A method for synthesizing (E)-2-butene-1,4-diol

Abstract

The invention discloses a method for synthesizing (E)-2-butene-1,4-diol, which comprises the following steps: in an organic solvent, subjecting a compound represented by formula I to a reduction reaction in the presence of NaBH4 and a Lewis acid to obtain the (E)-2-butene-1,4-diol; wherein the Lewis acid is CaCl2 and / or ZnCl2; in the compound represented by formula I, R and R' are respectively C 1‑3 The synthesis method of (E)-2-butene-1,4-diol of the present invention has one or more of the following advantages: high reaction yield, low cost, low reaction risk, simple post-treatment, low pollution, and easy application in industry.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing (E)-2-butene-1,4-diol. Background Art

[0002] The disclosed synthesis method of (E)-2-butene-1,4-diol is as follows:

[0003]

[0004]

[0005] In the method for synthesizing (E)-2-butene-1,4-diol reported in the above literature, diethyl fumarate is used as a raw material, the reducing agent used is diisobutylaluminum hydride (DIBAL-H), and the solvent is toluene or benzene, wherein toluene is a precursor reagent and a Class 3 carcinogen, and benzene is a Class 1 carcinogen; DIBAL-H requires anhydrous operation, is flammable and explosive, is very dangerous, cannot be scaled up, and has troublesome post-processing; the method reported in the literature has a low yield of 60%-80%; and the reaction time is relatively long.

[0006]

[0007]

[0008] In the method for synthesizing (E)-2-butene-1,4-diol reported in the above literature, dimethyl fumarate is used as a raw material, DIBAL-H is used as a reducing agent, and toluene is used as a solvent, wherein toluene is easy to make poisons; DIBAL-H has strict requirements for anhydrous operation, is flammable and explosive, is very dangerous, cannot be scaled up, and has troublesome post-processing; the reaction time is long; and the reaction yield is low, which is 76%.

[0009]

[0010]

[0011]

[0012] In the method for synthesizing (E)-2-butene-1,4-diol reported in the above literature, the yield of the method is relatively low, which is 72%; the reaction time is long; the reaction temperature is too high; and the price of raw material 4 is expensive.

[0013]

[0014]

[0015] In the method for synthesizing (E)-2-butene-1,4-diol reported in the above literature, 1,4-butynediol is used as a raw material, LiAlH4 As reducing agent, THF is solvent. This method has a violent reaction. LiAlH 4 It is flammable and explosive, dangerous to operate, and has strict anhydrous requirements for solvents. Post-processing is very troublesome and cannot be scaled up. It can only be scaled up to the laboratory ng level, and the scaled-up operation is very dangerous. In addition, the reaction will produce metal ions Al 3+ , Li + There are three waste pollution problems. Summary of the invention

[0016] In order to overcome one or more of the problems of high cost, high reaction risk, complex post-treatment, high pollution, and poor industrial application in the method for synthesizing (E)-2-butene-1,4-diol in the prior art, the present invention provides a method for synthesizing (E)-2-butene-1,4-diol. The method for synthesizing (E)-2-butene-1,4-diol of the present invention has one or more of the following advantages: high reaction yield, low cost, low reaction risk, simple post-treatment, low pollution, and easy application in industry.

[0017] The present invention solves the above technical problems through the following technical means.

[0018] The present invention provides a method for synthesizing (E)-2-butene-1,4-diol, which comprises the following steps:

[0019]

[0020] In an organic solvent, the compound shown in formula I is dissolved in NaBH 4 and Lewis acid to obtain the (E)-2-butene-1,4-diol; wherein the Lewis acid is CaCl 2 and / or ZnCl 2 In the compound of formula I, R and R' are respectively C 1-3 alkyl.

[0021] In some embodiments of the present invention, in the compound represented by formula I, R and R' are preferably ethyl or methyl, for example ethyl.

[0022] In some embodiments of the present invention, the NaBH 4 The molar ratio of the Lewis acid can be (1:1) to (5:1), preferably (1:1) to (3:1), for example 1:1, 2:1 or 3:1.

[0023] In some embodiments of the present invention, the compound represented by formula I and the NaBH 4The molar ratio of may be (1:1) to (1:12), preferably (1:2.5) to (1:10), for example 1:2.5, 1:3, 1:5, 1:6, 1:7.5, 1:9 and 1:10.

