Synthesis method of (S)-3-aminotetrahydrofuran

Abstract

The invention discloses a synthesis method of (S)-3-aminotetrahydrofuran, which comprises the following steps: (1) reacting (R)-3-hydroxytetrahydrofuran with phthalimide, triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to obtain a condensation product; and (2) reacting the condensation product obtained in the step (1) with a methylamine-ethanol solution, or reacting with hydrazine hydrate in methanol to obtain (S)-3-aminotetrahydrofuran. The method is efficient, low in cost and environmentally friendly, has the advantages of simple process, mild conditions, high yield, easily available raw materials and the like, provides a feasible technical scheme for industrial production of (S)-3-aminotetrahydrofuran, and has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing (S)-3-aminotetrahydrofuran. Background Art

[0002] (S)-3-Aminotetrahydrofuran (THF) is an important chiral drug intermediate, attracting significant attention due to its widespread application in the pharmaceutical field. This compound can be used to synthesize the antiarrhythmic drug CVT-510 and is also a key raw material for drugs treating cardiovascular disease, neurological disorders, cancer, and non-alcoholic steatohepatitis, among other diseases, possessing significant market prospects and application value. Because its optical purity directly impacts the activity and safety of the final drug, the development of efficient, low-cost synthesis methods that maintain high optical purity is of great significance. However, existing synthetic methods generally suffer from certain deficiencies, which limit their widespread industrial application.

[0003] In the prior art, a document (Tetrahedron: Asymmetry, 24 (2013), 663-668) reported a synthesis method using L-methionine as a raw material (hereinafter referred to as method (1)). Method 1 prepares (S)-3-aminotetrahydrofuran through multiple steps such as methylation, ring closure, acidification, amidation, sodium borohydride reduction, cycloetherification and amino deprotection. However, the methylation reagent iodomethane used in this method is expensive, and the reaction route is lengthy, resulting in a low total yield of the target product. In addition, the multi-step reaction increases the complexity of the process, making the production cost high and difficult to meet the needs of industrial production. On the other hand, U.S. Patent (US20080255377A1) discloses a synthesis method using L-aspartic acid methyl ester as a raw material (hereinafter referred to as method (2)). Method 2 includes the steps of amino protection, ester reduction, cycloetherification and amino deprotection. Although it can synthesize the target compound, it also has the problems of a long synthesis route, a complicated process and a low yield, resulting in a high production cost and limited industrial application.

[0004] Both of the above methods expose common problems in existing technologies: first, there are many reaction steps, which increases the difficulty and time cost of operation; second, some of the reagents used are expensive, which further increases the production cost; third, the total yield is low, which cannot meet the requirements of large-scale production for high efficiency. In addition, as a chiral compound, (S)-3-aminotetrahydrofuran needs to pay special attention to the maintenance of optical purity during the synthesis process, and the existing methods may introduce impurities or by-products under complex reaction conditions, affecting the quality of the product. Not only that, some toxic and harmful reagents or solvents, such as iodomethane, are often used in the prior art, which not only poses a threat to the safety of the operators, but also contradicts the current concept of green chemistry and sustainable development. Therefore, there is room for improvement in the existing synthesis methods in terms of economy, environmental protection and practicality.

[0005] Based on the above analysis, the current synthesis technology of (S)-3-aminotetrahydrofuran still needs to overcome existing limitations. Developing a synthetic route with low raw material costs, simple process, high yield, and mild conditions will not only promote the widespread application of this compound in the pharmaceutical field, but also meet the requirements of industrial production for high efficiency, environmental friendliness, and safety. Therefore, in response to the shortcomings of the existing technology, researching new synthetic methods has important practical significance and potential economic value. Summary of the Invention

[0006] The present invention aims to overcome the defects of the prior art and provide a method for synthesizing (S)-3-aminotetrahydrofuran.

[0007] The synthetic route of the present invention is:

[0008]

[0009] The technical solutions of the present invention are as follows:

[0010] A method for synthesizing (S)-3-aminotetrahydrofuran comprises the following steps:

[0011] (1) reacting (R)-3-hydroxytetrahydrofuran with phthalimide, triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to obtain a condensation product;

[0012] (2) reacting the condensation product obtained in step (1) with a methylamine-ethanol solution, or reacting it with hydrazine hydrate in methanol to obtain (S)-3-aminotetrahydrofuran.

[0013] In a preferred embodiment of the present invention, the step (1) comprises: uniformly mixing (R)-3-hydroxytetrahydrofuran and tetrahydrofuran at 0-10° C., then sequentially adding phthalimide, triphenylphosphine and diethyl azodicarboxylate, reacting at 15-35° C. for 10-24 hours, then sequentially removing tetrahydrofuran under reduced pressure, extracting with ethyl acetate and water, collecting the organic phase, removing the solvent under reduced pressure, and purifying by silica gel column chromatography to obtain the condensation product.

