A kind of preparation method of 5-hydroxymethyltetrahydrofuran-3-ol

Abstract

The present invention relates to a preparation method of 5-hydroxymethyltetrahydrofuran-3-alcohol, and the synthetic route based on the present invention includes route one, route two and route three, and four RS isomeric products and two cis-trans isomeric products are obtained. The present invention has the advantages of significantly improving the diastereoselectivity in the synthesis process, effectively reducing the generation of isomers, and thus more easily isolating high-purity 5-hydroxymethyltetrahydrofuran-3-alcohol; based on the synthetic route provided by the present invention, the raw materials are more economical and easy to obtain, and the raw material cost is reduced; the synthetic process is simple, and the yield and purity of the target product are significantly improved by accurately controlling the reaction conditions and the molar ratio; the process is green and environmentally friendly, and the conditions are mild, which is suitable for the needs of large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a method for preparing 5-hydroxymethyltetrahydrofuran-3-ol. Background Art

[0002] Currently, the preferred treatment for AIDS is to inhibit HIV reverse transcriptase (RT) using modified nucleosides. Therefore, compounds such as AZT, ddC, ddI, and BW-1685 show strong activity against HIV reverse transcriptase and, in some cases, have been used as a first line of defense against AIDS. Recently, it has been found that certain modified nucleosides in the enantiomeric series, such as L-3-TC and L-5-F-ddC, also show activity against HIV RT. Generally speaking, these compounds are much less toxic and therefore have better therapeutic indicators. In addition to these modified nucleoside analogs, they all have heterocyclic bases in the normal ectopic position. Examples of these compounds with antiviral activity are D- and L-dideoxyadenosine. 5-Hydroxymethyltetrahydrofuran-3-ol is a key intermediate in the synthesis of nucleosides and has been widely concerned and studied in recent years.

[0003] According to the synthesis of 5-hydroxymethyltetrahydrofuran-3-ol disclosed in the literature J. Org. Chem. 1998, 63, 2975-2981: Method 1: Mainly using 1,4-pentadiene as the raw material, 1,4-pentadiene (prepared by the reaction of allyl chloride and magnesium) is subjected to a sharp asymmetric dihydroxylation process using (DHQD)2PHAL to produce a mixture of optically active tetradienes in a ratio of about 1:1, which are converted into optically active diepoxides through their ditoluic acids. Method 2: The copper salt of 1,5-dichloropentane-2,4-dione is asymmetrically reduced using Nossler's catalyst and cyclized on a base. Method 3: d-ribose acid γ-lactone can be converted into optically active tetraenoic acid in six steps, then sulfonylated with TPSCl, and then treated with sodium hydride to obtain diepoxides. The three routes can then react with acid or base to obtain 5-hydroxymethyltetrahydrofuran-3-ol. However, the optical activity of the intermediate in route 1 is 1:1, and it cannot be separated by any simple method (crystallization, distillation or chromatography); the raw materials of methods 2 and 3 are expensive, resulting in high product costs, which limits industrial development. The reaction formula is as follows:

[0004]

[0005] According to the literature M. Tiecco et al. / Tetrahedron 63 (2007) 5482–5489, the synthesis of 5-hydroxymethyltetrahydrofuran-3-ol is mainly based on (R)-glycidol as raw material, and is obtained through five steps of ring opening, electrophilic addition, reduction, free radical cyclization, and TBDPS removal. However, the final 5-hydroxymethyltetrahydrofuran-3-ol isomers lack diastereoselectivity, and the isomer ratio is nearly 1:1. It is difficult to separate and obtain high-purity 5-hydroxymethyltetrahydrofuran-3-ol, which limits the development of the industry. The reaction formula is as follows:

[0006]

[0007] In the prior art, the synthesis of 5-hydroxymethyltetrahydrofuran-3-ol suffers from the lack of diastereoselectivity of the final product and a high isomer ratio, and it is difficult to separate high-purity 5-hydroxymethyltetrahydrofuran-3-ol. Summary of the invention

[0008] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing 5-hydroxymethyltetrahydrofuran-3-ol, which significantly improves the diastereoselectivity in the synthesis process, effectively reduces the generation of isomers, and thus makes it easier to separate high-purity 5-hydroxymethyltetrahydrofuran-3-ol; based on the synthesis route provided by the present invention, the raw materials are more economical and readily available, and the raw material cost is reduced; the synthesis process is simple, and the yield and purity of the target product are significantly improved by accurately controlling the reaction conditions and the molar ratio; the process is green and environmentally friendly, and the conditions are mild, which is suitable for the needs of large-scale industrial production.