[0024] In some embodiments of the present invention, the organic solvent is selected from one or more of methanol, ethanol and tetrahydrofuran, preferably methanol, ethanol, tetrahydrofuran, a mixed solvent of ethanol and methanol, or a mixed solvent of tetrahydrofuran and methanol. In the mixed solvent of tetrahydrofuran and methanol, the volume ratio of tetrahydrofuran to methanol can be (2:1) to (3:1). In the mixed solvent of ethanol and methanol, the volume ratio of ethanol to methanol can be (2:1) to (3:1).

[0025] In some embodiments of the present invention, R and R' are ethyl groups; the Lewis acid is CaCl 2 ; the NaBH 4 The molar ratio of the Lewis acid is 2:1; the temperature of the reduction reaction is 70° C.; and the organic solvent is a mixed solvent of tetrahydrofuran and methanol.

[0026] In some embodiments of the present invention, the temperature of the reduction reaction may be 25°C to 100°C, preferably 50°C to 90°C, such as 70°C to 80°C.

[0027] In some embodiments of the present invention, the reduction reaction time is the time required for the compound represented by Formula I to no longer react, such as 2-3 hours.

[0028] In some embodiments of the present invention, the reduction reaction may include the following steps: 4 The organic solution of Lewis acid is added in batches to the organic solution, and then the organic solution of the compound represented by formula I is added in batches, and the reduction reaction is carried out after the addition is complete. The NaBH 4 The organic solution of the Lewis acid, the organic solution of the compound of formula I, and the organic solution of the compound of formula I can be independently the aforementioned organic solvents. The batch addition method can be dropwise addition. 4 In the process of adding the Lewis acid solution in batches to the solution, NaBH 4 Before adding the organic solution of the compound represented by Formula I in batches, NaBH 4 The solution system of Lewis acid was reacted at 0°C for 30 min.

[0029] In some embodiments of the present invention, the synthesis method further comprises the following steps: after the compound represented by formula I stops reacting, the reaction solution is post-treated to obtain (E)-2-butene-1,4-diol.

[0030] In some embodiments of the present invention, the post-treatment step preferably includes: quenching the reaction solution, filtering out the solid, concentrating the obtained filtrate, and purifying it by column chromatography to obtain the product.

[0031] In some embodiments of the present invention, the quenching may be a conventional quenching method in the art, such as water quenching.

[0032] In some embodiments of the present invention, the reagent used for drying may be an inorganic salt conventional in the art, such as anhydrous magnesium sulfate.

[0033] In some embodiments of the present invention, the concentration may be a conventional concentration method in the art, such as reduced pressure concentration.

[0034] In some embodiments of the present invention, the column chromatography may be silica gel column chromatography. In some embodiments of the present invention, the eluent used in the column chromatography is a conventional eluent in the art, such as ethyl acetate and n-hexane, such as ethyl acetate and n-hexane in a volume ratio of 1:1.

[0035] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0036] The reagents and raw materials used in the present invention are commercially available.

[0037] The positive progressive effect of the present invention is that the synthesis method of (E)-2-butene-1,4-diol of the present invention has one or more of the following advantages: high reaction yield, low cost, low reaction risk, simple post-treatment, low pollution, and can be well applied in industry. DETAILED DESCRIPTION

[0038] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0039] In the following examples, the reactions were all carried out under normal pressure.

[0040]

[0041] Example 1

[0042] NaBH 4 (5.39 g, 142.58 mmol, 5 eq) was dissolved in 80 mL of anhydrous THF and CaCl was slowly added dropwise at 0 °C. 2(7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir at 0℃ for a while, warm to 25℃ for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 is completely reacted. Add 20mL of water to quench, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.75g of crude residue. Use 113g silica gel column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 1.39 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 55.2%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0043] Example 2

[0044] NaBH 4 (2.70 g, 71.29 mmol, 2.5 eq) was dissolved in 80 mL of anhydrous THF and CaCl was slowly added dropwise at 0 °C. 2 (7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir at 0℃ for a while, warm to 25℃ for reaction for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 is completely reacted. Add 20mL of water to quench, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.75g of crude residue. Use 113g silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 1.52 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 60.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0045] Example 3

