueous sodium hypochlorite solution (0.297 L, Wako Pure Chemical Industries, Ltd., available chlorine concentration: 5% or higher) was added dropwise over approximately 0.5 hours while stirring (internal temperature: 7°C to 9°C), followed by stirring for 1 hour under ice cooling (Step 2). After 1 hour, an additional aqueous sodium hypochlorite solution (0.1 L, Wako Pure Chemical Industries, Ltd., available chlorine concentration: 5% or higher) was added dropwise, and the mixture was stirred under ice cooling for 2 hours. After 2 hours, saturated aqueous sodium thiosulfate solution was added with stirring under ice cooling, then stirring was stopped, the organic solution was separated, and the aqueous layer was extracted four times with ethyl acetate (0.25 L) (Steps 3 and 4). All the organic solutions were mixed, and the mixed organic solution was washed twice with saturated brine (0.2 L), and anhydrous sodium sulfate (100 g) was added, followed by standing at room temperature for 16 hours. After 16 hours, the desiccant was filtered off to obtain a colorless ethyl acetate solution of Compound 2, a ketone form of diacetone-D-glucose.

[0378] (Synthesis Example 5-3) <Step 3: Production of Diacetone Allose> The ethyl acetate solution of compound 2 (crude product) obtained in Step 2 was concentrated under reduced pressure to obtain a concentrated ethyl acetate solution (approximately 0.5 L). Ethanol (50 mL, Wako Pure Chemical Industries, special grade) was placed in a 1 L flask and cooled in an ice bath. Sodium tetrahydroborate (3.675 g, Tokyo Chemical Industry) was added to the ethanol with stirring to prepare a suspension (Step 5). To the prepared suspension, the ethyl acetate solution of compound 2 was added dropwise over approximately 10 minutes at 4°C to 14°C while stirring, and the reaction mixture was stirred at 1°C to 14°C for 2 hours (Step 6). After 2 hours, the reaction mixture was added to saturated saline and extracted four times with ethyl acetate (0.1 L). All organic solutions were mixed, washed with saturated saline (0.1 L), added with anhydrous sodium sulfate (100 g), and allowed to stand at room temperature for 1 hour. After 1 hour, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The concentrated solution was filtered again through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (52.612 g) of compound 3, diacetone allose, as a colorless solid. The crude product (52.612 g) of compound 3 was dissolved in warm toluene (25 mL). A 500 mL flask was charged with heptane (136 mL) and seed crystals (1 mg, Tokyo Chemical Industry Co., Ltd.), and the mixture was cooled in an ice bath containing salt. The toluene solution prepared was added dropwise to heptane cooled to -6°C to 0°C while stirring, and the mixture was stirred at the same temperature for 1 hour. The resulting suspension was filtered, and the solid was washed with heptane and dried under reduced pressure to obtain primary crystals of compound 3 (40.085 g, yield for three steps: 55.5%) as a colorless solid. The filtrate was concentrated under reduced pressure, and the resulting residue was crystallized in the same manner to give secondary crystals of Compound 3 (0.579 g, yield for three steps: 0.8%) as a colorless solid.

[0379] Next, the effect of the oxidizing agent used in the production process of diacetone glucose ketone bodies and diacetone allose was examined.

[0380] Example 9: Diacetone-D-glucose (1.000 g, Fluorochem) was dissolved in ethyl acetate (6 mL) to obtain an ethyl acetate solution. Saturated aqueous sodium bicarbonate solution (4 mL) and potassium bromide (46 mg, Wako Pure Chemical Industries, Ltd.) were added to the resulting ethyl acetate solution, and the mixture was then ice-cooled. Silica gel-supported TEMPO (500 mg, Aldrich Chemical Co., Ltd.) was added to the mixture, and then aqueous sodium hypochlorite solution (10 mL, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred at 0°C to room temperature for 4 hours. After 4 hours, the solid was filtered off, and saturated aqueous sodium thiosulfate solution (3 mL) and sodium chloride (1 g) were added to the filtrate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (5 mL). The organic layer was washed with saturated brine (4 mL), and anhydrous sodium sulfate (3 g) was added to the organic layer and allowed to stand. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a ketone form of diacetone-D-glucose (745 mg, crude product) as a colorless solid.

[0381] The resulting diacetone-D-glucose ketone (745 mg) was dissolved in ethyl acetate (10 mL). Sodium tetrahydroborate (49 mg) was suspended in ethanol (2 mL) and cooled in an ice bath. The ethyl acetate solution was added dropwise to the stirred ethanol suspension, and the mixture was stirred in the ice bath for 1 hour. Acetone (0.5 mL) was added to the reaction mixture and stirred for 10 minutes. After 10 minutes, saturated aqueous sodium carbonate solution (5 mL) was added and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (5 mL). All organic layers were then mixed and washed with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added to the organic layer and allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield diacetone-D-allose (689 mg, crude product) as a colorless solid. The resulting crude product was dissolved in toluene (0.7 mL) in a water bath heated to 60°C. A 10 mL flask was charged with n-heptane (5 mL) and seed crystals, cooled in an ice bath, and the prepared toluene solution was added dropwise. The mixture was stirred at -10°C to 0°C for 30 minutes. The suspension was filtered and washed with n-heptane (5 mL), and the resulting solid was dried under reduced pressure to give diacetone-D-allose (612 mg) as a colorless solid. (Yield for two steps: 61.2%)

[0382] Example 10 Diacetone-D-glucose (1.000 g, Fluorochem) was dissolved in ethyl acetate (6 mL) to obtain an ethyl acetate solution. Saturated aqueous sodium bicarbonate solution (4 mL) and potassium bromide (46 mg, Wako Pure Chemical Industries, Ltd.) were added to the resulting ethyl acetate solution, and the mixture was then ice-cooled. A solution of nor-AZADO (0.031 mg) in ethyl acetate (0.5 mL) was added to the mixture, and then an aqueous solution (10 mL) of high-grade bleaching powder (589 mg, Wako Pure Chemical Industries, available chlorine concentration: 60% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred for 2 hours under ice cooling. After 2 hours, isopropanol (0.5 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (2 mL) was added with stirring under ice cooling, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (4 mL). All the organic layers were then combined, washed with saturated brine (3 mL), and anhydrous sodium sulfate (3 g) was added, followed by standing at room temperature for 1 hour. After 1 hour, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a ketone of diacetone-D-glucose (955 mg, crude product) as a colorless solid.

[0383] The resulting diacetone-D-glucose ketone (955 mg) was dissolved in ethyl acetate (10 mL). Sodium tetrahydroborate (49 mg) was suspended in ethanol (2 mL) and cooled in an ice bath. The ethyl acetate solution was added dropwise to the stirred ethanol suspension, and the mixture was stirred in the ice bath for 1 hour. Acetone (0.5 mL) was added to the reaction mixture and stirred for 10 minutes. After 10 minutes, saturated aqueous sodium carbonate solution (5 mL) was added and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (5 mL). All organic layers were then mixed and washed with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added to the organic layer and allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield diacetone-D-allose (905 mg, product) as a colorless solid. The resulting crude product was dissolved in toluene (0.7 mL) heated to 60°C. A 10 mL flask was charged with n-heptane (5 mL) and seed crystals, cooled in an ice bath, and the prepared toluene solution was added dropwise. The mixture was stirred at -10°C to 0°C for 30 minutes. The suspension was filtered and washed with n-heptane (5 mL), and the resulting solid was dried under reduced pressure to give diacetone-D-allose (730 mg) as a colorless solid. (Yield for two steps: 73.0%)

[0384] Example 11: Diacetone-D-glucose (1.000 g, Fluorochem) was dissolved in ethyl acetate (6 mL). To the resulting ethyl acetate solution, saturated aqueous sodium bicarbonate (4 mL) and potassium bromide (46 mg, Wako Pure Chemical Industries, Ltd.) were added, and the mixture was then ice-cooled. TEMPO (60 mg) was added to the mixture, and then an aqueous solution (20 mL) of high-grade bleaching powder (1.177 g, Wako Pure Chemical Industries, available chlorine concentration: 60% or higher) was added dropwise with stirring (internal temperature: 0°C to 10°C). The mixture was stirred for 1 hour under ice cooling. After 1 hour, tetrabutylammonium hydrogen sulfate (13 mg) was added, and the mixture was stirred for 2 hours in an ice bath. Saturated aqueous sodium thiosulfate (2 mL) was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (4 mL). All organic layers were then mixed, washed with saturated brine (3 mL), and anhydrous sodium sulfate (3 g) was added. The mixture was then allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain a ketone form of diacetone-D-glucose (970 mg, crude product) as a colorless solid.

[0385] The resulting diacetone-D-glucose ketone (970 mg) was dissolved in ethyl acetate (10 mL). Sodium tetrahydroborate (49 mg) was suspended in ethanol (2 mL) and cooled in an ice bath. The ethyl acetate solution was added dropwise to the stirred ethanol suspension, and the mixture was stirred in the ice bath for 1 hour. Acetone (0.5 mL) was added to the reaction mixture and stirred for 10 minutes. After 10 minutes, saturated aqueous sodium carbonate solution (5 mL) was added and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (5 mL). All organic layers were then combined and washed with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added to the organic layer and allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield diacetone-D-allose (913 mg, product) as a colorless solid. The resulting crude product was dissolved in toluene (0.7 mL) in a water bath heated to 60°C. A 10 mL flask was charged with n-heptane (5 mL) and seed crystals, cooled in an ice bath, and the prepared toluene solution was added dropwise. The mixture was stirred at -10°C to 0°C for 30 minutes. The suspension was filtered and washed with n-heptane (5 mL), and the resulting solid was dried under reduced pressure to give diacetone-D-allose (738 mg) as a colorless solid. (Yield for two steps: 73.8%)

[0386] Example 12 Diacetone-D-glucose (1.000 g, Fluorochem) was dissolved in ethyl acetate (6 mL), and nor-AZADO (1.5 mg), sodium nitrite (27 mg), and acetic acid (0.42 mL) were added. An air-filled balloon was attached and the mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was neutralized by adding saturated aqueous sodium bicarbonate (10 mL), and then sodium chloride (3 g) was added to separate the organic layer. The aqueous layer was extracted three times with ethyl acetate (5 mL). All the organic layers were then combined and washed with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added to the organic layer and the mixture was allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-D-glucose (1.019 g, crude product) as a colorless solid.