[0009] The present invention is achieved through the following technical solutions: On the one hand, a method for preparing 5-hydroxymethyltetrahydrofuran-3-ol is provided, comprising the following chiral isomers:

[0010]

[0011] Wherein, the molar ratio of the compound represented by formula (IX) to the compound represented by formula (X) is 4:1; the synthesis routes of the compound represented by formula (IX) and the compound represented by formula (X) are shown in the following route 1:

[0012] .

[0013] Furthermore, the following steps are included:

[0014] Step 1) Formula (I) The protective group reacts with an alcohol under alkaline conditions to produce a compound represented by formula (II);

[0015] Step 2) reacting the compound represented by formula (II) with vinylmagnesium bromide to obtain the compound represented by formula (III);

[0016] Step 3) reacting the compound represented by formula (III) with tetrabutylammonium fluoride to undergo a deprotection reaction to obtain a compound represented by formula (IV);

[0017] Step 4) treating the compound represented by formula (IV) with iodine and sodium carbonate to obtain a mixture of the compound represented by formula (V) and the compound represented by formula (VI);

[0018] Step 5) reacting the mixture of the compound represented by formula (V) and the compound represented by formula (VI) with p-nitrobenzoic acid to obtain a mixture of the compound represented by formula (VII) and the compound represented by formula (VIII);

[0019] Step 6) removing the protecting groups from the mixture of the compound represented by formula (VII) and the compound represented by formula (VIII) under the action of sodium tert-butoxide to obtain a mixture of the compound represented by formula (IX) and the compound represented by formula (X), and purifying the mixture of the compound represented by formula (IX) and the compound represented by formula (X) by column chromatography;

[0020] Wherein, in step 1), the molar ratio of the protecting group to the compound represented by formula (I) is (1-1.5):1; preferably 1.2:1.

[0021] In step 2), a catalyst CuI is also used, and the molar ratio of CuI to the compound represented by formula (II) is (0.1-0.3):1; preferably 0.3:1.

[0022] In step 3), the molar ratio of tetrabutylammonium fluoride to the compound represented by formula (III) is (1-1.5):1;

[0023] In step 4), the molar ratio of iodine to the compound represented by formula (IV) is (2-3):1; preferably 2.5:1.

[0024] In step 5), the molar ratio of the mixture of p-nitrobenzoic acid, the compound represented by formula (V) and the compound represented by formula (VI) is (4-8):1; preferably 6:1.

[0025] In step 6), the molar ratio of the mixture of sodium tert-butoxide and the compound represented by formula (VII) and the compound represented by formula (VIII) is (6-10):1; preferably 8:1.

[0026] Again, a method for preparing 5-hydroxymethyltetrahydrofuran-3-ol is provided, comprising the following chiral isomers:

[0027]

[0028] Wherein, the molar ratio of the compound represented by formula (XIX) to the compound represented by formula (XX) is 4:1.

[0029] Furthermore, the synthesis routes of the compound represented by formula (XIX) and the compound represented by formula (XX) are shown in the following route 2:

[0030] .

[0031] Furthermore, the following steps are included:

[0032] Step 1) Formula (XI) reacting with a protecting group and an alcohol under alkaline conditions to produce a compound represented by formula (XII);

[0033] Step 2) reacting the compound represented by formula (XII) with vinylmagnesium bromide to obtain the compound represented by formula (XIII);

[0034] Step 3) reacting the compound represented by formula (XIII) with tetrabutylammonium fluoride to undergo a deprotection reaction to obtain a compound represented by formula (XIV);

[0035] Step 4) treating the compound represented by formula (XIV) with iodine and sodium carbonate to obtain a mixture of the compound represented by formula (XV) and the compound represented by formula (XVI);

