A method for preparing tetrahydrofuran derivatives

Abstract

The present invention relates to a method for preparing tetrahydrofuran derivatives, which comprises contacting a compound of formula (I) with a reducing agent in an aqueous solution under reduction reaction conditions to obtain a reaction mixture; and then contacting the obtained reaction mixture with a strong acid under ring-closing condensation reaction conditions to obtain a reaction solution containing tetrahydrofuran derivatives, wherein R 1 and R 2 Each is independently selected from one of hydrogen, hydroxyl, protected hydroxyl, amino, mercapto, alkyl, alkoxy, olefin, aryl, alkyne or heterocyclic. The method of the invention shortens working hours, improves efficiency, reduces three wastes, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a tetrahydrofuran derivative. Background Art

[0002] Tetrahydrofuran derivatives are commonly used synthetic raw materials and important intermediates in the field of chemistry. Among them, as an important intermediate for preparing abasic deoxynucleoside phosphoramidite monomers, the preparation method of 1,2-dideoxy-D-ribose (1,2-DIDEOXY-D-RIBOSE, CAS No. 91547-59-0) has been described in the prior art. Khimiya Prirodnykh Soedinenii et al. disclosed in a non-patent literature (International Journal of Molecular Sciences (2024), 25(4), 2368 / (1990), (3), 417-19) a preparation method of 1,2-dideoxy-D-ribose using deoxy-D-ribose as a starting material, sodium borohydride reduction, and ring-closing condensation under acidic conditions. The process route is shown in the following formula (X):

[0003] Formula (X)

[0004] This method has the following main disadvantages:

[0005] First, after the first step of the reaction, the intermediate product 2 needs to be purified and separated. During purification, the reaction mixture needs to be neutralized with acid, and then desalted with ion exchange resin (Bio-Rad AG501 x 8 (D) 20-50 mesh). This resin is imported from abroad and is not easy to buy in China, and the price is relatively high. In addition, the use, activation, and regeneration of this resin require a large amount of acid and alkali, which will also produce a large amount of salt and wastewater. The elution and concentration of the product consume a lot of energy and man-hours, resulting in increased production costs and extended production cycles.

[0006] Secondly, the second step reaction takes 72 hours, and the long time leads to increased costs.

[0007] In addition, when separating the final product 3, it is necessary to concentrate and remove the volatile acid (hydrochloric acid) in the reaction mixture. The hydrogen chloride gas volatilized and the hydrochloric acid mist formed during the concentration process are easy to corrode pipeline equipment, resulting in increased production costs and additional safety risks. Summary of the invention

[0008] The present invention provides a method for preparing a tetrahydrofuran derivative, which comprises contacting a compound of formula (I) with a reducing agent in an aqueous solution under reduction reaction conditions to obtain a reaction mixture; and then contacting the obtained reaction mixture with a strong acid under ring-closing condensation reaction conditions.

[0009] Formula (I)

[0010] Wherein, R1 and R2 are each independently selected from one of hydrogen, hydroxyl, protected hydroxyl, amino, thiol, alkyl, alkoxy, olefin, alkyne, aromatic or heterocyclic groups.

[0011] Beneficial Effects

[0012] In the method of the present invention, the reaction mixture obtained under the reduction reaction conditions does not need to be separated, and the second step of ring-closing condensation reaction is directly carried out, thereby avoiding the product loss that may be generated during the separation process, improving the total yield, shortening the operation time, reducing the use of excess solvents and the generation of three wastes; in addition, the method of the present invention uses a non-volatile acid, and the ring-closing reaction time is shortened from the original 72 hours to 18-24 hours, which reduces energy consumption while also avoiding the generation of acidic gases. In addition, in the post-treatment process, there is no need to use a chromatography column, avoiding the use of specific chromatography resins that need to be imported. In summary, the method of the present invention reduces separation, shortens working hours, improves efficiency, reduces three wastes, avoids corrosion of pipeline equipment, and is suitable for large-scale industrial production.

[0013] Incorporated by Reference

[0014] All publications, patents, and patent applications mentioned in this specification are incorporated by reference into the present disclosure to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference into the present disclosure. DETAILED DESCRIPTION

[0015] The specific embodiments of the present disclosure are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present disclosure, and are not used to limit the present disclosure.