[0387] The resulting diacetone-D-glucose ketone (1.019 g) was dissolved in ethyl acetate. Sodium tetrahydroborate (51 mg) was suspended in ethanol (2 mL) and cooled in an ice bath. The prepared ethyl acetate solution was added dropwise to the ethanol suspension while stirring, and the mixture was stirred in the ice bath for 1 hour. Acetone (0.5 mL) was added to the reaction mixture and stirred for 10 minutes. After 10 minutes, saturated aqueous sodium carbonate solution (5 mL) was added and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (5 mL). All organic layers were then combined and washed with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added to the organic layer and allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain diacetone-D-allose (1.034 g, crude product) as a colorless solid. The resulting crude product was dissolved in toluene (0.7 mL) in a water bath heated to 60°C. A 10 mL flask was charged with n-heptane (5 mL) and seed crystals, cooled in an ice bath, and the prepared toluene solution was added dropwise. The mixture was stirred at -10°C to 0°C for 30 minutes. The suspension was filtered and washed with n-heptane (5 mL), and the resulting solid was dried under reduced pressure to give diacetone-D-allose (889 mg) as a colorless solid. (Yield for two steps: 88.9%)

[0388] Example 13: Diacetone-D-glucose (3.000 g, Fluorochem) was placed in a 100 mL flask and dissolved in ethyl acetate (20 mL). Then, saturated aqueous sodium bicarbonate (9 mL) and potassium bromide (137 mg) were added and the mixture was cooled in an ice bath. To the mixture was added a solution of nor-AZADO (0.089 mg) in ethyl acetate (0.5 mL), followed by the addition of sodium hypochlorite pentahydrate (2.276 g) in several portions (internal temperature: 2°C to 10°C). The mixture was stirred in an ice bath for 2 hours. After 2 hours, isopropanol (1 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate (10 mL) was added with stirring under ice cooling, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (12 mL). All organic layers were then mixed, washed with saturated brine (10 mL), and anhydrous sodium sulfate (6 g) was added. The mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain a ketone form of diacetone-D-glucose (3.000 g, crude product) as a colorless solid.

[0389] The resulting diacetone-D-glucose ketone (3.000 g, crude product) was dissolved in ethyl acetate (30 mL). Sodium tetrahydroborate (153 mg) was suspended in ethanol (5 mL) and cooled in an ice bath. The prepared ethyl acetate solution was added dropwise to the ethanol suspension while stirring, and the mixture was stirred in an ice bath for 1 hour. Acetone (0.5 mL) was added to the reaction mixture and stirred for 10 minutes. After 10 minutes, saturated aqueous sodium carbonate solution (20 mL) was added and stirred at room temperature for 10 minutes. Sodium chloride (1.5 g) was added and stirred, after which the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (6 mL). All organic layers were combined and washed with saturated brine (4 mL). Anhydrous sodium sulfate (6 g) was added to the organic layer and allowed to stand. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain diacetone-D-allose (2.990 g, crude product) as a colorless solid. The obtained crude product was dissolved in toluene (1.8 mL) in a water bath heated to 60°C. A 30 mL flask was charged with n-heptane (18 mL) and seed crystals, cooled in an ice bath, and the prepared toluene solution was added dropwise. The mixture was stirred at -10°C to 0°C for 30 minutes. The suspension was filtered and washed with n-heptane (10 mL), and the obtained solid was dried under reduced pressure to obtain diacetone-D-allose (2.611 g) as a colorless solid. (Yield for two steps: 87.0%)

[0390] Example 14 Diacetone-D-glucose (3 g, Fluorochem) was dissolved in ethyl acetate (20 mL). Sodium hypochlorite pentahydrate (3.032 g, Wako Pure Chemical Industries, Ltd.) and distilled water (2 mL) were placed in a 100 mL flask and stirred in an ice bath. Sodium hydrogen sulfate (80 mg) and potassium bromide (137 mg) were then added. A solution of nor-AZADO (0.089 mg) in ethyl acetate (0.5 mL) was added to the mixture, followed by the dropwise addition of the prepared ethyl acetate solution (internal temperature: 2°C to 5°C). The mixture was stirred in an ice bath for 2 hours. After 2 hours, isopropanol (0.5 mL) was added and the mixture was stirred for 10 minutes. A saturated aqueous solution of sodium thiosulfate (3 mL) was added while stirring under ice cooling. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (12 mL). All the organic layers were then combined, washed with saturated brine (10 mL), and anhydrous sodium sulfate (6 g) was added. The mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-D-glucose (2.972 g, crude product) as a colorless solid.

[0391] Next, the effect of the solvent used in the production method of diacetone allose was examined.

[0392] Example 15: Diacetone-D-glucose (5 g, manufactured by Fluorochem) was dissolved in methyl acetate (30 mL) to obtain a methyl acetate solution. Saturated aqueous sodium bicarbonate solution (15 mL) and potassium bromide (229 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added to the obtained methyl acetate solution, and the mixture was then ice-cooled. A solution of nor-AZADO (0.15 mg) in methyl acetate (0.5 mL) was added to the mixture, and then aqueous sodium hypochlorite solution (40 mL, manufactured by Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred for 2 hours under ice cooling. After 2 hours, isopropanol (1 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (12 mL) was added with stirring under ice cooling, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (20 mL). All the organic layers were then combined, washed with saturated brine (15 mL), and anhydrous sodium sulfate (10 g) was added, followed by standing at room temperature for 1 hour. After 1 hour, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-D-glucose (4.364 g, crude product) as a colorless solid.

[0393] The ketone form of diacetone-D-glucose (4.364 g, crude product) was dissolved in methyl acetate (50 mL). Sodium tetrahydroborate (254 mg, Wako Pure Chemical Industries, Ltd.) was suspended in ethanol (8 mL) cooled in an ice bath, and the prepared methyl acetate solution was added dropwise. The mixture was stirred in an ice bath for 1 hour. After 1 hour, acetone (1 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (20 mL) and sodium chloride (3 g) were added and stirred. The organic layer was separated, and the aqueous layer was extracted three times with methyl acetate (10 mL). All the organic layers were then mixed and washed with saturated brine (6 mL). Anhydrous sodium sulfate (10 g) was added and the mixture was left to stand. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain crude diacetone-D-allose (3.492 g). The crude diacetone-D-allose product (3.492 g) was dissolved in toluene (1.5 mL) heated to 60°C, and the solution was added dropwise to a mixture of n-heptane (15 mL) and seed crystals cooled in an ice bath, followed by stirring at -10°C to 0°C for 30 minutes. The suspension was filtered, and the solid was washed with chilled n-heptane to obtain diacetone-D-allose (3.300 g) as a colorless solid. (Yield for two steps: 66.0%)

[0394] Example 16: Diacetone-D-glucose (5 g, manufactured by Fluorochem) was dissolved in n-propyl acetate (30 mL) to obtain a n-propyl acetate solution. Saturated aqueous sodium bicarbonate solution (15 mL) and potassium bromide (229 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added to the obtained n-propyl acetate solution, and the mixture was then ice-cooled. A solution of nor-AZADO (0.15 mg) in n-propyl acetate (0.5 mL) was added to the mixture, and then aqueous sodium hypochlorite solution (40 mL, manufactured by Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred for 2 hours under ice cooling. After 2 hours, isopropanol (1 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (12 mL) was added with stirring under ice cooling, and the organic layer was separated. The aqueous layer was extracted three times with n-propyl acetate (20 mL). All the organic layers were then combined, washed with saturated brine (15 mL), and anhydrous sodium sulfate (10 g) was added, followed by standing at room temperature for 1 hour. After 1 hour, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-D-glucose (5.081 g, crude product) as a colorless solid.

[0395] The ketone form of diacetone-D-glucose (5.081 g, crude product) was dissolved in n-propyl acetate (60 mL). Sodium tetrahydroborate (254 mg, Wako Pure Chemical Industries, Ltd.) was suspended in ethanol (8 mL) cooled in an ice bath, and the prepared n-propyl acetate solution was added dropwise and stirred in the ice bath for 1 hour. After 1 hour, acetone (1 mL) was added and stirred at the same temperature for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (20 mL) and sodium chloride (3 g) were added and stirred. The organic layer was separated, and the aqueous layer was extracted three times with n-propyl acetate (10 mL). Next, all the organic layers were combined and washed with saturated brine (6 mL). Anhydrous sodium sulfate (10 g) was added and the mixture was left to stand. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain crude diacetone-D-allose (4.275 g). The crude diacetone-D-allose product (4.275 g) was dissolved in toluene (1.5 mL) heated to 60°C, and added dropwise to a mixture of n-heptane (15 mL) and seed crystals cooled in an ice bath, followed by stirring at -10°C to 0°C for 30 minutes. The suspension was filtered, and the solid was washed with chilled n-heptane to obtain diacetone-D-allose (3.394 g) as a colorless solid. (Yield for two steps: 67.9%)

[0396] Example 17 Diacetone-D-glucose (5 g, Fluorochem) was dissolved in isopropyl acetate (30 mL) to obtain an isopropyl acetate solution. Saturated aqueous sodium bicarbonate solution (15 mL) and potassium bromide (229 mg, Wako Pure Chemical Industries, Ltd.) were added to the obtained isopropyl acetate solution, and the mixture was then ice-cooled. A solution of nor-AZADO (0.15 mg) in isopropyl acetate (0.5 mL) was added to the mixture, and then aqueous sodium hypochlorite solution (40 mL, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred for 2 hours under ice cooling. After 2 hours, isopropanol (1 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (12 mL) was added with stirring under ice cooling, and the organic layer was separated, and the aqueous layer was extracted three times with isopropyl acetate (20 mL). All the organic layers were then combined, washed with saturated brine (15 mL), and anhydrous sodium sulfate (10 g) was added, followed by standing at room temperature for 1 hour. After 1 hour, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-D-glucose (4.255 g, crude product) as a colorless solid.