[0046] NaBH 4(5.39 g, 142.58 mmol, 5 eq) was dissolved in 80 mL of anhydrous THF and CaCl was slowly added dropwise at 0 °C. 2 (7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir for a while, heat to 70℃, reflux and stir for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacts completely. Add 20mL of water to quench, cool the temperature to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.84g of crude residue. Use 113g of silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 2.43 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 97.0%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0047] Example 4

[0048] NaBH 4 (8.09 g, 213.87 mmol, 7.5 eq) was dissolved in 80 mL of anhydrous THF and CaCl was slowly added dropwise at 0 °C. 2 (7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir for a while, heat to 70℃, reflux and stir for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacts completely. Add 20mL of water to quench, cool the temperature to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.84g of crude residue. Use 113g of silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 1.82 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 72.8%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0049] Example 5

[0050] NaBH 4 (5.39 g, 142.58 mmol, 5 eq) was dissolved in 80 mL of anhydrous ethanol and CaCl was slowly added dropwise at 0 °C. 2 (7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous ethanol (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir for a while, heat to 80℃ and reflux and stir for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacts completely. Add 20mL of water to quench, cool to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.78g of crude residue. Use 113g of silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 1.63 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 64.8%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0051] Example 6

[0052] NaBH 4 (5.39 g, 142.58 mmol, 5 eq) was dissolved in 80 mL of anhydrous methanol and CaCl was slowly added dropwise at 0 °C. 2 (7.91g, 71.29mmol, 2.5eq)-methanol (60mL) solution, after the addition is completed, stir at 0℃ for 30min, then slowly add diethyl fumarate (4.91g, 28.51mmol)-anhydrous methanol (80mL) solution to the reaction solution at 0℃, after the addition is completed, stir for a while, heat to 70℃ and reflux and stir for 2h, take a sample (dilute with ethyl acetate), TLC detection (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacts completely. Add 20mL of water to quench, cool to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 2.85g of crude residue. Use 113g of silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 2.03 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 80.8%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ]+ .

[0053] Example 7

[0054] NaBH 4 (1.32 g, 34.85 mmol, 3 eq) was dissolved in 80 mL of anhydrous THF and ZnCl was added at 0 °C. 2 Powder (4.75g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃, refluxed and stirred for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacted completely, added 20mL of water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.05g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.47 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 45.6%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0055] Example 8

[0056] NaBH 4 (2.64 g, 69.69 mmol, 6 eq) was dissolved in 80 mL of anhydrous THF and ZnCl was added at 0 °C. 2 Powder (4.75g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃ and stirred under reflux for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the reaction of raw material compound 1 was complete, quenched with 20mL of water, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.98g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.57 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 56.0%. LC-MS (ESI): m / z = 106.08 [M+NH 4] + .

[0057] Example 9

[0058] NaBH 4 (4.39 g, 116.16 mmol, 10 eq) was dissolved in 80 mL of anhydrous THF and ZnCl was added at 0 °C. 2 Powder (7.92g, 58.08mmol, 5eq), stirred at 0℃ for 30min, then diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution was slowly added to the reaction solution at 0℃, stirred for a while, heated to 70℃ and stirred under reflux for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:10), the raw material compound 1 reacted completely, added 20mL water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a while and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.95g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.78 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 76.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0059] Example 10

[0060] NaBH 4 (4.39 g, 116.16 mmol, 10 eq) was dissolved in 80 mL of anhydrous ethanol and ZnCl was added at 0 °C. 2 Powder (7.92g, 58.08mmol, 5eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous ethanol (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 80℃ and stirred under reflux for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacted completely, added 20mL water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.08g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.60 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 58.4%. LC-MS (ESI): m / z = 106.08 [M+NH4 ] + .