[0016] It will be understood by those skilled in the art that for any group comprising one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0017] The present disclosure provides a method for preparing tetrahydrofuran derivatives, which comprises contacting a compound of formula (I) with a reducing agent in an aqueous solution under reduction reaction conditions to obtain a reaction mixture; and then contacting the obtained reaction mixture with a strong acid under ring-closing condensation reaction conditions.

[0018] Formula (I)

[0019] R1 and R2 are each independently selected from one of hydrogen, hydroxyl, protected hydroxyl, amino, mercapto, alkyl, alkoxy, alkene, alkynyl, aromatic or heterocyclic groups.

[0020] In some embodiments, the "protected hydroxyl" refers to a hydroxyl functional group protected by a suitable protecting group, such as an acid-active acetal protecting group, in particular 1-(aryl)-4-alkoxypiperidin-4-yl, such as 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) or 1-(2-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep). In some embodiments, in the compound represented by formula (I), R1 and R2 may be unprotected hydroxyl groups, and a tetrahydrofuran derivative is formed by chemically selective ring-closing condensation to achieve the method described in the present invention.

[0021] As used herein, "alkyl" refers to straight and branched chain saturated hydrocarbon radicals having a specified number of carbon atoms, typically 1 to 20 carbon atoms, e.g., 1 to 10 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. For example, C1-C6 alkyl includes straight and branched chain alkyl radicals of 1 to 6 carbon atoms. When a residue having a specific number of alkyl radicals is mentioned, it is intended to encompass all branched and straight chain forms having that number of carbons; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl and tert-butyl; "propyl" includes n-propyl and isopropyl.

[0022] As used herein, "alkoxy" refers to an alkyl group of the specified number of carbon atoms attached through an oxygen bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms attached through an oxygen bridge. In some embodiments, the alkoxy group is methoxy, ethoxy, propoxy, or isopropoxy.

[0023] In some embodiments, the olefin group refers to a substituted or unsubstituted C2-C10 olefin group. In some embodiments, the olefin group is an olefin group with a carbon number of C2-C6. In some embodiments, the olefin group is vinyl or propenyl.

[0024] In some embodiments, the alkynyl group refers to a substituted or unsubstituted C2-C10 alkynyl group. In some embodiments, the alkynyl group is an alkynyl group with a carbon number of C2-C6. In some embodiments, the alkynyl group is an ethynyl group or a propynyl group.

[0025] As used herein, the aryl group represents an aromatic (family) ring that has lost one or more hydrogen atoms, including aromatic rings connected with other functional groups or substituents. In some embodiments, the aryl group is a substituted or unsubstituted C6-C30 aryl group. In some embodiments, the aryl group is an aryl group having a carbon number of C6-C11. In some embodiments, the aryl group is a phenyl group or a 4-methylphenyl group.

[0026] In some embodiments, the heterocyclic group may be a five-membered or six-membered heterocyclic group, wherein the five-membered or six-membered heterocyclic group represents a saturated or unsaturated five-membered heterocyclic group, or a saturated or unsaturated six-membered heterocyclic group. In some embodiments, the heterocyclic group is a 2-pyridyl group.

[0027] In some embodiments, in the compound of formula (I), R1 and R2 are each independently one of hydrogen, hydroxyl, C1-C4 alkyl and C1-C4 alkoxy. In some embodiments, in the compound of formula (I), R1 and R2 are both hydroxyl.

[0028] A person skilled in the art is aware of various reduction reaction conditions, and any reduction reaction conditions that can obtain the above reaction mixture after the compound of formula (I) is contacted with a reducing agent can be used in the present disclosure. In some embodiments, the reduction reaction conditions include contacting under alkaline or neutral conditions. In some embodiments, the reduction reaction conditions include a pH range of 10-13 for the aqueous solution. In some embodiments, the reduction reaction conditions include a reaction temperature of 5-40°C and normal pressure. In some embodiments, the reduction reaction is carried out at 10-35°C and normal pressure. In some embodiments, the reduction reaction conditions include carrying out under anaerobic conditions, such as an inert atmosphere. In some embodiments, the reduction reaction conditions include carrying out under a nitrogen atmosphere. In some embodiments, the reduction reaction conditions include a reaction time of 0.5-2.5 hours. In some embodiments, the reaction time is 1-2 hours. In some embodiments, the reduction reaction conditions include a pH range of 10-13 for the aqueous solution, and the reaction is carried out at room temperature, normal pressure, and nitrogen atmosphere; the reaction time is 1-2 hours.

