Preparation method of (S)-oxetane-2-methylamine

Abstract

The invention discloses a preparation method of (S)-oxetane-2-methylamine, and belongs to the technical field of organic synthesis. The preparation method comprises the following three steps: 1, carrying out substitution reaction on L-epichlorohydrin and bis (t-butyloxycarboryl) amine salt to generate an intermediate 1; 2, the intermediate 1 and trimethyl sulfoxide iodide are subjected to a ring expansion reaction in the presence of alkali, and an intermediate 2 is generated; and step 3, performing deprotection on the intermediate 2 in the presence of acid to generate the product. According to the technical scheme, operation is easy, convenient and stable, products in all steps are easy to separate, the yield is high, environment friendliness is achieved, and a new synthesis way is provided for the compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing (S)-oxetan-2-ylmethanamine. Background Art

[0002] As an oxetane with a strained four-membered ring structure, it is widely used in medicinal chemistry research. (S)-Oxetan-2-ylmethanamine, CAS: 2091328-57-1, is a key intermediate for the preparation of certain glucagon-like peptide-1 receptor agonists, including certain 1-[2-(oxetan-2-ylmethyl)]-1H-benzimidazole compounds disclosed in WO201810967.

[0003] The method for preparing (S)-oxetan-2-ylmethanamine disclosed in WO201810967 starts from (S)-2-((benzyloxy)methyl)oxirane and is carried out in five steps. The first step is a ring expansion reaction, which expands the oxirane to an oxetane. In the penultimate step, the use of azide compounds has the hazards of instability, explosiveness and high toxicity, resulting in the need for a large number of safety measures when this method is used for production.

[0004] Therefore, improved methods with lower resource density, cheaper and / or promoting more efficient production are needed, especially methods that avoid the use of toxic and dangerous azide compounds. US Patent US2019382384 discloses a method for preparing oxetan-2-ylmethanamine. However, the total yield of synthesizing oxetan-2-ylmethanamine by the above preparation method is only 19.3%, which is not suitable for large-scale production.

[0005] Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easy reaction control and a suitable overall yield. Summary of the Invention

[0006] The purpose of the present invention is to provide a method for producing (S)-oxetan-2-ylmethanamine with easily available raw materials, convenient operation, easy reaction control and a suitable overall yield. This method is carried out in three steps. In the first step, (S)-epichlorohydrin and bis(tert-butoxycarbonyl)amine salt undergo a substitution reaction in an organic solvent to form Intermediate 1. In the second step, Intermediate 1 and trimethylsulfoxonium iodide undergo a ring expansion reaction in an organic solvent under the action of a base to form Intermediate 2. In the third step, Intermediate 2 is deprotected in an organic solvent under the action of an acid in sequence to form the product. The technical solution of the present invention is simple and stable in operation, the products of each step are easy to separate, the yield is high, and it is environmentally friendly, providing a new synthetic route for this compound.

[0007] The synthetic route of (S)-oxetan-2-ylmethanamine of the present invention is carried out through three-step reactions, and is represented by the following reaction equation:

[0008]

[0009] The preparation method of (S)-oxetan-2-ylmethanamine according to the present invention comprises the following steps:

[0010] In the first step, (S)-epichlorohydrin and bis(tert-butoxycarbonyl)amine salt undergo a substitution reaction in an organic solvent to form intermediate 1.

[0011] Further, in the above technical solution, the molar ratio of (S)-epichlorohydrin to bis(tert-butoxycarbonyl)amine salt is 1:1 to 1.5.

[0012] Further, in the above technical solution, the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, and dimethyl sulfoxide.

[0013] In the second step, intermediate 1 and trimethylsulfoxonium iodide undergo a ring expansion reaction in an organic solvent in the presence of a base to form intermediate 2.

[0014] Further, in the above technical solution, the molar ratio of intermediate 1 to trimethylsulfoxonium iodide is 1:1 to 2.5.

[0015] Further, in the above technical solution, the base is selected from sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-pentoxide, and sodium tert-pentoxide.

[0016] Further, in the above technical solution, the organic solvent is selected from tert-butanol, tert-pentanol, dimethyl sulfoxide, or sulfolane.

[0017] In the optimization experiment of this step, it was found that the reaction solvent and additives have certain effects on the reaction. The best reaction solvents are tert-butanol, dimethyl sulfoxide, and sulfolane, among which: the mixture of tert-butanol and sulfolane is the best; when using tert-butanol as the solvent for optimization and adding different additives (such as adding BF 4 - , PF 6 - , BARF - etc.), it was found that when the counteranion is BARF (tetrakis(3,5-bis(trifluoromethyl)phenyl)borate), the yield is significantly improved, and the other counteranions do not change significantly. Under the best conditions (the mixed solvent of tert-butanol and sulfolane), when adding 0.2 - 0.4 eq NaBARF (relative to intermediate 1), the best yield is obtained, reaching 80 - 86%.