[0061] Embodiment 11

[0062] NaBH 4 (4.39 g, 116.16 mmol, 10 eq) was dissolved in 80 mL of anhydrous methanol and ZnCl was added at 0 °C. 2 Powder (7.92g, 58.08mmol, 5eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous methanol (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃, refluxed and stirred for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacted completely, added 20mL of water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.99g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.65 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 63.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0063] Comparative Example 1

[0064] According to the literature, LiAlH 4 (5.1g, 134.4mmol, 2.3eq) was placed in 150mL of anhydrous THF, and then a solution of butynediol (5g, 58.1mmol)-THF (150mL) was slowly added at 0℃. After the addition was completed, the solution was gray and the temperature was raised to 70℃ for condensation and reflux for 3h. Sampling (diluted with ethyl acetate) and TLC detection (ethyl acetate: n-hexane = 5:1) showed that there was no residual raw material. Heating was stopped, the temperature was cooled to 0℃, and 3M NaOH solution was slowly added to quench until no bubbles were generated, and the pH was adjusted to 8. Filter, wash the filter cake with ethyl acetate, and wash and filter repeatedly for several times until there was no product spot on the filter cake spot plate. Combine the filtrates, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 5.85g of crude residue. Use 200g of silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 4.17 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 81.5% and a purity of 92.53%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ]+ .

[0065] Comparative Example 2

[0066] NaBH 4 (1.32 g, 34.85 mmol, 3 eq) was dissolved in 80 mL of anhydrous THF and AlCl was added at 0 °C. 3 Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 25℃ and stirred, reacted for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 was not completely reacted, and a large amount of raw materials remained. Continue to react at 25℃ for 2h, TLC detected no changes, and the raw materials did not decrease. Add 20mL of water to quench, filter, wash the filter cake with ethyl acetate, stir for a moment and filter again until there is no product spot on the spot plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 0.8g of crude residue. Use 40 silica gel column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.05 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 5.0%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0067] Comparative Example 3

[0068] NaBH 4 (1.32 g, 34.85 mmol, 3 eq) was dissolved in 80 mL of anhydrous THF and AlCl was added at 0 °C. 3Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃, refluxed and stirred, reacted for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 was not completely reacted, and a large amount of raw materials remained. Continue to reflux for 2h, TLC detected no changes, and the raw materials did not decrease. Add 20mL of water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the spot plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.12g of crude residue. Use 113g silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.08 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 7.8%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0069] Comparative Example 4

[0070] NaBH 4 (2.64 g, 69.69 mmol, 6 eq) was dissolved in 80 mL of anhydrous THF and AlCl was added at 0 °C. 3 Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃ and refluxed, stirred for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 was not completely reacted, and a large amount of raw materials remained. Continue to reflux for 2h, TLC detected no changes, and the raw materials did not decrease. Add 20mL of water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the spot plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.00g of crude residue. Use 40g silica gel to load the column, dry sample, and eluent is ethyl acetate: n-hexane = 1:1 elution. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.15 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 14.2%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0071] Comparative Example 5

[0072] NaBH 4 (3.95 g, 104.54 mmol, 9 eq) was dissolved in 80 mL of anhydrous THF and AlCl was added at 0 °C. 3 Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous THF (80mL) solution to the reaction solution at 0℃, stirred for a while, heated to 70℃ and stirred under reflux, reacted for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacted completely, added 20mL water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a while and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.10g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.47 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 45.8%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0073] Comparative Example 6

[0074] NaBH 4 (3.95 g, 104.54 mmol, 9 eq) was dissolved in 80 mL of anhydrous ethanol and AlCl was added at 0 °C. 3 Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous ethanol (80mL) solution to the reaction solution at 0℃, stirred for a while, heated to 80℃ and stirred under reflux, reacted for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1), the raw material compound 1 reacted completely, added 20mL water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a while and filtered again until there was no product spot on the spot plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.10g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1 for elution. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.37 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 36.9%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0075] Comparative Example 7

[0076] NaBH 4 (3.95 g, 104.54 mmol, 9 eq) was dissolved in 80 mL of anhydrous methanol and AlCl was added at 0 °C. 3 Powder (4.65g, 34.85mmol, 3eq), stirred at 0℃ for 30min, then slowly added diethyl fumarate (2.00g, 11.62mmol)-anhydrous methanol (80mL) solution to the reaction solution at 0℃, stirred for a moment, heated to 70℃, stirred under reflux, reacted for 2h, sampled (diluted with ethyl acetate), TLC detected (ethyl acetate: n-hexane = 5:1) The raw material compound 1 reacted completely, added 20mL of water to quench, the temperature dropped to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a moment and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.10g of crude residue. 40g silica gel column was used for dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected and the solvent was evaporated under reduced pressure to obtain 0.39 g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 38.3%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0077] Comparative Example 8