[0014] More preferably, the molar ratio of the (R)-3-hydroxytetrahydrofuran to phthalimide, triphenylphosphine and diethyl azodicarboxylate is 0.8-1:1:1:1.

[0015] In a preferred embodiment of the present invention, the step (2) comprises: reacting the condensation product and a methylamine-ethanol solution having a methylamine mass concentration of 30-35 wt%, stirring at 15-35° C. for 12-72 hours; removing low-boiling point materials after the reaction, then adding an acetic acid aqueous solution to dissolve the solid product, washing with dichloromethane and performing phase separation; adjusting the pH of the obtained aqueous phase to 10-14 with a sodium hydroxide aqueous solution, then extracting with dichloromethane, collecting the organic phase, and removing the solvent under reduced pressure to obtain the (S)-3-aminotetrahydrofuran.

[0016] More preferably, the molar ratio of the methylamine to the condensation product is 50-100:1.

[0017] In a preferred embodiment of the present invention, the step (2) comprises: stirring the condensation product, methanol and hydrazine hydrate at 50-80° C. for 1-4 hours, then removing low-boiling point materials from the reaction solution, then adding sodium hydroxide aqueous solution to dissolve the solid product, then extracting with dichloromethane, collecting the organic phase, and removing the solvent under reduced pressure to obtain the (S)-3-aminotetrahydrofuran.

[0018] Further preferably, the molar ratio of the hydrazine hydrate to the condensation product is 3-6:1.

[0019] The beneficial effects of the present invention are:

[0020] 1. The present invention uses (R)-3-hydroxytetrahydrofuran and phthalimide as main raw materials. Compared with the expensive iodomethane or L-aspartic acid methyl ester in the prior art, the raw materials used in the present invention are more economical, effectively reducing production costs.

[0021] 2. The present invention can produce the target product through a two-step reaction of dehydration condensation and deprotection, which significantly reduces the number of reaction steps. Compared with the multi-step process of the prior art, the operation is simpler, which is conducive to improving production efficiency and reducing process complexity.

[0022] 3. The present invention carries out the first step condensation reaction under mild conditions of 0-35°C, and the second step deprotection reaction does not require high temperature and high pressure, thus avoiding energy consumption and equipment requirements under harsh conditions and improving production safety.

[0023] 4. The present invention demonstrates, in the examples, that the first-stage condensation product yield reaches 93-96%, and the final product (S)-3-aminotetrahydrofuran has a yield of up to 76%, with an ee value of 97.7%. Compared to the low yields achieved in prior art, the present invention significantly improves yield and ensures the optical purity of the chiral product, meeting the requirements of industrial production.

[0024] 5. The reagents and solvents (such as tetrahydrofuran and ethyl acetate) used in the present invention are relatively low in toxicity, and the use of toxic reagents is avoided in the process, thereby reducing harm to the environment and operators, and conforming to the development direction of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Schematic diagram of the reaction mechanism of Example 2 of the present invention. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is further illustrated and described below through specific implementation methods in conjunction with the accompanying drawings.

[0027] Example 1

[0028] The technical solution of this embodiment is as follows:

[0029] (1) Take 1g of substrate (R)-3-hydroxytetrahydrofuran, add 20mL of anhydrous THF and cool to 0℃, stir evenly, and add Pht (phthalimide, 1.1eq), PPh3 (triphenylphosphine, 1.0eq) and DEAD (diethyl azodicarboxylate, 1.0eq) in sequence. After the addition is completed, the temperature is raised to 25℃ and the reaction is carried out for 16h. After the reaction is completed, the solvent is removed under reduced pressure, and then ethyl acetate and water are added to the reaction flask for extraction. The organic phase is collected, and the crude product obtained after the solvent is removed under reduced pressure is chromatographed on a silica gel column (eluent: V 乙酸乙酯 :V 石油醚 =2:1) ​​and further purification gave the condensation product (white to pale yellow solid) in a yield of 96%.

[0030] (2) Add 2 g of the condensation product obtained in step (1) and 90 mL of a methylamine-ethanol solution (33% by mass of methylamine) to a reaction flask, and stir the reaction at 25° C. for 45 h. After the reaction is completed, remove the low-boiling point materials in the reaction solution, then add a 10% aqueous acetic acid solution to dissolve the solid product after removal of the solvent, wash with dichloromethane and separate the phases; the resulting aqueous phase is adjusted to pH 12 with a 10% aqueous sodium hydroxide solution, then extracted with dichloromethane, and the organic phase is collected. After removing the solvent under reduced pressure, the target product (S)-3-aminotetrahydrofuran is obtained with a yield of 76% and an ee value of 97.7%. Its nuclear magnetic resonance data are characterized as follows: 1 H NMR (CDCl3, 400 MHz): δ H 1.65-1.69 (m, 3H), δ H 2.09-2.16 (m, 1H), δ H 3.46-3.49 (m, 1H), δ H 3.60-3.63 (m, 1H), δ H 3.78-3.84 (m, 2H), δ H 3.93-4.02 (m, 1H).