[0029] In some embodiments, the alkaline conditions are formed by adding sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium phosphate, potassium carbonate and combinations thereof to an aqueous solution. Considering the cost and stability of the alkaline conditions, in some embodiments, the alkaline conditions are formed by adding sodium hydroxide to an aqueous solution.

[0030] In some embodiments, the reducing agent is at least one of borane, lithium aluminum tetrahydride, lithium borohydride, sodium cyanoborohydride, sodium acetate borohydride, sodium dihydrogen bis (dimethoxyethoxy) aluminate or sodium borohydride. Considering the material cost and the completeness of the reduction reaction, in some embodiments, the reducing agent is sodium borohydride. The amount of the reducing agent is related to the reducing ability and type of the reducing agent. In some embodiments, the molar ratio of the reducing agent to the compound of formula (I) can be 1:1-5:1, for example, 1.3:1-4:1, according to the number of hydrogen atoms in the reducing agent normalized to 1 (for example, sodium borohydride contains 4 hydrogen atoms, and the molar number is calculated as 4 times).

[0031] Considering the degree of reaction and the degree of solubility of the reaction mixture, in some embodiments, the concentration of the compound of formula (I) in the aqueous solution is 15-25 wt.%. In some embodiments, the concentration of the compound of formula (I) in the aqueous solution is 18-22 wt.%. In some embodiments, the ratio of water as a reaction solvent to the compound of formula (I) is 1:0.5-1:5 L / mol, for example, 1:1-1:3 L / mol.

[0032] In the method disclosed herein, after the compound of formula (I) is contacted with a reducing agent to obtain a reaction mixture, no additional separation and purification steps are required, and the reaction mixture is directly contacted with a strong acid. Thus, compared with the process routes recorded in the prior art, the method of the present invention saves the manpower, materials, equipment and time costs required for separation and purification, and reduces the generation of waste liquid (for example, solvents for recrystallization or chromatographic separation that need to be added during purification). In some embodiments, the method disclosed herein may also include an additional step of separating and purifying the reaction mixture. The separation and purification step, for example, after optional purification by a chromatographic column, evaporates and removes the solvent to obtain an intermediate mixture.

[0033] In the method disclosed herein, the reaction mixture (or, in the case of separation and purification, the intermediate mixture) is contacted with a strong acid under ring-closing condensation reaction conditions, so that the polyhydroxy compound (such as compound 2 or its borate shown in formula (X)) produced by the reduction reaction in the reaction mixture undergoes dehydration condensation between hydroxyl groups to form a ring closure to generate a tetrahydrofuran derivative. In some embodiments, the ring-closing condensation reaction conditions include: a reaction temperature of 80-98°C; a reaction time of 12-48 hours. In some embodiments, the ring-closing condensation reaction conditions include: a reaction temperature of 95-98°C; a reaction time of 14-45 hours. The ring-closing condensation reaction can be carried out at any suitable pressure, for example, at 0.8-10 atmospheres. In some embodiments, the ring-closing condensation reaction is carried out at normal pressure.

[0034] In some embodiments, the strong acid is an inorganic acid or an organic acid; examples of the inorganic acid include, but are not limited to, at least one of sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, or perchloric acid. Examples of the organic acid include, but are not limited to, p-toluenesulfonic acid, fluoromethanesulfonic acid, methanesulfonic acid, or trinitrobenzenesulfonic acid, such as toluenesulfonic acid, trifluoromethanesulfonic acid, or methanesulfonic acid. In some embodiments, the strong acid is a non-oxidizing inorganic strong acid. In some embodiments, the strong acid is a non-volatile strong acid, in which case the method of the present disclosure can reduce the volatilization of acidic gases, improve reaction efficiency, reduce pipeline corrosion, thereby saving costs and reducing safety risks. In some embodiments, the strong acid is sulfuric acid.

[0035] Calculated based on the number of hydrogen ions in the strong acid, in some embodiments, the concentration of the strong acid is 1-3 mol / L. In order to achieve a balance between cost and reaction completeness, in some embodiments, the concentration of the strong acid is 1.5-2.5 mol / L. The molar ratio of the compound of formula (I) to the strong acid can be 1:1.2-1.5, for example, the molar ratio of the compound of formula (I) to the strong acid is 1:1.25-1.45.