[0397] The ketone form of diacetone-D-glucose (4.255 g, crude product) was dissolved in isopropyl acetate (60 mL). Sodium tetrahydroborate (254 mg, Wako Pure Chemical Industries, Ltd.) was suspended in ethanol (8 mL) cooled in an ice bath, and the prepared isopropyl acetate solution was added dropwise. The mixture was stirred in an ice bath for 1 hour. After 1 hour, acetone (1 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (20 mL) and sodium chloride (3 g) were added and stirred. The organic layer was separated, and the aqueous layer was extracted three times with isopropyl acetate (10 mL). All the organic layers were then mixed and washed with saturated brine (6 mL). Anhydrous sodium sulfate (10 g) was added and the mixture was left to stand. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain crude diacetone-D-allose (3.875 g). The crude diacetone-D-allose product (3.875 g) was dissolved in toluene (1.5 mL) heated to 60°C, and added dropwise to a mixture of n-heptane (15 mL) and seed crystals cooled in an ice bath, followed by stirring at -10°C to 0°C for 30 minutes. The suspension was filtered, and the solid was washed with chilled n-heptane to obtain diacetone-D-allose (3.232 g) as a colorless solid. (Yield for two steps: 64.5%)

[0398] Example 18: Diacetone-D-glucose (5 g, manufactured by Fluorochem) was dissolved in n-butyl acetate (30 mL) to obtain an n-butyl acetate solution. Saturated aqueous sodium bicarbonate solution (15 mL) and potassium bromide (229 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added to the obtained n-butyl acetate solution, and the mixture was then ice-cooled. Nor-AZADO (0.15 mg) in n-butyl acetate (0.5 mL) was added to the mixture, and then aqueous sodium hypochlorite solution (40 mL, manufactured by Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 2°C to 10°C). The mixture was stirred for 2 hours under ice cooling. After 2 hours, isopropanol (1 mL) was added and the mixture was stirred for 10 minutes. Saturated aqueous sodium thiosulfate solution (12 mL) was added with stirring under ice cooling, and the organic layer was separated. The aqueous layer was extracted three times with n-butyl acetate (20 mL). Next, all the organic layers were combined, washed with saturated brine (15 mL), and anhydrous sodium sulfate (10 g) was added. The mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the diacetone-D-glucose ketone (3.765 g, crude product) as a colorless solid. The diacetone-D-glucose ketone (3.765 g, crude product) was dissolved in n-butyl acetate (70 mL). Sodium tetrahydroborate (254 mg, Wako Pure Chemical Industries, Ltd.) was suspended in ethanol (8 mL) cooled in an ice bath, and the prepared n-butyl acetate solution was added dropwise. The mixture was stirred in an ice bath for 1 hour. After 1 hour, acetone (1 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Then, saturated aqueous sodium bicarbonate (20 mL) and sodium chloride (3 g) were added and stirred. The organic layer was separated, and the aqueous layer was extracted three times with n-butyl acetate (10 mL). Next, all the organic layers were combined and washed with saturated brine (6 mL), followed by the addition of anhydrous sodium sulfate (10 g) and leaving to stand. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product of diacetone-D-allose (3.483 g). The crude product of diacetone-D-allose (3.483 g) was dissolved in toluene (1.5 mL) heated to 60°C, added dropwise to a mixture of n-heptane (15 mL) and seed crystals cooled in an ice bath, and then stirred at -10°C to 0°C for 30 minutes.The suspension was filtered and the solid was washed with chilled n-heptane to give diacetone-D-allose (3.012 g) as a colorless solid (yield for two steps: 60.2%).

[0399] <Examples relating to the production method of diacetone glucose> Hereinafter, the present invention will be explained in more detail by illustrating examples and comparative examples particularly relating to the production method of diacetone glucose, but the present invention is not limited to only these examples. Note that Figure 10 is a diagram showing a synthesis scheme of the examples.

[0400] <Production of diacetone-D-glucose> Example 1a (First dissolution step) 2 L of acetone (Wako Pure Chemical Industries, Ltd., Grade 1) as an aprotic polar solvent and acetonide, and 500 g of pulverized D-glucose (Wako Pure Chemical Industries, Ltd., Special Grade) were placed in a 2 L four-neck flask. After the atmosphere in the flask was replaced with argon, the contents were stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0401] (First Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Hikari Junyaku special grade) was added to the solution in four divided portions. The solution was then stirred for 3 hours in an oil bath set at 50°C to obtain a reaction solution containing solid unreacted D-glucose. The amount of solid unreacted D-glucose was 420 g to 440 g.

[0402] (Separation Step) The supernatant of the reaction solution was aspirated to carry out solid-liquid separation into the solid unreacted D-glucose and the reaction solution.

[0403] (Step of Producing Crude Product of D-Diacetone Glucose) (Neutralization Step) The reaction solution after solid-liquid separation was slowly added to 400 mL of an aqueous solution in which 100 g of sodium bicarbonate and 30 g of trisodium citrate were dissolved, to neutralize the solution. 100 mL of saturated saline was added to the neutralized reaction solution. Thereafter, the organic layer present at the top of the solution was removed, and approximately 1.4 L of the solvent was distilled off under reduced pressure.

[0404] By adding such saturated saline, excess water can be removed from the organic layer. When excess water is removed from the organic layer, the quality of the organic layer can be improved. Furthermore, if an emulsification (emulsion) occurs between the organic layer and water, separation becomes difficult, but by adding saturated saline, the formation of emulsification can be prevented and separation can be made easier. Furthermore, since diacetone glucose is slightly soluble in water, adding saturated saline can prevent diacetone glucose from going into the water layer, thereby suppressing a decrease in the yield of diacetone glucose.

[0405] Next, the concentrated organic layer and the aqueous layer were combined, and the organic layer was extracted four times with 200 mL of ethyl acetate. The combined organic layer was then washed twice with 200 mL of saturated brine. 200 g of anhydrous sodium sulfate was added to the washed organic layer as a drying agent for drying. The drying agent was then filtered off, and the filtrate was concentrated under reduced pressure to obtain a pale yellow to white crude product 1.

[0406] The distilled solvent can be reused as acetone to be used in the dissolving step by separating water of 0.1 wt % or less using a water separator.

[0407] (Second First Dissolution Step) 2 L of acetone was added to the unreacted D-glucose separated as a solid component in the separation step. Then, as in the first first dissolution step described above, the atmosphere in the flask was replaced with argon. Thereafter, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0408] (Second Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Wako Pure Chemical Industries, Ltd. special grade) was added to the solution in four divided portions. The solution was then stirred at room temperature for 16 hours to obtain a reaction solution containing solid unreacted D-glucose. In the second reaction step, the amount of solid unreacted D-glucose was 340 g to 380 g.

[0409] (Second Separation Step) The reaction solution was filtered to separate the solid unreacted D-glucose from the reaction solution.

[0410] (Second step of producing a crude product of D-diacetone glucose) The reaction solution after solid-liquid separation was subjected to post-treatment similar to that in the first step of producing a crude product, thereby obtaining a crude product 2.

[0411] The unreacted D-glucose separated as a solid component in the separation step was subjected to a total of four cycles of reaction at 50°C for 3 hours and reaction at room temperature for 16 hours, similar to the dissolution step and reaction step described above. In the crude composition production step, only the 3-hour reaction at 50°C may be repeated, or only the reaction at room temperature may be repeated. In the case of reaction at room temperature, production can be achieved in, for example, 12 to 16 hours. For large-scale synthesis, the crude composition production step is preferably carried out at 50°C for 3 to 5 hours.

[0412] (Second dissolution step) After repeating the above reaction four times, 2 L of acetone was added to the flask containing the remaining unreacted D-glucose. Next, the atmosphere in the flask was replaced with argon, as in each of the above dissolution steps. After that, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0413] (Second Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Wako Pure Chemical Industries, Ltd. special grade) was added to the solution in four divided portions. The solution was then stirred at room temperature for 16 hours to obtain a reaction solution in which unreacted D-glucose had completely disappeared. Whether or not unreacted D-glucose had completely disappeared was determined by visually checking whether or not solid unreacted D-glucose remained in the reaction solution.

[0414] (Step for Producing Crude Product of D-Diacetone Glucose) The reaction solution obtained in the second reaction step was subjected to post-treatment similar to that in the steps for producing each crude product described above, to obtain a crude product 2 colored light yellow.

[0415] (Diacetone-D-glucose Production Process) The crude products 1 and 2 obtained in the above four sets of reactions and the second reaction process were mixed. The mixed crude products were suspended in 400 mL of heptane. The suspension was stirred for 1 hour using a mechanical stirrer at a rotation speed of 200 rpm under ice cooling and then filtered. The filtered product was washed with 100 mL of heptane. The washed product was then dried to obtain Compound 1 as a white solid, as shown in Figure 10. The resulting Compound 1 was diacetone-D-glucose. The yield of Compound 1 was 568.18 g. The yield of Compound 1 was 78.7%.

[0416] Example 2a (First dissolution step) 60 mL of acetone (Wako Pure Chemical Industries, Ltd., Grade 1) as an aprotic polar solvent and acetonide, and 3 g of pulverized D-glucose (Wako Pure Chemical Industries, Ltd., Special Grade) were placed in a 200 mL flask. After the atmosphere in the flask was replaced with argon, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0417] (First Reaction Step) While stirring the solution, 891 mg of anhydrous iron(III) chloride (0.33 equivalents, Wako Pure Chemical Industries, Ltd.) was added to the solution at room temperature in one portion. The solution was then stirred for 3 hours in an oil bath set at 50°C to obtain a reaction solution containing solid unreacted D-glucose.