[0036] Step 5) reacting a mixture of the compound represented by formula (XV) and the compound represented by formula (XVI) with p-nitrobenzoic acid to obtain a mixture of the compound represented by formula (XVII) and the compound represented by formula (XVIII);

[0037] Step 6) removing the protecting groups from the mixture of the compound represented by formula (XVII) and the compound represented by formula (XVIII) under the action of sodium tert-butoxide to obtain a mixture of the compound represented by formula (XIX) and the compound represented by formula (XX), and purifying the mixture of the compound represented by formula (XIX) and the compound represented by formula (XX) by column chromatography;

[0038] Wherein, in step 1), the molar ratio of the protecting group to the compound represented by formula (XI) is (1-1.5):1; preferably 1.2:1.

[0039] In step 2), a catalyst CuI is also used, and the molar ratio of CuI to the compound represented by formula (XII) is (0.1-0.3):1; preferably 0.3:1.

[0040] In step 3), the molar ratio of tetrabutylammonium fluoride to the compound represented by formula (XIII) is (1-1.5):1;

[0041] In step 4), the molar ratio of iodine to the compound represented by formula (XIV) is (2-3):1; preferably 2.5:1.

[0042] In step 5), the molar ratio of the mixture of p-nitrobenzoic acid, the compound represented by formula (XV) and the compound represented by formula (XVI) is (4-8):1; preferably 6:1.

[0043] In step 6), the molar ratio of the mixture of sodium tert-butoxide and the compound represented by formula (XVII) and the compound represented by formula (XVIII) is (6-10):1; preferably 8:1.

[0044] Preferably, in step 1), the protecting group is selected from one of TBDPSCl, TESOTf and DTBMSCl.

[0045] Finally, a method for preparing 5-hydroxymethyltetrahydrofuran-3-ol is provided, comprising the following cis-trans isomers:

[0046]

[0047] Wherein, the molar ratio of the compound represented by formula (XXIX) to the compound represented by formula (XXX) is 4.1:1.

[0048] Furthermore, the synthesis routes of the compound represented by formula (XXIX) and the compound represented by formula (XXX) are shown in the following route 3:

[0049] .

[0050] Furthermore, the following steps are included:

[0051] Step 1) Substitute formula (XXI) Reaction with vinylmagnesium bromide to obtain a compound represented by formula (XXII);

[0052] Step 2) treating the compound represented by formula (XXII) with Na2CO3 to obtain the compound represented by formula (XXIII);

[0053] Step 3) boiling the compound represented by formula (XXIII) in water at 90°C to obtain the compound represented by formula (XXXIV);

[0054] Step 4) treating the compound represented by formula (XXIV) with iodine and sodium carbonate to obtain a mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI);

[0055] Step 5) reacting the mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI) with p-nitrobenzoic acid to obtain a mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII);

[0056] Step 6) removing the protecting groups from the mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII) under the action of sodium tert-butoxide to obtain a mixture of the compound represented by formula (XXIX) and the compound represented by formula (XXX), and purifying the compound represented by formula (XXIX) and the compound represented by formula (XXX) by column chromatography;

[0057] Wherein, in step 1), the molar ratio of the vinyl magnesium bromide to the compound represented by formula (XXI) is (1.05-1.5):1;

[0058] In step 2), the molar ratio of Na2CO3 to the compound represented by formula (XXII) is (1.05-1.5):1;

[0059] In step 4), the molar ratio of iodine to the compound represented by formula (XXIV) is (2-3): 1;

[0060] In step 5), the molar ratio of the mixture of p-nitrobenzoic acid, the compound represented by formula (XXV) and the compound represented by formula (XXVI) is (4-8):1;

[0061] In step 6), the molar ratio of the mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII) to sodium tert-butoxide is (6-10):1.

[0062] Beneficial Effects

[0063] The invention significantly improves the diastereoselectivity in the synthesis process by precisely controlling the reaction conditions and the molar ratio and using a specific catalyst and a protecting group; effectively reduces the generation of isomers, thereby making it easier to separate high-purity 5-hydroxymethyltetrahydrofuran-3-ol.