[0018] In the third step, intermediate 2 is deprotected in the presence of an acid to form the product.

[0019] Further, in the above technical solution, the acid is selected from hydrochloric acid, trifluoroacetic acid or hydrogen chloride solution, and the hydrogen chloride solution is selected from hydrogen chloride / dioxane, hydrogen chloride / ethyl acetate or acetyl chloride is dropped into methanol solution. Compared with the prior art, the present invention has the following remarkable advantages:

[0020] A. The overall production yield of the present invention is greatly improved compared with the currently known processes, and the synthesis process is more competitive in the market. The technical solution of the present invention is simple and stable in operation, the products of each step are easy to separate, the yield is high, it is environmentally friendly, and it provides a new synthesis route for this compound.

[0021] B. Using potassium bis(tert-butoxycarbonyl)amide, (S)-epichlorohydrin and trimethylsulfoxonium iodide as raw materials, the raw materials are cheap and easily available, reducing the raw material cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the HNMR spectrum of (S)-oxetan-2-ylmethanamine obtained in Example 1; DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood as being only for the purpose of illustrating the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0024] Example 1

[0025]

[0026] The first step:

[0027] Potassium bis(tert-butoxycarbonyl)amide (16.60 g, 0.065 mol) was added to a solution of (S)-epichlorohydrin (5 g, 0.054 mol) / N,N-dimethylformamide (25 mL), and the reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, water was added and the mixture was extracted with methyl tert-butyl ether. After evaporation to dryness, a crude product was obtained, which was purified by column chromatography to obtain Intermediate 1 (13.57 g, yield 92%).

[0028] The second step:

[0029] At room temperature, trimethylsulfoxonium iodide (20.69 g, 0.094 mol) and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (16.84 g, 0.019 mol) were added to a solution of potassium tert-butoxide (10.55 g, 0.094 mol) / tert-butanol (70 mL) and sulfolane (10 mL). The reaction mixture was heated to 60 °C and stirred for 2 hours. Intermediate 1 (13.1 g, 0.048 mol) was slowly added and the mixture was heated to 55 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated to obtain a crude product, which was purified by column chromatography to obtain Intermediate 2 (11.58 g, yield 84%).

[0030] The third step:

[0031] Intermediate 2 (8 g, 0.028 mol) was added to a solution of hydrogen chloride / dioxane (40 mL, 4 N). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated to obtain the product. After adjusting the pH value to 14 with 4 N aqueous sodium hydroxide solution, the mixture was extracted with dichloromethane 6 times. The organic phase was purified by vacuum distillation to obtain a colorless transparent liquid (2.27 g, yield 93%). The structure of the product was confirmed by NMR. 1 HNMR(CDCl 3 ):δ4.72-4.78(1H,m),4.60-4.65(1H,m),4.43-4.48(1H,m),2.83-2.84(2H,d),2.54-2.62(1H,m),2.34-2.43(1H,m).

[0032] Example 2

[0033]

[0034] The first step:

[0035] Sodium hydride (17.6 g, 0.44 mol, 60%) was added to a solution of diacetylamine (44.48 g, 0.44 mol) / N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 2 hours. (S)-(-)-Epichlorohydrin (20 g, 0.22 mol) was added to the above reaction mixture. The reaction mixture was heated to 80 °C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The solvent of the organic phase was evaporated to obtain a crude product, which was purified by column chromatography to obtain Intermediate 3 (31.79 g, yield 92%).

[0036] The second step:

[0037] At room temperature, trimethylsulfoxonium iodide (83.63 g, 0.38 mol) and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (50.51 g, 0.057 mol) were added to a solution of potassium tert-butoxide (42.64 g, 0.38 mol) / tert-butanol (150 mL) and sulfolane (30 mL). The reaction mixture was heated to 60 °C and stirred for 30 min. Intermediate 3 (30 g, 0.19 mol) was slowly added and the mixture was heated to 80 °C and stirred for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After evaporation, the crude product was obtained and purified by column chromatography to obtain Intermediate 4 (26.66 g, yield 82%).

[0038] The third step:

[0039] Potassium carbonate (4.15 g, 0.030 mol) was added to a solution of Intermediate 4 (17 g, 0.099 mol) / dioxane (85 mL). The mixture was stirred at room temperature for 4 h. After the reaction was completed, water and dichloromethane were added and the mixture was extracted 6 times. The organic phase was purified by vacuum distillation to obtain a colorless transparent liquid (7.85 g, yield 91%). The structure of the product was confirmed to be correct by NMR.

