Synthesis method of 3-oxetane formonitrile

Abstract

The invention discloses a synthesis method of 3-oxetane formonitrile, which comprises the following steps: taking 3-iodoxetane as a raw material, and reacting with trimethylsilyl cyanide under the action of cuprous iodide, phosphine ligand and alkali to obtain the target compound 3-oxetane formonitrile. According to the synthesis method disclosed by the invention, the 3-oxetane formonitrile is obtained through short steps, simple and convenient operation, mild reaction conditions and high yield, and a potential process route is provided for synthesis of the 3-oxetane formonitrile.

Description

Technical Field

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

[0002] Among oxetane compounds, 3-oxetane carbonitrile is an important molecular building block. For example, in patent WO2022 / 170200, 3-oxetane carbonitrile is used as a key intermediate in the synthesis of pyruvate kinase (PKR) and PKM2 activators. This active compound can be used to treat sickle cell disease, sickle cell anemia, thalassemia, hereditary non-spherical hemolytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, hyperproteinemia, sudden nocturnal hemoglobinuria, acquired hemolysis, cancer and anemia of chronic diseases; in patent WO2013 / 028670, 3-oxetane carbonitrile is also used as a key intermediate in the synthesis of BACE inhibitors. Therefore, it is of great significance to develop a method for synthesizing 3-oxetane carbonitrile.

[0003] In the prior art, the synthesis route of 3-oxetanecarbonitrile has not been reported yet. The development of its synthesis method is not only conducive to the development and application of the compound, but also conducive to the development and utilization of oxetane compounds. Summary of the invention

[0004] Based on this, the object of the present invention is to provide a method for synthesizing 3-oxetanecarbonitrile, the whole synthesis process is low in cost, the steps are short and easy to operate, the reaction conditions are mild and the yield is ideal.

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

[0006] The present invention provides a method for synthesizing 3-oxetanecarbonitrile, and the synthetic route is as follows:

[0007]

[0008] Specifically, the steps include:

[0009] (1) adding cuprous iodide (CuI), a phosphine ligand, a base and compound 2 (trimethylsilyl cyanide) to an organic solvent I, and then adding compound 1 (3-iodooxetane) under the protection of an inert gas, heating to 50-100° C., and stirring to react for 8-40 hours;

[0010] (2) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 3, i.e., 3-oxetanecarbonitrile.

[0011] Preferably, in step (1), the phosphine ligand is triphenylphosphine and / or tricyclohexylphosphine.

[0012] Preferably, in step (1), the base is cesium fluoride and / or potassium fluoride.

[0013] Preferably, in step (1), the organic solvent I is selected from one or more of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and toluene.

[0014] Preferably, in step (1), the inert gas is nitrogen and / or argon.

[0015] Preferably, in step (1), the molar ratio of compound 1 to cuprous iodide is 1:0.01-0.1.

[0016] Preferably, in step (1), the molar ratio of compound 1 to compound 2 is 1:1 to 1.5.

[0017] Preferably, in step (1), the mass volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL).

[0018] Preferably, in step (1), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1-0.2.

[0019] Preferably, in step (1), the molar ratio of the compound 1 to the base is 1:1-5.

[0020] Preferably, in step (2), the post-treatment process is: adding water to the reaction solution, extracting with organic solvent II, combining the organic phases, drying, filtering and concentrating the organic phases to obtain a crude product, and purifying the crude product to obtain the target compound 3.

[0021] More preferably, in step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

[0022] Preferably, in step (2), the purification method is distillation or column chromatography.

[0023] Compared with the prior art, the invention has the beneficial effects that: the invention provides a method for synthesizing 3-oxetanecarbonitrile, wherein 3-iodooxetane is used as a raw material, CuI is used as a catalyst, and trimethylsilyl cyanide is reacted under the action of a phosphine ligand and a base to obtain 3-oxetanecarbonitrile, and the target compound is obtained with short steps, simple operation, mild reaction conditions and high yield, thereby providing a potential process route for the synthesis of 3-oxetanecarbonitrile. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram of the synthesis route of 3-oxetanecarbonitrile in the embodiment.

[0025] Figure 2 The following is the H NMR spectrum of 3-oxetanecarbonitrile prepared in the example. DETAILED DESCRIPTION

[0026] In order to more fully understand and demonstrate the technical solutions, purposes and advantages of the present invention, the technical effects produced by the present invention are further described in detail and completely in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all. It should be pointed out that for those of ordinary skill in the art, other embodiments obtained without departing from the concept of the present invention all belong to the protection scope of the present invention. The present invention is described in detail in conjunction with the accompanying drawings and embodiments.

[0027] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0028] Example 1

[0029] This embodiment provides a method for synthesizing 3-oxetanecarbonitrile. The synthetic route is as follows: Figure 1 As shown, specifically:

[0030]

[0031] The specific steps are:

[0032] (1) Cuprous iodide (2.07 g, 10.87 mmol, 0.01 eq), triphenylphosphine (39.92 g, 152.19 mmol, 0.14 eq), cesium fluoride (330.27 g, 2.17 mol, 2.00 eq) and trimethylsilyl cyanide (161.77 g, 1.63 mol, 1.00 eq) were added to N,N-dimethylformamide (2.0 L). Under the protection of inert gas (nitrogen), 3-iodooxetane (200.00 g, 1.09 mol, 1.0 eq) was added, and the mixture was heated to 60°C and stirred for 12 hours.