[0078] NaBH 4 (3.30 g, 87.12 mmol, 3 eq) was dissolved in 50 mL of anhydrous THF and stirred at 0°C for 30 min. A solution of diethyl fumarate (5.00 g, 29.04 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction solution at 0°C. After the addition was completed, the mixture was stirred at 0°C for 30 min. Then, BF was slowly added dropwise to the reaction solution at 0°C. 3 -Ether solution (12.37 g, 87.12 mmol, 3 eq), after the addition was completed, the mixture was stirred at 0°C for 30 min, then heated to 25°C for 2 h, and sampled (diluted with ethyl acetate). TLC detection (ethyl acetate: n-hexane = 5:1) showed that the raw material compound 1 was not reacted. The reaction was continued at 25°C for 2 h, and no change was found by TLC detection, indicating that the raw material compound 1 was not reacted.

[0079] Comparative Example 9

[0080] NaBH 4(3.30 g, 87.12 mmol, 3 eq) was dissolved in 50 mL of anhydrous THF and stirred at 0°C for 30 min. A solution of diethyl fumarate (5.00 g, 29.04 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction solution at 0°C. After the addition was completed, the mixture was stirred at 0°C for 30 min. Then, BF was slowly added dropwise to the reaction solution at 0°C. 3 -Ether solution (12.37g, 87.12mmol, 3eq), after the addition is completed, stir at 0℃ for 30min, heat to 70℃, reflux and stir for 2h, take samples (dilute with ethyl acetate), and detect by TLC (ethyl acetate: n-hexane = 5:1). The raw material compound 1 has not reacted completely, and a large amount of raw materials remain. Continue to reflux for 2h, and there is no change in TLC detection, and the raw materials have not been reduced. Add 20mL of water to quench, cool the temperature to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 0.65g of crude residue. Use 30g silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. Collect the eluent of the target product, evaporate the solvent under reduced pressure, and obtain 0.14g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 13.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0081] Comparative Example 10

[0082] NaBH 4 (5.49 g, 145.20 mmol, 5 eq) was dissolved in 50 mL of anhydrous THF and stirred at 0°C for 30 min. A solution of diethyl fumarate (5.00 g, 29.04 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction solution at 0°C. After the addition was completed, the mixture was stirred at 0°C for 30 min. Then, BF was slowly added dropwise to the reaction solution at 0°C. 3-Ether solution (20.61g, 145.20mmol, 5eq), after the addition is completed, stir at 0℃ for 30min, heat to 70℃, reflux and stir for 2h, take a sample (dilute with ethyl acetate), and detect by TLC (ethyl acetate: n-hexane = 5:1). The raw material compound 1 has not reacted completely, and a large amount of raw material remains. Continue to reflux for 2h, and there is no change in TLC detection, and the raw material has not been reduced. Add 20mL of water to quench, reduce the temperature to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 0.78g of crude residue. Use 30g silica gel to load the column, dry load, and elute with ethyl acetate: n-hexane = 1:1. Collect the target product eluate, evaporate the solvent under reduced pressure, and obtain 0.23g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 22.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0083] Comparative Example 11

[0084] NaBH 4 (5.49 g, 145.20 mmol, 5 eq) was dissolved in 50 mL of anhydrous ethanol and stirred at 0 °C for 30 min. A solution of diethyl fumarate (5.00 g, 29.04 mmol) in anhydrous ethanol (20 mL) was slowly added dropwise to the reaction solution at 0 °C. After the addition was completed, the mixture was stirred at 0 °C for 30 min. Then, BF was slowly added dropwise to the reaction solution at 0 °C. 3 -Ether solution (2061g, 14520mmol, 5eq) was added dropwise, stirred at 0℃ for 30min, heated to 80℃, refluxed and stirred for 2h, sampled (diluted with ethyl acetate), and detected by TLC (ethyl acetate: n-hexane = 5:1). The raw material compound 1 was not completely reacted, and a large amount of raw material remained. The reflux reaction was continued for 2h, and there was no change in TLC detection, and the raw material was not reduced. Add 20mL of water to quench, the temperature was lowered to room temperature, filtered, the filter cake was washed with ethyl acetate, stirred for a while and filtered again until there was no product spot on the plate, the filtrate was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.59g of crude residue. 30g of silica gel was used to load the column, dry loading, and the eluent was ethyl acetate: n-hexane = 1:1. The target product eluate was collected, and the solvent was evaporated under reduced pressure to obtain 0.16g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 15.5%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0085] Comparative Example 12

