Preparation method of (S)-(+)-3-hydroxytetrahydrofuran

Abstract

The invention discloses a preparation method of (S)-(+)-3-hydroxytetrahydrofuran, which comprises the following steps: taking (S)-1, 2, 4-butantriol as a raw material, reacting at 90-120 DEG C under the action of a catalyst to obtain (S)-(+)-3-hydroxytetrahydrofuran, and the catalyst is a sulfonic acid type ionic liquid catalyst loaded by modified magnetic diatomite. The preparation method solves the problems of serious side reaction, complex reaction post-treatment, difficult product purification, serious acid pollution and the like in the prior art, has the advantages of catalyst recycling, less side reaction, high product purity, environmental protection and the like, can realize higher industrial production value and has a good medical application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for preparing a pharmaceutical auxiliary material (S)-(+)-3-hydroxytetrahydrofuran. Background Art

[0002] (S)-(+)-3-Hydroxytetrahydrofuran is an important pharmaceutical and pesticide intermediate, especially in the pharmaceutical field, where its demand is relatively large. It is widely used in the synthesis of anticancer drugs, hypoglycemic drugs, anti-AIDS drugs, etc. For example, it is used in the drug Empagliflozin, also known as Empagliflozin, with the systematic name (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-oxy]benzyl}phenyl)-D-glucitol, which is a selective sodium-glucose cotransporter-2 (SGLT-2) inhibitor developed by Boehringer Ingelheim GmbH and first approved for marketing in Australia in 2014. It is mainly used to treat type 2 diabetes and can be used alone or in combination with other hypoglycemic drugs to help lower blood sugar levels. Studies have shown that it also has a positive effect on improving cardiovascular health and is used to reduce the risk of cardiovascular disease, especially in patients with diabetes.

[0003] The current market demand for empagliflozin is large, and its research and development and production involve multiple chemical intermediates, among which (S)-(+)-3-hydroxytetrahydrofuran is a key intermediate for synthesizing empagliflozin. The current method for synthesizing (S)-(+)-3-hydroxytetrahydrofuran has many disadvantages. Patents CN104478833A and CN109503523A both use (S)-1,2,4-butanetriol as a raw material to synthesize (S)-(+)-3-hydroxytetrahydrofuran. These patents all use p-toluenesulfonic acid, which is difficult to remove, and the post-processing operation is complicated, there are many by-products, the product purification is difficult, and the acid pollution is serious. Therefore, there is an urgent need for an efficient S-(+)-3-hydroxytetrahydrofuran synthesis method that can recycle the acid catalyst, has low cost, few side reactions, high product purity, and is green and environmentally friendly. Summary of the invention

[0004] In view of the problems existing in the prior art, the present invention provides a method for preparing (S)-(+)-3-hydroxytetrahydrofuran. The method uses (S)-1,2,4-butanetriol as a raw material, uses a sulfonic acid type ionic liquid solid acid supported by modified magnetic diatomaceous earth to catalyze the dehydration ring reaction, avoids the use of p-toluenesulfonic acid with low yield and complicated post-treatment, and the advantages of the synthesis method are that the acid catalyst can be recycled, the cost is low, the side reaction is less, the product purity is high, it is green and environmentally friendly, etc., and has good prospects for industrial application.

[0005] To achieve the above object, the present invention adopts the following technical solution:

[0006] A method for preparing (S)-(+)-3-hydroxytetrahydrofuran comprises: using (S)-1,2,4-butanetriol as a raw material, reacting at 90-120° C. under the action of a catalyst to obtain (S)-(+)-3-hydroxytetrahydrofuran, wherein the catalyst is a sulfonic acid type ionic liquid catalyst supported by modified magnetic diatomaceous earth.

[0007] Preferably, the modified magnetic diatomite is 3-chloropropyltriethoxysilane-modified magnetic diatomite. The method for obtaining magnetic diatomite is prior art.

[0008] Preferably, the sulfonic acid ionic liquid is one of 1-propyl imidazolium sulfonate trifluoromethanesulfonate, 1-propyl imidazolium sulfonate phosphate, 1-propyl imidazolium sulfonate hydrogen sulfate, 1-propyl imidazolium sulfonate chloride, and 1-propyl imidazolium sulfonate p-toluenesulfonate; the most preferred is 1-propyl imidazolium sulfonate trifluoromethanesulfonate.