[0418] (Separation Step) The reaction solution was discharged from the flask to separate the unreacted D-glucose from the reaction solution into a solid and a liquid.

[0419] (Step of Producing Crude Product of D-Diacetone Glucose) The reaction solution after solid-liquid separation was subjected to post-treatment similar to that in the above steps of producing each crude product, thereby obtaining a crude product 1.

[0420] (Second dissolution step) 60 mL of acetone (Wako Pure Chemical Industries, Ltd. Grade 1) was added to the unreacted D-glucose remaining in the flask, which had been separated as a solid component in the separation step. Then, as in each of the above dissolution steps, the atmosphere in the flask was replaced with argon, and the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0421] (Second Reaction Step) While stirring the solution, 540 mg of anhydrous iron(III) chloride (0.2 equivalents, Wako Pure Chemical Industries, Ltd.) was added to the solution at room temperature in one portion. The solution was then stirred for 2 hours in an oil bath set at 50°C to obtain a reaction solution in which no unreacted D-glucose remained, i.e., a reaction solution in which the unreacted D-glucose had completely disappeared.

[0422] (Step of Producing Crude Product of D-Diacetone Glucose) (Neutralization Step) The reaction solution separated as a liquid component in the separation step was mixed with the reaction solution obtained in the second reaction step. Furthermore, the mixed reaction solution was neutralized by adding saturated aqueous sodium bicarbonate solution and trisodium citrate. This neutralized reaction solution was extracted four times with 5 mL of ethyl acetate, and the organic layer was washed twice with 5 mL of saturated saline. Anhydrous sodium sulfate was added as a desiccant to the washed organic layer for drying. The desiccant was then filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product of diacetone-D-glucose. The yield of this crude product was 4.116 g.

[0423] (Diacetone-D-glucose Production Step) The obtained crude diacetone-D-glucose product was suspended in heptane. The suspension was stirred for 1 hour under ice cooling using a mechanical stirrer at a rotation speed of 200 rpm, and then filtered. The filtered product was washed with heptane. The washed product was then dried to obtain Compound 1 as a colorless solid. The yield of Compound 1 was 3.425 g. The yield of Compound 1 was 79%.

[0424] Comparative Example 1a (First Dissolution Step) 150 mL of acetone (Wako Pure Chemical Industries, Ltd., Grade 1) as an aprotic polar solvent and acetonide, and 3 g of pulverized D-glucose (Wako Pure Chemical Industries, Ltd., Special Grade) were placed in a 300 mL flask. After the atmosphere in the flask was replaced with argon, the contents were stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a dissolution solution.

[0425] (First Reaction Step) While stirring the solution, 891 mg of anhydrous iron(III) chloride (0.33 equivalents, Wako Pure Chemical Industries, Ltd.) was added to the solution at room temperature in one portion. The solution was then stirred for 3 hours in an oil bath set at 50°C to obtain a reaction solution containing solid unreacted D-glucose.

[0426] (Separation Step) The reaction solution was filtered to separate 80 mg of unreacted D-glucose from the reaction solution.

[0427] (Step for Producing Crude Diacetone-D-Glucose Product) (Neutralization Step) The filtrate after solid-liquid separation, i.e., the reaction solution, was neutralized by adding it to 100 mL of saturated aqueous sodium bicarbonate solution. This neutralized reaction solution was extracted four times with 20 mL of ethyl acetate, and the organic layer was washed twice with 20 mL of saturated brine. Anhydrous sodium sulfate was added to the washed organic layer as a desiccant to dry it. The desiccant was then filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude diacetone-D-glucose product.

[0428] (Diacetone-D-glucose production process) The obtained crude diacetone-D-glucose product was suspended in heptane. The suspension was stirred for 1 hour under ice cooling using a mechanical stirrer at a rotation speed of 200 rpm, and then filtered. The filtered product was washed with heptane. The washed product was then dried to obtain Compound 1 as a colorless solid. The yield of Compound 1 was 3.218 g. The yield of Compound 1 was 74.2%.

[0429] Comparative Example 2a: 30 mL of acetone (Wako Pure Chemical Industries, Grade 1) as an aprotic polar solvent and acetonide, and 2 g of ground D-glucose (Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and the contents of the flask were vigorously stirred for 5 minutes. Then, 1 mL of concentrated sulfuric acid (Wako Pure Chemical Industries, Grade 1) was gradually added dropwise to the flask, and the mixture was stirred at room temperature for 20 hours. After 20 hours, glucose remained in the reaction solution in the flask, and the reaction solution turned brown, confirming an increase in impurities. Therefore, the reaction solution was disposed of in an appropriate manner.

[0430] Comparative Example 3a: 5 mL of acetone (Wako Pure Chemical Industries, Ltd., Grade 1) as an aprotic polar solvent and acetonide, 1 g of ground D-glucose (Wako Pure Chemical Industries, Ltd., Special Grade), and 10 mg of toluenesulfonic acid monohydrate were added to a 10 mL flask and stirred under reflux for 3 hours. After 3 hours, raw materials remained in the reaction solution in the flask, and the reaction solution turned brown, confirming an increase in impurities. Therefore, the reaction solution was disposed of in an appropriate manner.

[0431] Comparative Example 4a: 50 mL of acetone (Wako Pure Chemicals Grade 1) as an aprotic polar solvent and acetonide, 1 g of ground D-glucose (Wako Pure Chemicals Special Grade), and 300 mg of anhydrous iron(III) chloride (0.33 equivalents, Wako Pure Chemicals) were added to a 100 mL flask and stirred at 60°C for 3 hours. After 3 hours, the reaction solution was neutralized by adding saturated sodium carbonate solution. The mixture was then filtered through Celite and washed with ethyl acetate to remove any gel-like material that had formed in the mixture. The filtrate was concentrated, and the residue was extracted four times with ethyl acetate. The organic layer was washed with saturated saline and then dried using anhydrous magnesium sulfate as a desiccant. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain crude diacetone-D-glucose (1.287 g). The resulting crude diacetone-D-glucose was suspended in hexane and stirred under ice cooling. The resulting suspension was filtered, washed with hexane, and then dried to obtain diacetone glucose as a colorless solid (880 mg, yield 61%).

[0432] As described above, the production method of Comparative Example 1a, which did not include the second dissolution step and the second reaction step, resulted in a lower yield of diacetone-D-glucose than the production methods of Examples 1a and 2a, despite the use of a larger-capacity reaction vessel. Furthermore, Comparative Examples 2a and 3a, which used sulfuric acid or toluenesulfonic acid monohydrate as a catalyst, resulted in colored products. Furthermore, Comparative Example 4a, which did not use a gelation inhibitor, resulted in a low yield.

[0433] On the other hand, the production methods of Examples 1a and 2a, although they did not use a large-capacity reaction vessel, resulted in the production of diacetone-D-glucose without coloration and in a higher yield and in a relatively simple manner. In other words, it was found that the production methods of Examples 1a and 2a enable the production of diacetone-D-glucose in a relatively simple manner.

[0434] Next, the effect of the catalyst used in the method for producing diacetone glucose was examined.

[0435] Example 3a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and while stirring at room temperature, iron(III) chloride hexahydrate (495 mg, 0.33 equivalents, Wako Pure Chemical Industries, Special Grade) was added all at once. The mixture was then stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding it to a neutralizing solution prepared by mixing saturated aqueous sodium bicarbonate (19 mL), trisodium citrate (1.9 g), and sodium chloride (1.5 g). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were combined, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.239 g, crude product) as a colorless solid. The crude product was suspended in heptane (6 mL) and stirred at room temperature for 1 hour. After 1 hour, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (688 mg) as a colorless solid. (Yield: 47.6%)

[0436] Example 4a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and while stirring at room temperature, zinc chloride (840 mg, 0.33 equivalents, Wako Pure Chemical Industries) and 85% phosphoric acid (0.1 mL, Wako Pure Chemical Industries) were added all at once. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (30 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). All organic layers were then mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.309 g, crude product) as a colorless solid. The crude product was suspended in heptane (6 mL) and stirred at room temperature for 1 hour. After 1 hour, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (1.103 g) as a colorless solid. (Yield: 76.3%)

[0437] Example 5a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and aluminum chloride (244 mg, 0.33 equivalents, Wako Pure Chemical Industries, Special Grade) was added all at once while stirring at room temperature. The mixture was then stirred in an oil bath at 50-55 °C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding it to a neutralizing solution prepared by mixing saturated aqueous sodium bicarbonate (19 mL), trisodium citrate (1.9 g), and sodium chloride (1.5 g). The mixture was concentrated under reduced pressure (water bath temperature: 40 °C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.341 g, crude product) as a colorless solid. The crude product was suspended in heptane (6 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (902 mg) as a colorless solid. (Yield: 62.4%)

[0438] Example 6a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and ytterbium(III) trifluoromethanesulfonate (1.136 g, 0.33 equivalents, Wako Pure Chemical Industries) was added all at once while stirring at room temperature. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (20 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.505 g, crude product) as a colorless solid. The crude product was suspended in heptane (6 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (1.177 g) as a colorless solid. (Yield: 81.5%)

[0439] Example 7a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and while stirring at room temperature, scandium(III) trifluoromethanesulfonate (874 mg, 0.33 equivalents, Wako Pure Chemical Industries) was added all at once. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (20 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were combined, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.397 g, crude product) as a colorless solid. The crude product was purified by flash column chromatography (Wakogel (registered trademark) 60N (mesh: 150-425 μm, 65 g), using an elution solvent of ethyl acetate:n-hexane = 50:50 to 100:0) to give diacetone-D-glucose (946 mg) as a colorless solid. (Yield: 65.5%)