[0036] In some embodiments, the tetrahydrofuran derivative obtained by the method of the present disclosure has a structure shown in formula (II):

[0037] Formula (II).

[0038] Wherein, the definition and selection range of R1 and R2 are the same as above. In some embodiments, in the above formula (II), R1 and R2 are each independently a hydroxyl group or a protected hydroxyl group. In some embodiments, R1 and R2 are both hydroxyl groups.

[0039] In some embodiments, the preparation method further comprises the step of separating and purifying the product mixture obtained after the reaction mixture is contacted with a strong acid, thereby obtaining a tetrahydrofuran derivative. In the above and below, the "separation and purification" can be carried out by any suitable method capable of separating and purifying tetrahydrofuran derivatives. In some embodiments, the separation and purification step comprises: adjusting the pH of the reaction system to 6-8 at 20-50°C so that the strong acid forms a salt; heating and concentrating to remove water, then adding an organic solvent that can azeotrope with water and concentrating to remove the remaining water in the product mixture; then adding an organic solvent to precipitate the salt formed by the strong acid; filtering the mixture and collecting the filtrate; the filtrate is concentrated to remove the solvent to obtain a crude product; the crude product is distilled under reduced pressure, and the fractions are collected to obtain a purified tetrahydrofuran derivative. In some embodiments, the separation and purification step comprises: cooling the product mixture to 20-50°C, adding an alkaline compound to adjust the pH of the reaction system to 6-8; heating and concentrating to remove water, then adding an organic solvent to concentrate, removing the remaining water in the product mixture by azeotropic means, and controlling the temperature to be 55-65°C during concentration; then adding an organic solvent to allow the salt formed by the strong acid to precipitate when the alkaline compound is added; collecting the reaction solution, filtering, and controlling the temperature to be 5-15°C during filtration; concentrating the filtrate to obtain a crude product; distilling the crude product under reduced pressure, collecting fractions, and obtaining the compound represented by formula (II). In some embodiments, the alkaline compound is sodium hydroxide. The organic solvent is a solvent that can azeotrope with water and dissolve the tetrahydrofuran derivative, but the solubility of the salt formed by the strong acid in the organic solvent is relatively low. In some embodiments, the organic solvent is an alcohol or ester solvent. In some embodiments, the organic solvent is ethanol. The amount of the organic solvent used is based on the ability to dissolve the tetrahydrofuran derivative and to precipitate the salt formed by the strong acid as much as possible. In some embodiments, the amount of the organic solvent relative to the compound of formula (I) may be 2.5-3.5 L / Kg, for example 2.5-3.5 L / Kg. In some embodiments, the filtration may be performed using a silica gel pad, or a filter aid such as diatomaceous earth, activated carbon or cellulose.

[0040] In some embodiments, the vacuum distillation of the crude product can be divided into two stages. The conditions of the vacuum distillation in the first stage include: pressure of 100-200 Pa, temperature of 80-100° C., and time of 30-60 min; the conditions of the vacuum distillation in the second stage include: pressure of <10 Pa, temperature of 110-120° C., and vacuum distillation until no fraction continues to flow out.

[0041] Example

[0042] The present invention and its beneficial effects are described in detail below in conjunction with specific embodiments.

[0043] The sources of the reagents and instruments used in the following examples are shown in Table 1 below:

[0044] Table 1 Sources of reagents and instruments

[0045] Reagents / Instruments Model / Purity Manufacturer / Supplier 1,2-Dideoxy-D-ribose ≥98.0% Beijing Dilong Chemical Co., Ltd. Sodium borohydride ≥98.0% Tianjin Baima Technology Co., Ltd. Concentrated sulfuric acid >98.0% Tianjin Bohai Chemical Group Supply and Marketing Company Sodium hydroxide >96.0% Tianjin Damao Chemical Reagent Factory Ethanol >99.5% Tianjin Jinweier Chemical Co., Ltd. Silicone 150 mesh Qingdao Hailang Silica Gel Desiccant Co., Ltd. Glass Reactor 100L Zhengzhou Great Wall Science, Industry and Trade Co., Ltd. Hot and cold cycle machine -20~100℃ Nantong Purui Technology Instrument Co., Ltd. Dry vacuum pump GZL8 Shandong Yining Environmental Protection Technology Co., Ltd. Rotary evaporator 50L Zhengzhou Great Wall Science, Industry and Trade Co., Ltd. Box type resistance furnace SX-4-10DⅡ Tianjin Test Instrument Co., Ltd. Electronic balance AUW120D Shimadzu Enterprise Management (China) Co., Ltd.