[0064] The synthetic routes of the present invention include route one, route two and route three, and four RS isomeric products and two cis-trans isomeric products are obtained. The raw materials are cheap and easily available, and the synthetic method is simple, which not only reduces the generation of by-products, but also simplifies the subsequent purification steps, which is conducive to achieving a higher yield and purity.

[0065] The process is green and environmentally friendly, the conditions are mild, and it is suitable for the needs of large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 is the 1HNMR spectrum of the compound represented by formula (IX);

[0067] Figure 2 1HNMR spectrum of the compound represented by formula (X). DETAILED DESCRIPTION

[0068] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0069] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The experimental methods without specific conditions in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions or parts are by weight.

[0070] Unless otherwise specified, the reagents and raw materials used in the examples and comparative examples of the present invention can be obtained through commercial channels.

[0071] Example 1

[0072]

[0073] Synthesis of the compound represented by formula (II):

[0074] 1.1 kg of TBDPSCl and 239 g of imidazole were added to 2 L of DMF, cooled to 0-5°C, and 200 g of the compound represented by formula (I) was added dropwise, and the temperature was controlled not to be higher than 10°C. After the addition was completed, the temperature was raised to 25°C and the reaction was continued for 2 hours. The reaction was completed by TLC monitoring, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 506 g of the compound represented by formula (II) with a yield of 60%.

[0075] Synthesis of the compound represented by formula (III):

[0076] 93 g of CuI was added to 2.5 L of anhydrous THF, cooled to -15°C, and 4.8 L of vinyl magnesium bromide was added dropwise. After the addition was completed, the temperature was controlled between -10°C and -20°C, and 506 g of a THF solution of the compound represented by formula (II) (the compound represented by formula (II) was dissolved in 2.5 L of THF) was added dropwise to the reaction system. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. TLC monitored the reaction to be complete, water was added to quench, the mixture was extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 430 g of the compound represented by formula (III) with a yield of 78%.

[0077] Synthesis of the compound represented by formula (IV):

[0078] 430 g of the compound represented by formula (III) was added to 2.1 L of anhydrous THF, and a THF solution of TBAF was added dropwise under an ice bath (0°C). After the addition was completed, the temperature was raised to room temperature. The reaction was monitored by TLC to be complete. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain 116 g of the compound represented by formula (IV) with a yield of 90%.

[0079] Synthesis of the compound represented by formula (V) and the compound represented by formula (VI):

[0080] 116 g of the compound represented by formula (IV) was dissolved in 1.3 L THF, stirred in an ice bath for 20 minutes, and then 301 g of Na2CO3 was added in batches. The mixture was heated to room temperature and stirred for 30 minutes, then cooled to 0°C again, and 577 g of solid iodine was added in batches. After the addition, the system was naturally heated to room temperature. The reaction was monitored by TLC to be complete. Solid sodium sulfite was added to neutralize excess iodine until the reaction solution became clear and transparent, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 205 g of a mixture of the compound represented by formula (VI) and the compound represented by formula (VII), with a yield of 79%.

[0081] Synthesis of the compound represented by formula (VII) and the compound represented by formula (VIII):

[0082] 205 g of a mixture of the compound represented by formula (VI) and the compound represented by formula (VII) was dissolved in 1 L of DMF, and then 101 g of 18-crown ether-6 and 315 g of p-nitrobenzoic acid were added, and the mixture was reacted at 90° C. overnight. TLC monitored the reaction to be complete, and after adding ice water and stirring for 15 minutes, the mixture was extracted with ethyl acetate, washed with sodium thiosulfate aqueous solution, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 164 g of a mixture of the compound represented by formula (XI) and the compound represented by formula (XII), with a yield of 80%.

[0083] Synthesis of the compound represented by formula (IX) and the compound represented by formula (X):

[0084] A mixture of 164 g of the compound represented by formula (XI) and the compound represented by formula (XII) was dissolved in 820 mL of ACN, and 354 g of sodium tert-butoxide was added in batches. The mixture was reacted at room temperature for 3-4 hours under nitrogen protection. The reaction was completed after TLC monitoring. The reaction solution was filtered and the filtrate was concentrated to obtain a mixture of the compound represented by formula (XI) and the compound represented by formula (XII). 41 g of the compound represented by formula (IX) and 10 g of the compound represented by formula (X) were separated by column chromatography, and the yield was 70%.