[0440] Example 8a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and while stirring at room temperature, lanthanum(III) trifluoromethanesulfonate (1.073 g, 0.33 equivalents, Wako Pure Chemical Industries) was added all at once. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (20 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). All organic layers were then mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (289 mg, crude product) as a colorless solid. The crude product was purified by flash column chromatography (Wakogel (registered trademark) 60N (mesh: 150-425 μm, 65 g), using an elution solvent of ethyl acetate:n-hexane = 50:50 to 100:0) to give diacetone-D-glucose (175 mg) as a colorless solid. (Yield: 12.1%)

[0441] Example 9a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and cerium(III) trifluoromethanesulfonate (1.076 g, 0.33 equivalents, Wako Pure Chemical Industries) was added all at once while stirring at room temperature. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (20 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were combined, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.163 g, crude product) as a colorless solid. The crude product was suspended in heptane (6 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (859 mg) as a colorless solid. (Yield: 59.5%)

[0442] Example 10a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and while stirring at room temperature, europium(III) trifluoromethanesulfonate (1.097 g, 0.33 equivalents, Combi Blocks) was added all at once. The mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding saturated aqueous sodium bicarbonate (20 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were combined, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (351 mg, crude product) as a colorless solid. The crude product was purified by flash column chromatography (Wakogel (registered trademark) 60N (mesh: 150-425 μm, 65 g) using an elution solvent of ethyl acetate:n-hexane = 50:50 to 100:0) to give diacetone-D-glucose (201 mg) as a colorless solid. (Yield: 13.9%)

[0443] Example 11a: Acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were placed in a 100 mL flask, and tetrabutylammonium tribromide (268 mg, 0.33 equivalents, Wako Pure Chemical Industries, Special Grade) was added at room temperature. The mixture was stirred for 3 hours in an oil bath at 50-55 °C. After 3 hours, the reaction solution was slowly added to saturated aqueous sodium bicarbonate (20 mL) to neutralize the mixture, followed by the addition of saturated aqueous sodium thiosulfate (5 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40 °C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.117 g, crude product) as a brown solid. The crude product was purified by flash column chromatography (Wakogel (registered trademark) 60N (mesh: 150-425 μm, 65 g), using an elution solvent of ethyl acetate:n-hexane = 50:50 to 100:0) to give diacetone-D-glucose (866 mg) as a colorless solid. (Yield: 59.9%)

[0444] Example 12a: Acetone (50 mL, Wako Pure Chemicals Grade 1) and D-glucose (1.000 g, Wako Pure Chemicals Special Grade) were placed in a 100 mL flask, and montmorillonite (1 g, Thermo Scientific) was added all at once while stirring at room temperature. The mixture was stirred in an oil bath at 50-55 °C for 3 hours. After 3 hours, the solid was filtered off, and the filtrate was concentrated under reduced pressure (water bath temperature: 40 °C, vacuum: 100-150 hPa), yielding diacetone-D-glucose (371 mg, crude product) as a colorless solid. The resulting crude product was purified by flash column chromatography (Wakogel (registered trademark) 60N (mesh: 150-425 μm, 65 g), using a solvent of ethyl acetate: n-hexane = 50:50-100:0 as the elution solvent), yielding diacetone-D-glucose (188 mg) as a colorless solid. (Yield: 13.0%)

[0445] Example 13a: Acetone (50 mL, Wako Pure Chemicals, Grade 1) and D-glucose (1.000 g, Wako Pure Chemicals, Special Grade) were placed in a 100 mL flask, and mordenite (1 g, Zeolite HS-690, Hydrogen, Wako Pure Chemicals) was added all at once while stirring at room temperature. The mixture was then stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the solid was filtered off, and the filtrate was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa) to obtain diacetone-D-glucose (638 mg, crude product) as a colorless solid. The resulting crude product was suspended in heptane (3 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to obtain diacetone-D-glucose (339 mg) as a colorless solid. (Yield: 23.5%)

[0446] Example 14a: Iodine (70 mg, 0.1 equivalents) was added to isopropanol (1 mL, Merck) and stirred in an oil bath at 50-55°C for 1 hour. After 1 hour, acetone (50 mL, Wako Pure Chemical Industries, First Grade) and D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade) were added, and the mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was slowly added to a mixture of saturated aqueous sodium bicarbonate (20 mL) and saturated aqueous sodium thiosulfate (6 mL). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.191 g, crude product) as a colorless solid. The crude product was suspended in heptane (5 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (899 mg) as a colorless solid. (Yield: 62.2%)

[0447] Example 15a: Acetone (50 mL, Wako Pure Chemical Industries, Ltd., first grade), D-glucose (1.000 g, Wako Pure Chemical Industries, Ltd., special grade), and Amberlyst® 15 (1 g, manufactured by Angene Chemical Co., Ltd.) were added to a 100 mL flask and stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa). The residual solution was diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium bicarbonate solution (5 mL). The aqueous layer was extracted three times with ethyl acetate (5 mL). Next, all organic layers were mixed, and the combined organic layers were washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, special grade) was added, and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give diacetone-D-glucose (1.388 g, crude product) as a colorless solid. The crude product was suspended in heptane (5 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered, and the filtered solid was washed with heptane to give diacetone-D-glucose (1.063 g) as a colorless solid. (Yield: 73.6%)

[0448] Example 16a Diethyl ether (50 mL) and silica gel (10 g, Wakogel (registered trademark) 60N (mesh: 150-425 μm) were placed in a 200 mL flask, and concentrated sulfuric acid (1 mL) was added dropwise in small portions. The mixture was stirred for 5 minutes, and then the diethyl ether was distilled off under reduced pressure. The resulting residue was heated at 120° C. for 3 hours.

[0449] Acetone (50 mL, Wako Pure Chemical Industries, First Grade), D-glucose (1.000 g, Wako Pure Chemical Industries, Special Grade), and the prepared sulfuric acid-supported silica gel (1 g) were added to a 100 mL flask and stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the solids were removed by filtration, and the filtrate was added to saturated aqueous sodium bicarbonate (5 mL) and concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa). The residual solution was extracted four times with ethyl acetate (5 mL). All organic layers were then combined, washed with saturated brine (4 mL), and anhydrous sodium sulfate (3 g, Wako Pure Chemical Industries, Special Grade) was added. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain diacetone-D-glucose (1.201 g, crude product) as a colorless solid. The resulting crude product was suspended in heptane (6 mL) and stirred at room temperature for 0.5 hours. After 0.5 hours, the suspension was filtered and the filtered solid was washed with heptane to give diacetone-D-glucose (1.084 g) as a colorless solid (yield: 75.0%).

[0450] Next, the effect of using recycled acetone in the production of diacetone glucose was examined.

[0451] Example 17a: Acetone (50 mL, Wako Pure Chemicals Grade 1) was placed in a 100 mL flask and cooled in an ice bath. Anhydrous iron(III) chloride (1.44 g, 0.33 equivalents, Wako Pure Chemicals) was added in several portions (approximately 5°C) to the cooled acetone (approximately 2°C). Acetone (200 mL) and D-glucose (5 g, Wako Pure Chemicals) were added to the mixture and stirred for 3 hours in an oil bath at 50°C to 55°C. After 3 hours, the reaction solution was neutralized by slowly adding it to a neutralization solution prepared by mixing saturated aqueous sodium bicarbonate (90 mL), trisodium citrate (9.0 g), and sodium chloride (7.5 g). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa) to obtain spent acetone (225 mL) and a residual solution. The residual solution was extracted four times with ethyl acetate (30 mL). All the organic layers were then combined, washed twice with saturated brine (20 mL), and then filtered. The filtrate was concentrated under reduced pressure to obtain a solution of diacetone-D-glucose (crude product) in ethyl acetate.

[0452] The moisture content of the recovered acetone (225 mL) was measured using a Karl Fischer moisture meter (Nitto Seiko Analytech) and found to be 3.887%. The recovered used acetone was placed in a 500 mL flask equipped with a zeolite membrane dehydrator (Kiriyama Seisakusho), and the flask was heated to 80°C in an oil bath while reducing the pressure inside the zeolite membrane with a vacuum pump. Acetone (110 mL) distilled from the top of the zeolite membrane dehydrator was recovered. The moisture content of the resulting acetone was measured using a Karl Fischer moisture meter (Nitto Seiko Analytech) and found to be 0.181%.

[0453] D-glucose (1 g, Wako Pure Chemical Industries, Ltd.) was added to acetone (50 mL) obtained by dehydration using a zeolite membrane dehydrator. Anhydrous iron(III) chloride (288 mg, 0.33 equivalents, Wako Pure Chemical Industries, Ltd.) was added in several portions, and the mixture was stirred in an oil bath at 50-55°C for 3 hours. After 3 hours, the reaction solution was neutralized by slowly adding it to a neutralization solution prepared by mixing saturated aqueous sodium bicarbonate (19 mL), trisodium citrate (1.9 g), and sodium chloride (1.5 g). The mixture was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa) to obtain a residual solution. The residual solution was extracted four times with ethyl acetate (6 mL). Next, all organic layers were mixed, and the combined organic layer was washed twice with saturated brine (4 mL). Anhydrous sodium sulfate (3 g) was added, and the mixture was allowed to stand. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain diacetone-D-glucose (crude product, 1.45 g) as a colorless solid. The obtained crude product was suspended in n-heptane (5 mL) and stirred at 50°C for 1 hour, and then at -10°C for 1 hour. The suspension was filtered, and the solid was washed with ice-cold n-heptane (5 mL) to obtain diacetone-D-glucose (1.129 g) as a colorless solid. (Yield: 78.2%)

[0454] <Examples of the method for producing allose> The present invention will be explained in more detail below by way of examples and comparative examples particularly relating to the method for producing allose, but the present invention is not limited to these examples.