[0046] Unless otherwise specified, other starting materials, reaction reagents or solvents used in the following examples are commercially available.

[0047] Example 1

[0048] To a solution of 20.0 g 2-deoxy-D-ribose (150 mmol) in 100 mL water, add 1.2 g sodium hydroxide (30 mmol), and slowly add 1.9 g sodium borohydride (50 mmol) under nitrogen atmosphere, and react for 1.5 hours under stirring. Slowly add 20 g concentrated sulfuric acid (204 mmol) to the reaction mixture, heat to >95°C, and react for 48 hours under stirring to obtain a product mixture. Control the reaction temperature to be less than 50°C, slowly add 8.4 g of solid sodium hydroxide (208 mmol) to the product mixture, concentrate to remove the solvent, then add 20 mL of ethanol, concentrate until no liquid flows out, continue to add 40 mL of ethanol and stir, filter the product mixture with a silica gel pad to remove the precipitated solid sodium sulfate, the amount of silica gel is 20-40 g, wash the silica gel pad with 20 mL of ethanol, combine and collect all the filtrate and washing liquid, and concentrate under reduced pressure to remove the solvent to obtain 15.9 g of a crude product containing the product 1,2-dideoxy-D-ribose, with a yield of 90%.

[0049] Example 2: Selection of reducing agent dosage

[0050] The preparation method and process conditions of Example 1 were used, except that the amount of sodium borohydride and / or 2-deoxy-D-ribose was changed. The amount and yield of the compounds in different Example groups are shown in Table 2 below:

[0051] Table 2: Amount of compound and reducing agent used and crude product yield

[0052]

[0053] From the results in Table 2, it can be seen that the use of various amounts of reducing agents can obtain 1,2-dideoxy-D-ribose products with a high yield, the yield of at least 70%; further, when the molar ratio of the reducing agent to 2-deoxy-D-ribose is 1.32:1-4:1 after normalization (i.e., calculated according to the reducing power of the reducing agent, for example, the chemical formula of sodium borohydride contains 4 hydrogens, so when calculated as 1 hydrogen, the amount of the substance is calculated as 4 times), the yield is significantly further improved, the lowest is 90%, and even up to 95%. The above results show that when using different amounts of reducing agents, the method disclosed in the present invention can efficiently and conveniently synthesize tetrahydrofuran derivatives.

[0054] Example 3: Screening of concentration and type of strong acid

[0055] The preparation method and process conditions of Example 1 were used for preparation, except that the acid concentration and reaction temperature were changed, and the reaction time after adding the strong acid was 48 hours. The acid concentration and reaction temperature and product conversion rate in different example groups are shown in Table 3 below:

[0056] Table 3: Acid concentration, reaction temperature and product conversion

[0057]

[0058] The ring-closing condensation reaction is a slow reaction. The reaction temperature and the concentration of the acid will directly affect the reaction speed. From the results in Table 3, under the same reaction time of 48h, the reaction temperature in the range of 20-75°C only gave a lower yield. Under the condition of 90°C-reflux temperature, the method disclosed in the present invention obtains a higher yield, at least 72%; secondly, the concentration of 1-3 mol / L (2-6 mol / L calculated as hydrogen ions) can achieve a higher yield. Further, when the concentration of the acid is 2-3 mol / L, the yield is further improved to 87-89%. Considering that a large amount of acid will also bring difficulties to the separation and purification of the product and increase the cost, comprehensive consideration, calculated as hydrogen ions, the concentration of the acid in the reaction system can be 4-6 mol / L, preferably 4 mol / L.

[0059] Furthermore, the preparation method and process conditions of Example 1 were used for preparation, except that the type of acid was changed while the concentration of the strong acid calculated as hydrogen ions was kept the same. The types and yields of the acids in different example groups are shown in Table 4 below:

[0060] Table 4 Acid types and yields

[0061]

[0062] As can be seen from the results of Table 4, various inorganic strong acids can prepare tetrahydrofuran derivatives with a conversion rate of 66%-91. Further, the reaction effect of non-oxidizing strong acids is significantly higher than that of oxidizing nitric acid and perchloric acid, and the yield can reach 89%-91%. Due to the formation of azeotropes and acid mists under high temperature conditions, hydrochloric acid and water will form an azeotrope, which will corrode the emptying pipeline, and the irritating acid mist will bring difficulties to sampling. At the same time, the sodium sulfate solid formed in the post-treatment has a larger particle size and is easier to filter than sodium chloride. Considering comprehensively, in the method disclosed herein, it is best to use sulfuric acid as the strong acid used.