[0085] The 1HNMR spectra of the prepared formula (IX) and the 1HNMR spectra of the formula (X) are as follows: Figure 1 and Figure 2 shown.

[0086] Example 2

[0087]

[0088] Synthesis of the compound represented by formula (XII):

[0089] 1.67 kg of TBDPSCl and 358 g of imidazole were added to 2 L of DMF, cooled to 0-5°C, and 300 g of the compound represented by formula (XI) was added dropwise, and the temperature was controlled not to be higher than 10°C. After the addition was completed, the temperature was raised to 25°C and the reaction was continued for 2 hours. The reaction was completed by TLC monitoring, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 759 g of the compound represented by formula (XII) with a yield of 60%.

[0090] Synthesis of the compound represented by formula (XIII):

[0091] 139 g of CuI was added to 3.8 L of anhydrous THF, cooled to -15°C, and 7.3 L of vinyl magnesium bromide was added dropwise. After the addition was completed, the temperature was controlled between -10°C and -20°C, and 759 g of a THF solution of the compound represented by formula (XII) (the compound represented by formula (XII) was dissolved in 2.5 L of THF) was added dropwise to the reaction system. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. TLC monitored the reaction to be complete, water was added to quench, the reaction was extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 645 g of the compound represented by formula (XIII) with a yield of 78%.

[0092] Synthesis of the compound represented by formula (XIV):

[0093] 645 g of the compound represented by formula (XII) was added to 3.2 L of anhydrous THF, and a THF solution of TBAF was added dropwise under an ice bath (0°C). After the addition was completed, the temperature was raised to room temperature. The reaction was monitored by TLC to be complete. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain 174 g of the compound represented by formula (XIV) with a yield of 90%.

[0094] Synthesis of the compound represented by formula (XV) and the compound represented by formula (XVI):

[0095] 174 g of the compound represented by formula (XIV) was dissolved in 1.3 L THF, and stirred for 20 minutes under ice bath. Then 430 g of Na2CO3 was added in batches. After the temperature was raised to room temperature and stirred for 30 minutes, the temperature was lowered to 0°C again, and 866 g of solid iodine was added in batches. After the addition, the system was naturally heated to room temperature. The reaction was completed by TLC monitoring. Solid sodium sulfite was added to neutralize the excess iodine until the reaction solution became clear and transparent. The solution was extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 307 g of a mixture of the compound represented by formula (XV) and the compound represented by formula (XVI), with a yield of 79%.

[0096] The compound represented by formula (XVII) and the synthesis of the compound represented by formula (XVII):

[0097] 307 g of a mixture of the compound represented by formula (XV) and the compound represented by formula (XVI) was dissolved in 1 L of DMF, and then 152 g of 18-crown ether-6 and 472 g of p-nitrobenzoic acid were added, and the mixture was reacted at 90° C. overnight. The reaction was monitored by TLC. After adding ice water and stirring for 15 minutes, the mixture was extracted with ethyl acetate, washed with sodium thiosulfate aqueous solution, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 246 g of a mixture of the compound represented by formula (XVII) and the compound represented by formula (XVII), with a yield of 80%.

[0098] Synthesis of the compound represented by formula (XIX) and the compound represented by formula (XX):

[0099] 246 g of a mixture of the compound represented by formula (XVII) and the compound represented by formula (XVII) was dissolved in 1.2 mL of ACN, 530 g of sodium tert-butoxide was added in batches, and the mixture was reacted at room temperature for 3-4 hours under nitrogen protection. The reaction was completed after TLC monitoring. The reaction liquid was filtered, and the filtrate was concentrated to obtain a mixture of the compound represented by formula (XI) and the compound represented by formula (XIX). 61 g of the compound represented by formula (XI) and 15 g of the compound represented by formula (XIX) were separated by column chromatography, and the yield was 70%.