[0455] Reference Example 1b <Production of diacetone-D-glucose> (First dissolution step) 2 L of acetone (Wako Pure Chemical Industries, Ltd., Grade 1) as an aprotic polar solvent and an acetonidation reagent, and 500 g of pulverized D-glucose (Wako Pure Chemical Industries, Ltd., Special Grade) were placed in a 2 L four-neck flask. After the atmosphere in the flask was replaced with argon, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0456] (First Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Hikari Junyaku special grade) was added to the solution in four divided portions. The solution was then stirred for 3 hours in an oil bath set at 50°C to obtain a reaction solution containing solid unreacted D-glucose. The amount of solid unreacted D-glucose was 420 g to 440 g.

[0457] (Separation Step) The supernatant of the reaction solution was aspirated to carry out solid-liquid separation into the solid unreacted D-glucose and the reaction solution.

[0458] (Step of Producing Crude Product of D-Diacetone Glucose) (Neutralization Step) The reaction solution after solid-liquid separation was slowly added to 400 mL of an aqueous solution in which 100 g of sodium bicarbonate and 30 g of trisodium citrate were dissolved, to neutralize the solution. 100 mL of saturated saline was added to the neutralized reaction solution. Thereafter, the organic layer present at the top of the solution was removed, and approximately 1.4 L of the solvent was distilled off under reduced pressure.

[0459] By adding such saturated saline, excess water can be removed from the organic layer. When excess water is removed from the organic layer, the quality of the organic layer can be improved. Furthermore, if an emulsification (emulsion) occurs between the organic layer and water, separation becomes difficult, but by adding saturated saline, the formation of emulsification can be prevented and separation can be made easier. Furthermore, since diacetone glucose is slightly soluble in water, adding saturated saline can prevent diacetone glucose from going into the water layer, thereby suppressing a decrease in the yield of diacetone glucose.

[0460] Next, the concentrated organic layer and the aqueous layer were combined, and the organic layer was extracted four times with 200 mL of ethyl acetate. The combined organic layer was then washed twice with 200 mL of saturated brine. 200 g of anhydrous sodium sulfate was added to the washed organic layer as a drying agent for drying. The drying agent was then filtered off, and the filtrate was concentrated under reduced pressure to obtain a pale yellow to white crude product 1.

[0461] The distilled solvent can be reused as acetone to be used in the dissolving step by separating water of 0.1 wt % or less using a water separator.

[0462] (Second First Dissolution Step) 2 L of acetone was added to the unreacted D-glucose separated as a solid component in the separation step. Then, as in the first first dissolution step described above, the atmosphere in the flask was replaced with argon. Thereafter, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0463] (Second Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Wako Pure Chemical Industries, Ltd. special grade) was added to the solution in four divided portions. The solution was then stirred at room temperature for 16 hours to obtain a reaction solution containing solid unreacted D-glucose. In the second reaction step, the amount of solid unreacted D-glucose was 340 g to 380 g.

[0464] (Second Separation Step) The reaction solution was filtered to separate the solid unreacted D-glucose from the reaction solution.

[0465] (Second step of producing a crude product of D-diacetone glucose) The reaction solution after solid-liquid separation was subjected to post-treatment similar to that in the first step of producing a crude product, thereby obtaining a crude product 2.

[0466] The unreacted D-glucose separated as a solid component in the separation step was subjected to a total of four cycles of reaction at 50°C for 3 hours and reaction at room temperature for 16 hours, similar to the dissolution step and reaction step described above. In the crude composition production step, only the 3-hour reaction at 50°C may be repeated, or only the reaction at room temperature may be repeated. In the case of reaction at room temperature, production can be achieved in, for example, 12 to 16 hours. For large-scale synthesis, the crude composition production step is preferably carried out at 50°C for 3 to 5 hours.

[0467] (Second dissolution step) After repeating the above reaction four times, 2 L of acetone was added to the flask containing the remaining unreacted D-glucose. Next, the atmosphere in the flask was replaced with argon, as in each of the above dissolution steps. After that, the mixture was stirred at room temperature using a mechanical stirrer at a rotation speed of 200 rpm to obtain a solution.

[0468] (Second Reaction Step) While stirring the solution, 30 g of anhydrous iron(III) chloride (0.067 equivalents, Wako Pure Chemical Industries, Ltd. special grade) was added to the solution in four divided portions. The solution was then stirred at room temperature for 16 hours to obtain a reaction solution in which unreacted D-glucose had completely disappeared. Whether or not unreacted D-glucose had completely disappeared was determined by visually checking whether or not solid unreacted D-glucose remained in the reaction solution.

[0469] (Step for Producing Crude Product of D-Diacetone Glucose) The reaction solution obtained in the second reaction step was subjected to post-treatment similar to that in the steps for producing each crude product described above, to obtain a crude product 2 colored light yellow.

[0470] (Diacetone-D-glucose Production Step) The crude products 1 and 2 obtained in the above four sets of reactions and the second reaction step were mixed. The mixed crude products were suspended in 400 mL of heptane. The suspension was stirred for 1 hour using a mechanical stirrer at a rotation speed of 200 rpm under ice cooling and then filtered. The filtered product was washed with 100 mL of heptane. The washed product was then dried to obtain Compound 1 as a white solid. The obtained Compound 1 was diacetone-D-glucose. The yield of Compound 1 was 568.18 g. The yield of Compound 1 was 78.7%.

[0471] Reference Example 2b <Production of Ketone Form from Diacetone Glucose> Diacetone-D-glucose (Compound 1) (1 g) and ethyl acetate (4.2 mL) were placed in a 50 mL flask and stirred at room temperature to dissolve. Saturated aqueous sodium bicarbonate solution (1.8 mL) and potassium bromide (46 mg) were added, and the mixture was cooled in an ice bath. nor-AZADO (0.03 mg) was added as an ethyl acetate solution to the cooled mixture, and then aqueous sodium hypochlorite solution (4.2 mL, Wako Pure Chemical Industries, available chlorine concentration: 5% or higher) was added dropwise and stirred at room temperature for 1 hour. Saturated aqueous sodium thiosulfate solution (1.2 mL) was added to the reaction solution and stirred, followed by extraction four times with ethyl acetate (4 mL). The organic layers were combined and washed with saturated brine (2 mL), and then dried by adding anhydrous sodium sulfate (5 g). The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (Compound 2), a ketone form of diacetone glucose, as a colorless solid.

[0472] <Preparation of diacetone allose from ketone> Compound 2 prepared as described above was dissolved in tetrahydrofuran (1.56 L). A 2-L flask was charged with 99.5% ethanol (0.52 L) and cooled to 10°C in an ice bath. Sodium tetrahydroborate (26.607 g) was added to prepare a suspension. The prepared tetrahydrofuran solution was added dropwise over approximately 1 hour while stirring the suspension with a mechanical stirrer, followed by stirring at 5°C to 10°C for 1 hour. After adding 5% aqueous ammonium chloride solution (1.65 L), the reaction mixture was extracted four times with ethyl acetate (0.3 L). The extracted organic layers were combined and washed with saturated saline (0.3 L). Anhydrous sodium sulfate (300 g) was added to the organic layer, and the mixture was dried for 16 hours. The desiccant was filtered off, and the resulting filtrate was concentrated under reduced pressure to obtain a crude product (450.79 g). The resulting crude product was dissolved in toluene (0.35 L) while heating, and seed crystals were added to n-heptane (1.75 L) stirred with a mechanical stirrer in an ice bath. The toluene solution was then slowly added dropwise, and the mixture was stirred in the ice bath for 1 hour. The resulting crystals were collected by filtration and washed with n-heptane (0.3 L), yielding diacetone allose, Compound 3 (382.48 g), as a colorless solid. (Total yield: 67.3%)

[0473] Example 1b <Production Example 1 of D-Allose from Diacetone-D-Allose> Diacetone-D-allose (Compound 3) (5 g) was dissolved in tetrahydrofuran (5 mL, Wako Pure Chemical Industries, Ltd.) and to this solution was added distilled water (10 mL) and a solid acid catalyst that had been washed with distilled water and tetrahydrofuran, respectively, followed by stirring for 3 hours at 50° C. A strongly acidic cation exchange resin of a styrene-divinylbenzene copolymer was used as the solid acid catalyst.

[0474] The solid acid catalyst was pre-washed by preparing water (approximately 1.5 mL) and THF (approximately 0.75 mL) for the reaction with 1 g of strongly acidic cation exchange resin. 1.5 mL of water was added to 1 g of strongly acidic cation exchange resin, and the mixture was stirred for approximately 5 minutes. After stirring, the mixture was filtered through a funnel (Kiriyama Funnel) to remove the water. The strongly acidic cation exchange resin filtered onto filter paper was then washed by alternately pouring room temperature water and THF into the mixture while being sucked. The solid acid catalyst was used in the reaction only after visually confirming that the filtrate was not colored after washing.

[0475] After adding the solid acid catalyst and stirring for 3 hours, the strongly acidic cation exchange resin was filtered off, and the filtrate was concentrated for the first time under reduced pressure until it was reduced to about 1 / 5 of its original volume (Brix value measured with a KEM portable sugar content meter BX-1, manufactured by Kyoto Electronics Manufacturing Co., Ltd.: 40 to 50). The filtrate was colorless and transparent (see FIG. 15).

[0476] Next, ethanol (30 mL) was added to the concentrated filtrate, and the mixture was concentrated a second time to about half its original volume under reduced pressure. Ethanol (30 mL) and a small amount of seed crystals (1 mg) were added to the concentrated filtrate, and about half of the solvent was removed under reduced pressure. For example, Tokyo Chemical Industry Co., Ltd.'s D-(+)-allose A1488 can be used as the seed crystal.

[0477] Ethanol (30 mL) was added to the concentrated filtrate, and the mixture was concentrated a third time to about half its original volume under reduced pressure in a water bath at 50°C. The resulting suspension was cooled by stirring in an ice bath for 30 minutes. The suspension was filtered, and the crystals were washed with ethanol (10 mL) to obtain primary crystals (2.433 g).