[0009] Preferably, the amount of the catalyst added is 1% to 5% of the mass of the raw material, preferably 3%.

[0010] Preferably, the reaction time is 0.5 to 3.0 h, preferably 1 h.

[0011] Preferably, the reaction temperature is 90-130°C, preferably 100°C.

[0012] Preferably, the preparation method further comprises the step of recovering the catalyst after the reaction is completed and repeatedly using it.

[0013] The preparation process of the catalyst of the present invention is shown in the following reaction formula:

[0014] ,

[0015] Wherein, X represents the anion part of the ionic liquid.

[0016] The reaction formula of the preparation method of the (S)-(+)-3-hydroxytetrahydrofuran is as follows:

[0017] .

[0018] The beneficial effects of the present invention are:

[0019] The invention provides a synthesis method for preparing a key intermediate (S)-(+)-3-hydroxytetrahydrofuran for drugs. (S)-1,2,4-butanetriol is used as a raw material, and a sulfonic acid-type ionic liquid catalyst supported by modified magnetic diatomaceous earth is used to catalyze the dehydration ring reaction, thereby avoiding the use of p-toluenesulfonic acid with low yield, many side reactions and complicated post-treatment. The advantages of the synthesis method include acid catalyst recycling, few side reactions, high product purity, green environmental protection, etc., and it is convenient for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the H NMR spectrum of (S)-(+)-3-hydroxytetrahydrofuran prepared in Example 1. DETAILED DESCRIPTION

[0021] Example 1

[0022] (1) Preparation of catalyst:

[0023] 4.1 g FeCl3·6H2O and 2.6 g FeCl2·4H2O were dissolved in a certain amount of deionized water and mixed with ultrasound. After sufficient shaking, 6.0 g (0.1 mol) diatomaceous earth was added, and the mixture was mechanically stirred at 80°C for 30 min in a three-necked flask (250 mL) and protected with nitrogen. The pH value of the reaction system was adjusted to 10 with ammonia water, and then stirring was continued for 1 h. After the reaction was completed, the mixture was cooled to room temperature and allowed to stand for crystallization for 2 h. After drying, magnetic diatomaceous earth was obtained, and then the obtained magnetic diatomaceous earth was added to 500 mL toluene and ultrasonically mixed for 0.5 h. Then 3-chloropropyltriethoxysilane (0.3 mol) was added, and the reaction system was heated to reflux for 12 h under nitrogen protection, the diatomaceous earth was separated by a magnetic field, washed several times with ethanol, and vacuum dried at 45°C to obtain modified magnetic diatomaceous earth. The modified magnetic diatomaceous earth and 1 mol of imidazole were dissolved in 500 mL of chloroform, stirred and refluxed at 65°C for 18 hours, the diatomaceous earth was separated by a magnetic field, washed with ether and ethyl acetate 3 times each and then dried, the obtained product and 0.1 mol of 1,3-propane sultone were added to 500 mL of toluene, stirred and refluxed at 120°C for 10 hours, the diatomaceous earth was separated by a magnetic field, washed with ether and ethyl acetate 3 times each and then dried, the obtained solid was divided into 5 equal parts and added to aqueous solutions of trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid (0.026 mol) respectively, stirred at room temperature for 10 hours, filtered, washed with water 3 times, and dried to obtain the catalyst.

[0024] (2) Add (S)-1,2,4-butanetriol (2.4 g, 22.62 mmol) to a 25 ml bottle, and add the catalyst prepared in (1) (2% of the mass of (S)-1,2,4-butanetriol) under stirring. The reaction temperature is 120°C and the reaction time is 2 h. After the reaction is completed, the catalyst is separated by a magnetic field and vacuum distilled to obtain the fraction obtained at 80°C / 50 Pa, namely (S)-(+)-3-hydroxytetrahydrofuran.

[0025] The catalysts and reaction results are shown in Table 1.