[0040] Example 3

[0041]

[0042] The first step:

[0043] A solution of lithium bis(tert-butyldimethylsilyl)amide / tetrahydrofuran (1.31 L, 1.31 mol, 1 N) was added to a solution of (S)-epichlorohydrin (100 g, 1.09 mol) / N,N-dimethylformamide (500 mL). The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, water was added and the mixture was extracted with methyl tert-butyl ether. After evaporation, the crude product was obtained and purified by column chromatography to obtain Intermediate 5 (302.07 g, yield 92%).

[0044] The second step:

[0045] At room temperature, trimethylsulfoxonium iodide (426.94 g, 1.94 mol) was added to a solution of potassium tert-butoxide (217.69 g, 1.94 mol) / tert-butanol (1 L). The reaction mixture was heated to 60 °C and stirred for 30 min. Intermediate 5 (292.19 g, 0.97 mol) was added and the mixture was heated to 80 °C and stirred for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After evaporation, the crude product was obtained and purified by column chromatography to obtain Intermediate 6 (155.95 g, yield 51%).

[0046] The third step:

[0047] Intermediate 6 (148.16 g, 0.47 mol) was added to a solution of hydrogen chloride / dioxane (600 mL, 4N), and the mixture was stirred at room temperature for 4 hours. After evaporation to dryness, the product was obtained. The pH value was adjusted to 14 by adding 4N aqueous sodium hydroxide solution, and then the mixture was extracted with dichloromethane 6 times. The organic phase was purified by distillation under reduced pressure to obtain a colorless transparent liquid (37.24 g, yield 91%). The structure of the product was confirmed to be correct by NMR.

[0048] Example 4

[0049]

[0050] The first step:

[0051] A solution of sodium bis(trimethylsilyl)amide / tetrahydrofuran (130 mL, 0.13 mol, 1N) was added to a solution of (S)-epichlorohydrin (10 g, 0.11 mol) / N,N-dimethylformamide (50 mL), and the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was extracted with methyl tert-butyl ether. The crude product obtained after evaporation to dryness was purified by column chromatography to obtain Intermediate 7 (21.97 g, yield 92%).

[0052] The second step:

[0053] At room temperature, trimethylsulfoxonium iodide (39.61 g, 0.18 mol) was added to a solution of potassium tert-butoxide (20.20 g, 0.18 mol) / tert-butanol (100 mL). The reaction mixture was heated to 60 °C and stirred for 30 min. Intermediate 7 (20 g, 0.092 mol) was added and the mixture was heated to 80 °C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The crude product obtained after evaporation to dryness was purified by column chromatography to obtain Intermediate 8 (11.48 g, yield 54%).

[0054] The third step:

[0055] Intermediate 8 (11 g, 0.048 mol) was added to a solution of hydrogen chloride / dioxane (50 mL, 4N), and the mixture was stirred at room temperature for 4 hours. After evaporation to dryness, the product was obtained. The pH value was adjusted to 14 by adding 4N aqueous sodium hydroxide solution, and then the mixture was extracted with dichloromethane 6 times. The organic phase was purified by distillation under reduced pressure to obtain a colorless transparent liquid (3.8 g, yield 91%). The structure of the product was confirmed to be correct by NMR.

[0056] As described above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. A method for preparing (S)-oxetane-2-methylamine, characterized in that: The steps include: In the first step, levorotatory epichlorohydrin and bis(tert-butyloxycarbonyl)amine salt undergo a substitution reaction in an organic solvent to generate intermediate 1; In the second step, intermediate 1 and trimethylsulfoxide iodide undergo a ring expansion reaction in an organic solvent in the presence of a base to generate intermediate 2; In the third step, intermediate 2 is deprotected in an organic solvent in the presence of an acid to generate (S)-oxetane-2-methylamine.

2. A method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the first step, the molar ratio of the levorotatory epichlorohydrin to the bis(tert-butyloxycarbonyl)amine salt is 1:1 to 1.

5.

3. A method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the first step, the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dioxane or dimethyl sulfoxide.

4. A method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the second step, the molar ratio of the intermediate 1 to trimethylsulfoxide iodide is 1:1-2.

5.

5. The method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the second step, the base is selected from sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate.

6. The method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the second step, the organic solvent is selected from tert-butyl alcohol, tert-amyl alcohol, dimethyl sulfoxide or sulfolane.

7. The method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the second step, 0.2-0.4 eq NaBARF additive relative to intermediate 1 was added.

8. The method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that: In the third step, the acid is selected from hydrochloric acid, trifluoroacetic acid or hydrogen chloride solution.

9. The method for preparing (S)-oxetane-2-methylamine according to claim 8, characterized in that: In the third step, the hydrogen chloride solution is selected from hydrogen chloride / dioxane, hydrogen chloride / ethyl acetate or acetyl chloride is added dropwise into the methanol solution.

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