[0031] Example 2

[0032] The technical solution of this embodiment is shown as follows Figure 1 As shown, the details are as follows:

[0033] (1) Take 1g of substrate (R)-3-hydroxytetrahydrofuran, add 20mL of anhydrous THF and cool to 0℃, stir evenly, and add Pht (phthalimide, 1.1eq), PPh3 (triphenylphosphine, 1.0eq) and DEAD (diethyl azodicarboxylate, 1.0eq) in sequence. After the addition is completed, the temperature is raised to 25℃ and the reaction is carried out for 16h. After the reaction is completed, the solvent is removed under reduced pressure, and then ethyl acetate and water are added to the reaction flask for extraction. The organic phase is collected, and the crude product obtained after the solvent is removed under reduced pressure is chromatographed on a silica gel column (eluent: V 乙酸乙酯 :V 石油醚 =2:1) ​​and further purification gave the condensation product (white to pale yellow solid) in a yield of 93%.

[0034] (2) 1.43 g of the condensation product obtained in step (1) was added to the reaction flask, methanol (33.0 mL) was added, and the mixture was stirred evenly. Then, hydrazine hydrate (5.0 eq) was added, and the temperature was raised to 65° C. and stirred for 2 h. After the reaction, the low-boiling point materials in the reaction solution were removed, and then a 2M aqueous solution of NaOH was added to dissolve the solid product after desolvation. The solid product was extracted with dichloromethane, and the organic phase was collected. After removing the solvent under reduced pressure, the target product (S)-3-aminotetrahydrofuran was obtained with a yield of 55%. Its NMR data were characterized as follows: 1HNMR (CDCl3, 400MHz): δ H 1.65-1.69 (m, 3H), δ H 2.09-2.16 (m, 1H), δ H 3.46-3.49 (m, 1H), δ H 3.60-3.63 (m, 1H), δ H 3.78-3.84 (m, 2H), δ H 3.93-4.02 (m, 1H).

[0035] The above description is merely a preferred embodiment of the present invention and therefore cannot be used to limit the scope of the present invention. In other words, equivalent changes and modifications made within the scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A synthetic method for (S)-3-aminotetrahydrofuran, characterized in that: The steps include: (1) reacting (R)-3-hydroxytetrahydrofuran with phthalimide, triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to obtain a condensation product; (2) reacting the condensation product obtained in step (1) with a methylamine-ethanol solution, or reacting it with hydrazine hydrate in methanol to obtain (S)-3-aminotetrahydrofuran.

2. The synthesis method according to claim 1, wherein: The step (1) comprises: uniformly mixing (R)-3-hydroxytetrahydrofuran and tetrahydrofuran at 0-10° C., then sequentially adding phthalimide, triphenylphosphine and diethyl azodicarboxylate, reacting at 15-35° C. for 10-24 hours, then sequentially removing tetrahydrofuran under reduced pressure, extracting with ethyl acetate and water, collecting the organic phase, removing the solvent under reduced pressure, and purifying by silica gel column chromatography to obtain the condensation product.

3. The synthesis method according to claim 2, wherein: The molar ratio of the (R)-3-hydroxytetrahydrofuran to phthalimide, triphenylphosphine and diethyl azodicarboxylate is 0.8-1:1:1:

1.

4. The synthesis method according to any one of claims 1 to 3, characterized in that: The step (2) comprises: reacting the condensation product and a methylamine-ethanol solution having a methylamine mass concentration of 30-35 wt%, stirring at 15-35° C. for 12-72 hours; removing low-boiling point materials after the reaction, then adding an acetic acid aqueous solution to dissolve the solid product, washing with dichloromethane and performing phase separation; adjusting the pH of the obtained aqueous phase to 10-14 with a sodium hydroxide aqueous solution, then extracting with dichloromethane, collecting the organic phase, and removing the solvent under reduced pressure to obtain the (S)-3-aminotetrahydrofuran.

5. The synthesis method according to claim 4, wherein: The molar ratio of the methylamine to the condensation product is 50-100:

1.

6. The synthesis method according to any one of claims 1 to 3, wherein: The step (2) comprises: stirring the condensation product, methanol and hydrazine hydrate at 50-80° C. for 1-4 hours, removing low-boiling point materials from the reaction solution, adding a sodium hydroxide aqueous solution to dissolve the solid product, extracting with dichloromethane, collecting the organic phase, and removing the solvent under reduced pressure to obtain the (S)-3-aminotetrahydrofuran.

7. The synthesis method according to claim 6, wherein: The molar ratio of the hydrazine hydrate to the condensation product is 3-6:1.

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