[0063] Example 4: Reaction time screening

[0064] The preparation method and process conditions of Example 1 were adopted, except that the reaction time was changed. The reaction time and yield in different example groups are shown in the following Table 5:

[0065] Table 5 Reaction time and conversion rate

[0066]

[0067] It can be seen from the results in Table 5 that at different reaction times, the method disclosed herein can obtain a higher yield, ranging from 51% to 91%. Taking into account the balance between yield and reaction time, in the method disclosed herein, the reaction time is 12-72h, preferably 36-48h.

[0068] Example 5: Screening of Base Types for Post-treatment Neutralization

[0069] The preparation method and process conditions of Example 1 were adopted, except that the type of base was changed, and the amount of base used and the amount of sulfuric acid were both 1:1, calculated based on the equivalent amount of hydrogen neutralized by the base.

[0070] Accurately weigh 2g of the crude product obtained by the reaction on an electronic balance and place it in a crucible that has been calcined to constant weight. Place the crucible in a box-type resistance furnace and slowly calcine it to 700°C to completely carbonize the crude product to obtain a black powder. Cool the black powder to below 50°C, add 1mL of 98% concentrated sulfuric acid to moisten it, heat it to 400°C to remove all sulfuric acid vapor, and calcine it at 800°C to completely incinerate the black powder. Transfer the crucible and place it in a dryer, cool it to 25°C, accurately weigh it on an electronic balance, and then calcine it at 800°C to constant weight, and measure the mass of the remaining residue. Calculate the calcination residue rate of the crude product according to the following formula:

[0071] Crude product ignition residue rate = residue mass / crude product mass × 100%

[0072] The types and equivalents of the alkali in different example groups and the crude product ignition residue rate are shown in the following Table 6:

[0073] Table 6 Type and equivalent of alkali and ignition residue rate of crude product

[0074]

[0075] As shown in Table 6, when various alkalis are used for neutralization, a lower crude product ignition residue rate can be obtained, with a maximum of no more than 8.4%. Further, when the metal ion in the alkali used is sodium, the solubility of the formed sodium salt in the organic solvent is low, and it is easier to precipitate and be filtered out, so the purification effect is relatively good; further, considering that sodium carbonate and sodium bicarbonate will produce a large number of bubbles and form a large amount of foam, which is not suitable for amplified production, the alkali used in the present disclosure is optimal with sodium hydroxide. In addition, in order to reduce the amount of water used, the use of the alkali is carried out in a manner of adding sodium hydroxide solid to the reaction mixture.

[0076] Example 6: Screening of organic solvents and times used for azeotropic distillation to remove water

[0077] The preparation method and process conditions of Example 1 were used, except that the type of organic solvent and the number of azeotropic water removal were changed, and after the preparation was completed, the crude product ignition residue rate was measured and calculated according to the method described in Example 5. The types of organic solvents, the number of azeotropic water removals, and the crude product ignition residue rates in different example groups are shown in Table 7 below:

[0078] Table 7 Type and number of solvent replacement and crude product ignition residue rate

[0079]

[0080] It can be seen from the results of Table 7 that various solvents that can azeotropize with water can achieve azeotropic dehydration, and the resulting crude product has a lower crude product ignition residue rate. The highest does not exceed 8.5%. Further, when ethanol, tetrahydrofuran and acetonitrile are used, the crude product has a significantly lower crude product ignition residue rate, which is only 1.3-3.3%. Considering the solvent cost factor, the organic solvent described in the method disclosed in the present invention is preferably ethanol. Compared with the method without azeotropic dehydration, 1-2 times of azeotropic dehydration can significantly reduce the crude product ignition residue rate of the resulting crude product, indicating that it has a better desalination effect. And after azeotropic dehydration once, most of the salt can be effectively removed, and the crude product ignition residue rate of the resulting crude product is only 2.4%. Considering the process cost and desalination efficiency, it is preferred to perform an azeotropic dehydration step.