[0478] The filtrate was completely concentrated, and a minimum amount of distilled water was added to the residue, followed by concentration under reduced pressure. Ethanol (10 mL) was added to the concentrated filtrate (first time), and the mixture was concentrated to about half its volume under reduced pressure. Ethanol (10 mL) and a small amount of seed crystals were added to the concentrated filtrate (second time), and about half of the solvent was distilled off under reduced pressure. Ethanol (10 mL) was added to the concentrated filtrate (third time), and the mixture was concentrated to about half its volume. A water bath at 50°C was added, and the resulting suspension was stirred in an ice bath for 30 minutes. The suspension was filtered, and the crystals were washed with ethanol (5 mL), yielding secondary crystals (0.546 g).

[0479] Next, the primary and secondary crystals were mixed and suspended in ethanol (10 mL). After suspension, the mixture was stirred at room temperature for 30 minutes and then in an ice bath for 30 minutes. The resulting suspension was filtered and washed with ethanol (10 mL), yielding D-allose (2.929 g) as a colorless solid (yield: 84.6%). The resulting D-allose had a melting temperature of 140-141°C, and the XRD results are shown in Figure 16. In Figure 16, the peaks overlapping with the solid line are stable Form I, and the other peaks overlapping with the dashed line are peaks of metastable Form II. Figure 16 confirmed that the resulting crystalline form was a mixture of stable Form I and metastable Form II. The NMR results (see Figure 17) confirmed that the D-allose was free of organic impurities.

[0480] <Production Example 2 of D-Allose from Diacetone-D-Allose> Diacetone-D-allose (Compound 3) (5 g) was added to diacetone-D-allose (12 mL) and a solid acid catalyst that had been washed with distilled water in advance, and the mixture was stirred for 3 hours at 50° C. A strongly acidic cation exchange resin of a styrene-divinylbenzene copolymer was used as the solid acid catalyst.

[0481] The solid acid catalyst was pre-washed by preparing water (approximately 1.5 mL) and THF (approximately 0.75 mL) for the reaction with 1 g of strongly acidic cation exchange resin. 1.5 mL of water was added to 1 g of strongly acidic cation exchange resin, and the mixture was stirred for approximately 5 minutes. After stirring, the mixture was filtered through a funnel (Kiriyama Funnel) to remove the water. The strongly acidic cation exchange resin filtered onto filter paper was then washed by alternately pouring room temperature water and THF into the mixture while suctioning. The solid acid catalyst was used in the reaction only after visually confirming that the filtrate was not colored after washing.

[0482] After adding the solid acid catalyst and stirring for 3 hours, the strongly acidic cation exchange resin was filtered off, and the water content of the filtrate was removed using the apparatus shown in FIG. 12 . Distilled water (5 mL) was added to the resulting syrupy residue to prepare D-allose aqueous solution 1 (Brix value measured with a KEM portable sugar meter BX-1, manufactured by Kyoto Electronics Manufacturing Co., Ltd.: 57.7).

[0483] Ethanol (10 mL) was added to the prepared D-allose aqueous solution, and then ethanol (42 mL) was distilled off by heating in an oil bath (108°C) while adding ethanol (50 mL) using a dropping funnel under normal pressure using the apparatus shown in Figure 12. Ethanol (10 mL) was added to the obtained concentrated solution, and the mixture was allowed to cool from 79°C to room temperature while stirring, and then further stirred in an ice bath for 1 hour. The obtained suspension was filtered, and the solid was washed with ethanol to obtain primary crystals (2.428 g). The filtrate was concentrated under reduced pressure, and distilled water (2 mL) was added to the obtained residue to prepare allose aqueous solution 2 (Brix value measured with a KEM portable sugar meter BX-1, manufactured by Kyoto Electronics Manufacturing Co., Ltd.: 52.4).

[0484] Ethanol (2 mL) was added to the prepared D-allose aqueous solution, and then ethanol (8 mL) was distilled off by heating in an oil bath (108 °C) while adding ethanol (10 mL) using a dropping funnel under normal pressure using the apparatus shown in Figure 12. Ethanol (2 mL) was added to the resulting concentrated solution, and the mixture was allowed to cool from 79 °C to room temperature while stirring, and then stirred in an ice bath for 1 hour. The resulting suspension was filtered, and the solid was washed with ethanol to obtain secondary crystals (0.260 g). The primary and secondary crystals were mixed and suspended in ethanol (10 mL), and the suspension was stirred in an ice bath for 1 hour. The suspension was filtered and washed with ethanol (3 mL) to obtain D-allose (3.111 g) as a colorless solid. (Yield: 89.9%)

[0485] Comparative Example 1b D-allose was obtained as a solid in the same manner as in Example 1b, except that a solution of diacetone allose (5 g) in tetrahydrofuran (5 mL, Wako Pure Chemical Industries, Ltd.) was added with distilled water (10 mL) and an acid catalyst that had not been washed in advance was used.

[0486] Diacetone allose in tetrahydrofuran and a strongly acidic cation exchange resin as an acid catalyst were stirred for 3 hours, and then the strongly acidic cation exchange resin was filtered off. The filtrate obtained was colored pink, and the presence of impurities was confirmed (see FIG. 15 ).

[0487] Example 2b Production of L-allose from L-glucose <Step 1: Production of diacetone-L-glucose from L-glucose> (5 g scale) Acetone (100 mL, Wako Pure Chemical Industries, Ltd.) and L-glucose (5 g, Fluorochem) were placed in a 300 mL flask, and the atmosphere inside the vessel was replaced with argon gas. Then, anhydrous iron(III) chloride (1.486 g, 0.33 equivalents, Wako Pure Chemical Industries, Ltd.) was added in approximately four portions with stirring at room temperature, and the mixture was stirred in an oil bath at 50°C for 3 hours. After 3 hours, the solid unreacted L-glucose and reaction solution 1 were separated, and reaction solution 1 was slowly added to a neutralizing aqueous solution prepared by mixing saturated aqueous sodium bicarbonate (75 mL), trisodium citrate (7.5 g), and sodium chloride (6 g) to neutralize the mixture. The separated organic layer was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was mixed again with the neutralization aqueous solution. Acetone (100 mL, Wako Pure Chemical Industries, Ltd., Grade 1) was added to the solid, unreacted L-glucose remaining in the reaction vessel, and anhydrous iron(III) chloride (0.9 g, 0.2 equivalents, Wako Pure Chemical Industries, Ltd.) was added in approximately four portions while stirring at room temperature. The mixture was stirred in an oil bath at 50°C for 2 hours. After 2 hours, visual inspection confirmed that no solid L-glucose remained, and the resulting reaction solution 2 was slowly added to the neutralization aqueous solution for neutralization. The separated organic layer was concentrated under reduced pressure (water bath temperature: 40°C, vacuum: 100-150 hPa), and the residual solution was mixed again with the neutralization aqueous solution. The neutralization aqueous solution was extracted four times with ethyl acetate (25 mL). All organic layers were mixed, washed twice with saturated saline (20 mL), and then anhydrous sodium sulfate (7 g, Wako Pure Chemical Industries, special grade) was added and the mixture was allowed to stand at room temperature for 1 hour. After 1 hour, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain diacetone-L-glucose (5.389 g, crude product) as a pale yellow solid. Diacetone-L-glucose (5.389 g, crude product) was suspended in heptane (70 mL) and stirred at room temperature for 1 hour. After 1 hour, the suspension was filtered, and the filtered solid was washed with heptane to obtain diacetone-L-glucose (5.128 g) as a colorless solid. (Yield: 70.9%)

[0488] <Step 2: Production of Ketone from Diacetone-L-Glucose> Diacetone-L-glucose (4.949 g) obtained in Step 1 was dissolved in ethyl acetate (22 mL). Saturated aqueous sodium bicarbonate (8.6 mL) and potassium bromide (226 mg, Wako Pure Chemical Industries, Ltd.) were added to the resulting ethyl acetate solution, and the mixture was then ice-cooled. nor-AZADO (0.5 mg) was added to the mixture, and aqueous sodium hypochlorite (20.6 L, Wako Pure Chemical Industries, effective chlorine concentration: 5% or higher) was added dropwise with stirring (internal temperature: 20°C or less). The mixture was stirred under ice cooling for 1 hour. After 1 hour, saturated aqueous sodium thiosulfate (1.5 mL) was added with stirring under ice cooling, the organic layer was separated, and the aqueous layer was extracted four times with ethyl acetate (3 mL). All organic layers were mixed, washed with saturated brine (3 mL), added with anhydrous sodium sulfate (3 g), and allowed to stand at room temperature for 1 hour. After 1 hour, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the ketone form of diacetone-L-glucose (4.123 g, crude product) as a colorless solid.

[0489] <Step 3: Production of diacetone-L-allose from the ketone form of diacetone-L-glucose> The ketone form of diacetone-L-glucose (4.123 g, crude product) obtained in Step 2 was dissolved in THF (12 mL) to prepare a THF solution. Ethanol (4 mL, Wako Pure Chemical Industries, special grade) was placed in a 50 mL flask and cooled in an ice bath. Sodium tetrahydroborate (211 mg, Tokyo Chemical Industry) was added to the ethanol with stirring to prepare a suspension. The THF solution was added dropwise to the prepared ethanol suspension with stirring, and the reaction mixture was stirred in an ice bath for 1 hour. After 1 hour, the reaction mixture was added to saturated saline and extracted four times with ethyl acetate (6 mL). All organic layers were combined, washed with saturated saline (4 mL), added with anhydrous sodium sulfate (3 g), and allowed to stand at room temperature for 1 hour. After 1 hour, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The concentrated solution was filtered again through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain diacetone-L-allose (3.753 g, crude product) as a colorless solid. Diacetone-L-allose (3.753 g, crude product) was dissolved in warm toluene (3 mL). Heptane (15 mL) was placed in a 50 mL flask and cooled in an ice bath. The prepared toluene solution was added dropwise with stirring, and after the dropwise addition, the mixture was stirred at the same temperature for 1 hour. The resulting suspension was filtered, and the solid was washed with ice-cold heptane and then dried under reduced pressure to obtain diacetone-L-allose (3.351 g) as a colorless solid (yield: 80.7%).