[0033] (2) After the reaction was completed, water (3.0 L) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (2.0 L×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was distilled under reduced pressure to obtain the target compound 3, i.e., 3-oxetanecarbonitrile (yellow liquid, weight 87.11 g, purity 96%, yield 93%).

[0034] The H NMR spectrum of the obtained 3-oxetanecarbonitrile is as follows Figure 2 The characterization data are as follows:

[0035] 1 H NMR (400MHz, cdcl3) δ4.82 (dq, J=8.5, 6.2Hz, 4H), 3.89 (tt, J=8.6, 7.2Hz, 1H).

[0036] Embodiments 2 to 13

[0037] Examples 2 to 13 are the same as Example 1, except that the catalyst, phosphine ligand, base, organic solvent I, reaction temperature, reaction time, etc. used in the reaction process are adjusted to obtain compound 3, as shown in Table 1.

[0038] Comparative Examples 1-2

[0039] Comparative Examples 1-2 are the same as Example 1, except that the catalyst used in the reaction process is adjusted, as shown in Table 1.

[0040] Compound 3 was prepared under different reaction conditions through Examples 1 to 13 and Comparative Examples 1 to 2, and the effects of various reaction conditions on the reaction yield in the synthesis of 3-oxetanecarbonitrile were investigated. The results are shown in Table 1.

[0041] Table 1

[0042]

[0043] Combined with Table 1, we can see that:

[0044] Comparing Example 1 with Comparative Examples 1 and 2, when cuprous iodide is replaced with cuprous chloride or cuprous bromide, the reaction can hardly obtain the target product.

[0045] Comparing Examples 1 and 2, the reaction can obtain the target product by using triphenylphosphine or tricyclohexylphosphine as the phosphine ligand, and the effect of using triphenylphosphine is better.

[0046] Comparing Examples 1 and 3, the reaction can obtain the target product by using cesium fluoride or potassium fluoride as the base, and the effect of using cesium fluoride is better.

[0047] Comparing Examples 1 and 4, when the molar ratio of compound 1 to the catalyst is 1.0:0.03, the reaction effect is already very good.

[0048] Comparing Examples 1, 5, and 6, when the molar ratio of compound 1 to the phosphine ligand is 1.0:0.14, the reaction effect is already very good.

[0049] Comparing Examples 1, 7, and 8, when the molar ratio of compound 1 to base is 1.0:2.0, the reaction effect is already very good.

[0050] Comparing Examples 1, 9 and 10, the reaction can obtain the target product in the solvents N,N-dimethylformamide, dioxane and tetrahydrofuran, and N,N-dimethylformamide is more effective as a solvent.

[0051] Comparing Examples 1 and 11, when the reaction temperature is 60°C, the reaction effect is already very good.

[0052] Comparing Examples 1, 12, and 13, when the reaction time reaches 12 hours, the reaction effect is already very good.

[0053] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3-oxetanecarbonitrile, characterized in that: The synthetic route is shown below: The synthesis method comprises the following steps: (1) adding cuprous iodide, a phosphine ligand, a base and compound 2 (trimethylsilyl cyanide) to an organic solvent I, and then adding compound 1 (3-iodooxetane) under the protection of an inert gas, heating to 50-100° C., and stirring to react for 8-40 hours; (2) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 3, i.e., 3-oxetanecarbonitrile.

2. The synthetic method of 3-oxetanecarbonitrile according to claim 1, characterized in that In step (1), the phosphine ligand is triphenylphosphine and / or tricyclohexylphosphine; and / or the base is cesium fluoride and / or potassium fluoride; and / or the organic solvent I is selected from one or more of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and toluene; And / or the inert gas is nitrogen and / or argon.

3. The synthetic method of 3-oxetanecarbonitrile according to claim 1, characterized in that In step (1), the molar ratio of compound 1 to cuprous iodide is 1:0.01-0.

1.

4. The synthetic method of 3-oxetanecarbonitrile according to claim 1, characterized in that In step (1), the molar ratio of compound 1 to compound 2 is 1:1 to 1.

5.

5. The synthetic method of 3-oxetanecarbonitrile according to claim 1, characterized in that In step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

6. The method for synthesizing 3-oxetanecarbonitrile according to claim 1, wherein In step (1), the molar ratio of the compound 1 to the phosphine ligand is 1:0.1-0.

2.

7. The method for synthesizing 3-oxetanecarbonitrile according to claim 1, wherein In step (1), the molar ratio of the compound 1 to the base is 1:1-5.

8. The method for synthesizing 3-oxetanecarbonitrile according to claim 1, wherein In step (2), the post-treatment process is: adding water to the reaction solution, extracting with organic solvent II, combining the organic phases, drying the organic phases, filtering, and concentrating to obtain a crude product, and purifying the crude product to obtain the target compound 3.

9. The method for synthesizing 3-oxetanecarbonitrile according to claim 8, wherein In step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

10. The method for synthesizing 3-oxetanecarbonitrile according to claim 8, characterized in that: In step (2), the purification method is distillation or column chromatography.

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