[0081] Example 7: Preparation of 1,2-dideoxy-D-ribose

[0082] 600 g of sodium hydroxide (15 mol) was added to a solution of 10.0 kg of 2-deoxy-D-ribose (75 mol) in 50 L of water, and the mixture was stirred at 90 rpm for 20 minutes. 950 g of sodium borohydride solid (25 mol) was added to the reaction system at 15°C under a nitrogen atmosphere. The mixture was stirred for 1.5 hours under a nitrogen atmosphere to obtain a reaction mixture.

[0083] The reaction temperature was controlled below 50°C, 10 kg of concentrated sulfuric acid (102 mol) was added to the obtained reaction mixture, and stirred for 36 hours under reflux conditions at a temperature of >95°C. 4.2 kg of solid sodium hydroxide (104 mol) was added to the reaction system at 20-30°C to obtain a product mixture.

[0084] The product mixture was divided into 3 equal parts, and one part of the product mixture was concentrated at not higher than 60°C until no fraction flowed out, 10L of ethanol was added, and the mixture was stirred evenly under a low vacuum of 0.045Mpa, and then concentrated under a high vacuum of 0.01Mpa for 2 hours, and 20L of ethanol was added, and the mixture was stirred under a low vacuum of 0.045Mpa for 1.5 hours. The other two reaction solutions were treated in the same manner, and the obtained product mixtures were combined. Filtered with a Buchner funnel, 1.5kg of 150-mesh silica gel was placed in the funnel, and after filtration, the silica gel pad was rinsed with 10L of ethanol, the filtrate and the washing liquid were combined, and concentrated until no fraction flowed out, and 11kg of crude product was obtained by weighing.

[0085] The crude product was distilled under reduced pressure at 90°C for 45 minutes under a vacuum condition of 150 Pa, and the vacuum was gradually increased to below 10 Pa, and the temperature was raised to 115°C. When the product was flowing out steadily, the fractions were collected until no fraction continued to flow out. The fractions were combined and weighed to obtain 7.5 kg of the product 1,2-dideoxy-D-ribose, with a yield of 85%.

Claims

1. A method for preparing a tetrahydrofuran derivative, comprising contacting a compound of formula (I) with a reducing agent in an aqueous solution under reduction reaction conditions to obtain a reaction mixture; and then contacting the obtained reaction mixture with sulfuric acid under ring-closing condensation reaction conditions. Formula (I) in, The tetrahydrofuran derivative has a structure as shown in formula (II): Formula (II), R1 and R2 are both hydroxyl groups, The method further comprises the step of separating and purifying the product mixture obtained after the reaction mixture is contacted with sulfuric acid, wherein the separation and purification comprises: adjusting the pH of the reaction system to 6-8 with sodium hydroxide at 20-50° C. so that the sulfuric acid forms sodium sulfate, Wherein, the reduction reaction conditions include: Alkaline conditions; The reaction temperature is 5-40°C; The reaction time is 0.5-2.5 hours; The ring-closing condensation reaction conditions include: The reaction temperature is 80-98°C; The reaction time is 12-72 hours; The molar ratio of the reducing agent to the compound of formula (I) is 1:1-5:1, calculated based on the number of hydrogen atoms in the reducing agent being normalized to 1; The molar ratio of the compound of formula (I) to sulfuric acid is 1:1.2-1.

5.

2. The method according to claim 1, wherein: The pH range of the aqueous solution is 10-13.

3. The method according to claim 1, wherein: The alkaline condition is formed by adding sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium phosphate, potassium carbonate and a combination thereof into an aqueous solution.

4. The method according to claim 3, wherein: The alkaline condition is formed by adding sodium hydroxide to the aqueous solution.

5. The method according to claim 1, wherein: The reducing agent is at least one of borane, lithium aluminum tetrahydride, lithium borohydride, sodium cyanoborohydride, sodium acetate borohydride, sodium dihydrogen bis(dimethoxyethoxy)aluminate or sodium borohydride.

6. The method according to claim 5, wherein: The reducing agent is sodium borohydride.

7. The method according to claim 1, wherein: In the aqueous solution, the concentration of the compound of formula (I) is 15-25 wt.%.

8. The method according to claim 1, wherein: The reaction time is 36-48 hours.

9. The method according to claim 1, wherein: Calculated based on the number of hydrogen ions in sulfuric acid, the concentration of sulfuric acid is 1-3 mol / L.

10. The method according to claim 9, wherein: The concentration of sulfuric acid is 1.5-2.5 mol / L.

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