[0490] <Step 4: Production of L-allose from diacetone-L-allose> Diacetone-L-allose (3.341 g) obtained in step 3 was dissolved in tetrahydrofuran (3.3 mL, Wako Pure Chemical Industries) to a solution, and distilled water (6.6 mL, Wako Pure Chemical Industries) and Amberlite® IRC-120(H) (5.68 g, Thermo Scientific), a strongly acidic cation exchange resin of styrene-divinylbenzene copolymer, which had been washed with distilled water and tetrahydrofuran, respectively, were added and stirred at 50 °C for 3 hours. After 3 hours, the strongly acidic cation exchange resin was filtered off, and the resin was washed with distilled water (3 mL, Wako Pure Chemical Industries), and the filtrate was concentrated a first time under reduced pressure until it was reduced to about 1 / 5 (Brix value: 45). Ethanol (18 mL) was added to the concentrated filtrate, and a second time under reduced pressure was concentrated until the solution volume was reduced to about half. Ethanol (18 mL) was added to the concentrated filtrate, and the mixture was concentrated a third time under reduced pressure until the volume of the solution was reduced to about one-third. Ethanol (10 mL) was added to the concentrated filtrate, and the mixture was concentrated a fourth time under reduced pressure until the volume of the solution was reduced to about half. The resulting suspension was stirred in an ice bath for 30 minutes. The suspension was filtered, and the crystals were washed with ethanol (5 mL) to obtain primary crystals (1.764 g).

[0491] The filtrate was completely concentrated, and a minimum amount of distilled water was added to the residue. The first concentration was performed under reduced pressure until the solution volume was reduced to approximately 1 / 5 (Brix value: 50). Ethanol (5 mL) was added to the concentrated filtrate, and the second concentration was performed under reduced pressure until the solution volume was reduced to approximately half. Ethanol (5 mL) was added to the concentrated filtrate, and the third concentration was performed under reduced pressure until the solution volume was reduced to approximately half. Ethanol (5 mL) was added to the concentrated filtrate, and the fourth concentration was performed under reduced pressure until the solution volume was reduced to approximately half. The resulting suspension was stirred in an ice bath for 30 minutes. The suspension was filtered, and the crystals were washed with ethanol (5 mL) to obtain secondary crystals (0.252 g). The primary and secondary crystals were mixed, suspended in ethanol (5 mL), stirred at room temperature for 30 minutes, and then stirred in an ice bath for 30 minutes. The resulting suspension was filtered, and the solid was washed with ethanol (10 mL) to obtain L-allose (1.866 g) as a colorless solid (yield: 80.7%).

[0492] Next, the effect of using isopropanol for crystallization of D-allose was examined.

[0493] Example 3b: Diacetone-D-allose (5 g) was added with distilled water (12 mL) and Amberlite® IRC-120(H) (8 g, Thermo Scientific, wet form), and the mixture was stirred at 50°C for 3 hours. The Amberlite® IRC-120(H) was washed with distilled water (80 mL) before use. After 3 hours, the Amberlite® was filtered off and washed with distilled water (30 mL). Activated carbon (200 mg, Wako Pure Chemical Industries, lot: CKF2306, powder) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off, and a weak anion exchange resin (200 mg, Organo Corporation, IRA96SB-HG) that had been previously washed with distilled water was added to the filtrate, followed by stirring at room temperature for 30 minutes. The mixture was filtered through a membrane filter (Merck, A-F-150, 0.2 μm, Φ47 mm), and the filtrate was concentrated under reduced pressure to obtain a syrupy residue. Distilled water (2.5 mL) was added to a flask (100 mL) containing the residue to prepare an aqueous solution of D-allose (Brix value: 52.5%), followed by the addition of isopropanol (5 mL, Merck), and the flask was equipped with a dropping funnel, a Tripod tube, a Liebig condenser, and a solvent recovery flask. The flask was heated in an oil bath (temperature: 113°C), and isopropanol (30 mL) was added in approximately six divided portions with stirring while the solvent was distilled off. When the amount of distilled solvent reached 20 mL, heating was stopped, and the reaction mixture was allowed to cool to 90°C. After adding seed crystals, the mixture was stirred for 30 minutes at an external temperature of 90°C. After 30 minutes, isopropanol (20 mL) was added in about five portions while distilling. When 20 mL of solvent had been distilled, heating was stopped, isopropanol (10 mL) was added, and the mixture was allowed to cool. The suspension was stirred in an ice bath for 1 hour, and the crystals were filtered and washed with isopropanol (10 mL) to obtain D-allose (2.791 g) as a colorless solid. (Yield: 80.6%)

[0494] REFERENCE SIGNS LIST 1 Magnetic stirrer 2 Oil bath 3 Reaction liquid / acetone solution 4 Zeolite membrane 5 Cooler 6 First cooling water 7 Removed water vapor 8 Vacuum pump 9 Cold trap 10 Reaction vessel 11 Dropping funnel 12 Second cooling water 13 Reduced pressure 14 Recovery vessel 1b Magnetic stirrer 2b Oil bath 3b Reaction liquid / acetone solution 4b Zeolite membrane 5b Cooler 6b Cooling water 7b Removed water vapor 8b Vacuum pump 9b Cold trap 10b First reaction vessel 11b First dropping funnel 12b First cooling water 13b First reduced pressure 14b First recovery vessel 15b Second reaction vessel 16b Second dropping funnel 17b Second cooling water 18b Second reduced pressure 19b Second collection container 20b opening

Claims

1. A method for producing a solution of diacetone glucose containing ketone bodies, comprising: a first step of producing a first solution by dissolving diacetone glucose in acetic ester; a second step of mixing the first solution with a first aqueous solution containing an oxidizing agent and oxidizing the diacetone glucose to ketone bodies in the presence of an oxidation catalyst; a third step of separating the second solution after the oxidation reaction obtained in the second step into an organic solution and a second aqueous solution; and a fourth step of obtaining the organic solution.

2. The method for producing a ketone body-containing solution according to claim 1, wherein the oxidizing agent is hypochlorous acid or a salt thereof, or molecular oxygen.

3. The method for producing a ketone body-containing solution according to claim 1, wherein the oxidation catalyst is an organic nitroxyl radical-based oxidation catalyst.

4. The oxidation catalyst is nor-AZADO, 2-azaadamantane-N-oxyl (AZADO), 2-hydroxy-2-azaadamantane (AZADOL), [4-hydroxy-TEMPO + NaCl] / SiO ２ The method for producing a ketone body-containing solution according to claim 1, wherein the ketone body is at least one selected from the group consisting of:

5. The method for producing a ketone body-containing solution according to claim 1, wherein the amount of the oxidation catalyst added is 0.001 mol % to 1 mol % relative to the diacetone glucose.

6. The method for producing a ketone body-containing solution according to claim 1, wherein the organic solution contains a mixture of ketone bodies and hydrates of diacetone glucose, and the ratio of the ketone bodies to the hydrates is 3:1 to 7:

1.

7. A method for producing ketone bodies from diacetone glucose, which is obtained by concentrating a ketone body-containing solution obtained by the method for producing a ketone body-containing solution described in claim 1.

8. A method for producing diacetone allose, comprising: a fifth step of suspending a reducing agent in a lower alcohol to produce a suspension; and a sixth step of mixing the ketone body-containing solution obtained by the method for producing a ketone body-containing solution described in claim 1 with the suspension from the fifth step, and reducing the ketone body to diacetone allose.

9. A method for producing diacetone allose as described in claim 8, wherein in the mixing, the ketone body-containing solution obtained by the method for producing a ketone body-containing solution as described in claim 1 is added dropwise while stirring the suspension of the fifth step.

10. The method for producing diacetone allose according to claim 8, further comprising the steps of: dissolving diacetone allose produced by the reduction reaction in a first organic solvent to produce a dissolved solution; and mixing the dissolved solution with a heptane solution containing diacetone allose seed crystals to crystallize the diacetone allose.

11. The method for producing diacetone allose according to claim 10, wherein the first organic solvent is selected from the group consisting of esters, ethers, hydrocarbons, ketones, alcohols and cyano compounds.

12. The method for producing diacetone allose according to claim 10, wherein the first organic solvent is toluene or ethyl acetate.

13. A method for producing a ketone body-containing solution according to claim 1, wherein the diacetone glucose is produced by a method comprising the following steps: a first dissolution step of mixing glucose, an aprotic polar solvent in which the glucose is soluble, and acetonide to produce a solution; a first reaction step of adding a Lewis acid or protonic acid catalyst that promotes the reaction between the glucose and the acetonide to the solution to produce a reaction solution; and a first neutralization step of adding a third aqueous solution containing a neutralizing agent to neutralize the reaction solution.

14. The method for producing a ketone body-containing solution according to claim 13, wherein the catalyst is iron chloride or aluminum chloride, and in the first neutralization step, the third aqueous solution further contains a gelation inhibitor.

15. A method for producing a ketone body-containing solution according to claim 13 or 14, further comprising a removal step of removing water and / or the aprotic polar solvent from the reaction solution after the first neutralization step.

16. The method for producing a ketone body-containing solution according to claim 15, wherein the removal step is carried out by utilizing a reflux dehydration reaction apparatus equipped with a reaction vessel for carrying out the first dissolution step, the first reaction step, and the first neutralization step, a membrane that is permeable to water vapor but not to the aprotic polar solvent, a water separator connected to a vacuum pump and a cold trap, and a cooler.

17. The method for producing a ketone body-containing solution according to claim 16, wherein the membrane is a zeolite membrane.

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