[0086] NaBH 4(5.49 g, 145.20 mmol, 5 eq) was dissolved in 50 mL of anhydrous ethanol and stirred at 0 °C for 30 min. A solution of diethyl fumarate (5.00 g, 29.04 mmol) in anhydrous ethanol (20 mL) was slowly added dropwise to the reaction solution at 0 °C. After the addition was completed, the mixture was stirred at 0 °C for 30 min. Then, BF was slowly added dropwise to the reaction solution at 0 °C. 3 -Ether solution (20.61g, 145.20mmol, 5eq), after the addition is completed, stir at 0℃ for 30min, heat to 80℃, reflux and stir for 2h, take samples (dilute with ethyl acetate), and detect by TLC (ethyl acetate: n-hexane = 5:1). The raw material compound 1 has not reacted completely, and a large amount of raw materials remain. Continue to reflux for 2h, and there is no change in TLC detection, and the raw materials have not been reduced. Add 20mL of water to quench, cool the temperature to room temperature, filter, wash the filter cake with ethyl acetate, stir for a while and filter again until there is no product spot on the plate, combine the filtrate, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain 0.62g of crude residue. Use 30g silica gel to load the column, dry sample, and elute with ethyl acetate: n-hexane = 1:1. Collect the eluent of the target product, evaporate the solvent under reduced pressure, and obtain 0.19g of (E)-2-butene-1,4-diol as a colorless oily liquid with a yield of 18.4%. LC-MS (ESI): m / z = 106.08 [M+NH 4 ] + .

[0087] HPLC testing

[0088] HPLC normalization method: chromatographic column Waters T3 column, mobile phase: 500mL water + 0.75mL phosphoric acid + 1.5mL acetonitrile, injection volume 20μL, sample preparation 3mg / mL, detection wavelength 210nm, flow rate 1.0mL / min, column temperature 35℃.

[0089] The HPLC test data of (E)-2-butene-1,4-diol synthesized in Example 3 is shown in Table 1, and the purity is 96.3071%.

[0090] Table 1

[0091]

[0092] The HPLC test data of (E)-2-butene-1,4-diol synthesized in Comparative Example 1 is shown in Table 2, and the purity is 92.5261%.

[0093] Table 2

[0094]

[0095] The experimental results show that the purity of (E)-2-butene-1,4-diol prepared by the present invention is better than that of Comparative Example 1.

Claims

1. A method for synthesizing (E)-2-butene-1,4-diol, characterized in that: It includes the following steps: In an organic solvent, the compound represented by formula I is subjected to a reduction reaction in the presence of NaBH4 and a Lewis acid to obtain the (E)-2-butene-1,4-diol; wherein the Lewis acid is CaCl2; The molar ratio of the compound represented by formula I to the NaBH4 is 1:(3-6); The molar ratio of the NaBH4 to the Lewis acid is (2-3):1 R and R' are C 1-3 alkyl; The temperature of the reduction reaction is 70°C to 80°C; The organic solvent is a mixed solvent of tetrahydrofuran and methanol.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the NaBH4 to the Lewis acid is 2:1 or 3:

1.

3. The synthesis method according to claim 1, characterized in that The molar ratio of the compound represented by formula I to the NaBH4 is 1:3, 1:5 or 1:

6.

4. The synthesis method according to claim 1, characterized in that The volume ratio of tetrahydrofuran to methanol is (2:1) to (3:1).

5. The synthesis method according to claim 1, characterized in that The R and R' are ethyl groups; the molar ratio of the NaBH4 to the Lewis acid is 2:1; the temperature of the reduction reaction is 70°C; and the organic solvent is a mixed solvent of tetrahydrofuran and methanol.

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