[0100] Example 3

[0101]

[0102] Synthesis of the compound represented by formula (XXII):

[0103] At -50-60°C, 3.7 L of vinyl magnesium bromide was added to a 1.2 L THF solution of 107 g of CuBr, and then 230 g of the compound represented by (XXI) was slowly added dropwise to the above system. After the addition, the temperature was gradually raised to -30°C and the reaction was allowed to proceed overnight. TLC monitored the reaction to be complete, and the reaction solution was added to saturated ammonium chloride, extracted with ethyl acetate, concentrated under reduced pressure, and subjected to column chromatography to obtain 285 g of the compound represented by formula (XXII) with a yield of 95%.

[0104] Synthesis of the compound represented by formula (XXIII):

[0105] 501 g of Na2CO3 solid was added to 285 g of the compound represented by formula (XXII), and the temperature was raised to 90°C and the reaction was carried out overnight. The reaction was completed by TLC monitoring, and the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and subjected to column chromatography to obtain 161 g of the compound represented by formula (XXIII) with a yield of 81%.

[0106] Synthesis of the compound represented by formula (XXIV):

[0107] 161 g of the compound represented by formula (XXIII) was added to 805 mL of water, and the temperature was raised to 90°C and the reaction was carried out overnight. TLC monitored the completion of the reaction, and the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and subjected to column chromatography to obtain 111 g of the compound represented by formula (XXIV) with a yield of 57%.

[0108] Synthesis of the compound represented by formula (XXV) and the compound represented by formula (XXVI):

[0109] 111 g of the compound represented by formula (XXIV) was dissolved in 1.3 L THF, stirred in an ice bath for 20 minutes, and then 275 g of Na2CO3 was added in batches. After the temperature was raised to room temperature and stirred for 30 minutes, the temperature was lowered to 0°C again, and 554 g of solid iodine was added in batches. After the addition, the system was naturally heated to room temperature. The reaction was completed by TLC monitoring, and solid sodium sulfite was added to neutralize excess iodine until the reaction solution became clear and transparent. The solution was extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 189 g of a mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI), with a yield of 76%.

[0110] Synthesis of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII):

[0111] 189 g of a mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI) was dissolved in 1 L of DMF, and then 93 g of 18-crown ether-6 and 290 g of p-nitrobenzoic acid were added, and the mixture was reacted at 90° C. overnight. The reaction was monitored by TLC. After adding ice water and stirring for 15 minutes, the mixture was extracted with ethyl acetate, washed with sodium thiosulfate aqueous solution, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 151 g of a mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII), with a yield of 80%.

[0112] Synthesis of the compound represented by formula (XXIX) and the compound represented by formula (XXX):

[0113] A mixture of 151 g of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII) was dissolved in 820 mL of ACN, and 326 g of sodium tert-butoxide was added in batches. The mixture was reacted at room temperature for 3-4 hours under nitrogen protection. The reaction was completed after TLC monitoring. The reaction solution was filtered and the filtrate was concentrated to obtain a mixture of the compound represented by formula (XXIX) and the compound represented by formula (XXX). Column chromatography separation was performed to obtain 37 g of the compound represented by formula (XXIX) and 9 g of the compound represented by formula (XXX), with a yield of 69%.