[0026] Table 1 Catalytic effects of different acid catalysts

[0027]

[0028] Example 2

[0029] Add (S)-1,2,4-butanetriol (2.4 g, 22.62 mmol) to a 25 ml bottle, add different masses of 1-propylsulfonic acid imidazolium trifluoromethanesulfonate catalyst supported on modified magnetic diatomite under stirring, and heat the reaction for a period of time. After the reaction, separate the catalyst with a magnetic field, perform vacuum distillation, and take the fraction obtained at 80°C / 50 Pa, which is (S)-(+)-3-hydroxytetrahydrofuran.

[0030] The reaction results with different catalyst addition amounts are shown in Table 2. The reaction temperature is 120°C and the reaction time is 2 h.

[0031] Table 2 Catalytic effect of different catalyst addition amounts

[0032]

[0033] The reaction results at different reaction temperatures are shown in Table 3 (the amount of solid acid catalyst added was 3% of the mass of (S)-1,2,4-butanetriol, and the reaction time was 2 h).

[0034] Table 3 Reaction results at different reaction temperatures

[0035]

[0036] The reaction results at different reaction times are shown in Table 4 (the amount of solid acid catalyst added was 3% of the mass of (S)-1,2,4-butanetriol, and the reaction temperature was 100°C).

[0037] Table 4 Reaction results of different reaction times

[0038]

[0039] Example 3 Catalyst Reuse

[0040] Add (S)-1,2,4-butanetriol (2.4 g, 22.62 mmol) to a 25 ml bottle, add 1-propylsulfonic acid imidazolyl trifluoromethanesulfonate catalyst supported by modified magnetic diatomite (3% of the mass of (S)-1,2,4-butanetriol) under stirring, the reaction temperature is 100 ° C, and the reaction time is 1 h. After the reaction, the 1-propylsulfonic acid imidazolyl trifluoromethanesulfonate solid acid catalyst supported by modified magnetic diatomite is separated by magnetic field, and vacuum distillation is performed to take the fraction obtained at 80 ° C / 50 Pa, namely (S)-(+)-3-hydroxytetrahydrofuran, and the separated catalyst is reused in the next batch of reactions. Repeat the above experimental process to investigate the number of times the catalyst can be reused.

[0041] The effect of catalyst reuse is shown in Table 5

[0042] Table 5 Effect of repeated use of solid acid catalyst

[0043]

[0044] The present invention is not limited to the specific technical solutions described in the above embodiments, and all technical solutions formed by equivalent replacement are within the protection scope required by the present invention.

Claims

1. A method for preparing (S)-(+)-3-hydroxytetrahydrofuran, characterized in that: include: (S)-1,2,4-butanetriol is used as a raw material, and under the action of a catalyst, a reaction is carried out at 90-120° C. to obtain (S)-(+)-3-hydroxytetrahydrofuran, wherein the catalyst is a sulfonic acid type ionic liquid catalyst supported by modified magnetic diatomaceous earth.

2. The preparation method according to claim 1, characterized in that: The modified magnetic diatomaceous earth is magnetic diatomaceous earth modified by 3-chloropropyltriethoxysilane.

3. The preparation method according to claim 1, characterized in that: The sulfonic acid type ionic liquid is one of 1-propyl imidazole sulfonic acid trifluoromethanesulfonate, 1-propyl imidazole sulfonic acid phosphate, 1-propyl imidazole sulfonic acid hydrogen sulfate, 1-propyl imidazole sulfonic acid chloride, and 1-propyl imidazole sulfonic acid p-toluenesulfonate.

4. The preparation method according to claim 1, characterized in that: The amount of the catalyst added is 1% to 5% of the mass of the raw material.

5. The preparation method according to claim 4, characterized in that: The amount of the catalyst added is 3% of the mass of the raw material.

6. The preparation method according to claim 1, characterized in that: The reaction time is 0.5 to 3.0 hours.

7. The preparation method according to claim 6, characterized in that: The reaction time is 1 h.

8. The preparation method according to claim 1, characterized in that: The reaction temperature is 90-130°C.

9. The preparation method according to claim 8, characterized in that: The reaction temperature was 100°C.

10. The preparation method according to claim 1, characterized in that: The preparation method further comprises the step of recovering the catalyst after the reaction is completed and repeatedly using it.

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