[0114] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 5-hydroxymethyltetrahydrofuran-3-ol, characterized in that: Includes the following chiral isomers: ； The synthesis routes of the compound represented by formula (IX) and the compound represented by formula (X) are shown in the following route 1: ; The method comprises the following steps: Step 1) Formula (I) The protective group reacts with an alcohol under alkaline conditions to produce a compound represented by formula (II); Step 2) reacting the compound represented by formula (II) with vinylmagnesium bromide to obtain the compound represented by formula (III); Step 3) reacting the compound represented by formula (III) with tetrabutylammonium fluoride to undergo a deprotection reaction to obtain a compound represented by formula (IV); Step 4) treating the compound represented by formula (IV) with iodine and sodium carbonate to obtain a mixture of the compound represented by formula (V) and the compound represented by formula (VI); Step 5) Synthesis of the compound represented by formula (VII) and the compound represented by formula (VIII): 205 g of a mixture of the compound represented by formula (V) and the compound represented by formula (VI) was dissolved in 1 L DMF, and then 101 g of 18-crown ether-6 and 315 g of p-nitrobenzoic acid were added, and the mixture was reacted at 90° C. overnight; TLC monitored the reaction to be complete, ice water was added and stirred for 15 minutes, and then the mixture was extracted with ethyl acetate, washed with sodium thiosulfate aqueous solution, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 164 g of a mixture of the compound represented by formula (VII) and the compound represented by formula (VIII); Step 6) Synthesis of the compound represented by formula (IX) and the compound represented by formula (X): 164 g of a mixture of the compound represented by formula (VII) and the compound represented by formula (VIII) was dissolved in 820 mL of ACN, 354 g of sodium tert-butoxide was added in batches, and the mixture was reacted at room temperature for 3-4 hours under nitrogen protection. The reaction was completed after TLC monitoring. The reaction solution was filtered, and the filtrate was concentrated to obtain a mixture of the compound represented by formula (IX) and the compound represented by formula (X). 41 g of the compound represented by formula (IX) and 10 g of the compound represented by formula (X) were separated by column chromatography; Wherein, in step 1), the molar ratio of the protecting group to the compound represented by formula (I) is (1-1.5): 1; In step 2), a catalyst CuI is also used, and the molar ratio of CuI to the compound represented by formula (II) is (0.1-0.3):1; In step 3), the molar ratio of tetrabutylammonium fluoride to the compound represented by formula (III) is (1-1.5):1; In step 4), the molar ratio of iodine to the compound represented by formula (IV) is (2-3):

1.

2. The method for preparing 5-hydroxymethyltetrahydrofuran-3-ol according to claim 1, characterized in that: In step 1), the protecting group is selected from one of TBDPSCl, TESOTf and DTBMSCl.

3. A method for preparing 5-hydroxymethyltetrahydrofuran-3-ol, characterized in that: Includes the following cis and trans isomers: ； The synthesis routes of the compound represented by formula (XXIX) and the compound represented by formula (XXX) are shown in the following route 3: ； The method further comprises the following steps: Step 1) Substitute formula (XXI) Reaction with vinylmagnesium bromide to obtain a compound represented by formula (XXII); Step 2) treating the compound represented by formula (XXII) with Na2CO3 to obtain the compound represented by formula (XXIII); Step 3) boiling the compound represented by formula (XXIII) in water at 90°C to obtain the compound represented by formula (XXIV); Step 4) treating the compound represented by formula (XXIV) with iodine and sodium carbonate to obtain a mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI); Step 5) Synthesis of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII): 189 g of a mixture of the compound represented by formula (XXV) and the compound represented by formula (XXVI) was dissolved in 1 L DMF, and then 93 g of 18-crown ether-6 and 290 g of p-nitrobenzoic acid were added, and the mixture was reacted at 90° C. overnight. The reaction was monitored by TLC to be complete. After adding ice water and stirring for 15 minutes, the mixture was extracted with ethyl acetate, washed with sodium thiosulfate aqueous solution, washed with saturated brine, concentrated under reduced pressure, and subjected to column chromatography to obtain 151 g of a mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII); Step 6) Synthesis of the compound represented by formula (XXIX) and the compound represented by formula (XXX): 151 g of a mixture of the compound represented by formula (XXVII) and the compound represented by formula (XXVIII) was dissolved in 820 mL of ACN, 326 g of sodium tert-butoxide was added in batches, and the mixture was reacted at room temperature for 3-4 hours under nitrogen protection. The reaction was completed after TLC monitoring. The reaction solution was filtered, and the filtrate was concentrated to obtain a mixture of the compound represented by formula (XXIX) and the compound represented by formula (XXX). 37 g of the compound represented by formula (XXIX) and 9 g of the compound represented by formula (XXX) were separated by column chromatography. Wherein, in step 1), the molar ratio of the vinyl magnesium bromide to the compound represented by formula (XXI) is (1.05-1.5):1; In step 2), the molar ratio of Na2CO3 to the compound represented by formula (XXII) is (1.05-1.5):1; In step 4), the molar ratio of iodine to the compound represented by formula (XXIV) is (2-3):1.

Images