A method for synthesizing (S)-oxetane-2-methylamine

Abstract

The present invention belongs to the technical field of organic synthesis, and relates to a method for synthesizing (S)-oxetane-2-methylamine. The present invention uses glycidol as a reaction starting material, and realizes the synthesis of (S)-oxetane-2-methylamine through a six-step reaction. The present invention solves the technical problem that the use of azide compounds in the preparation process of synthesizing (S)-oxetane-2-methylamine by a five-step reaction using (S)-2-((benzyloxy)methyl)oxirane as a starting material leads to unsafe production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for synthesizing (S)-oxetane-2-methylamine. Background Art

[0002] (S)-Oxetane-2-methylamine is a key intermediate in the preparation of certain glucagon-like peptide-1 receptor agonists, including certain 1-[2-oxetane-2-ylmethyl]-1H-benzimidazole compounds disclosed in WO2018 / 109607. The method for preparing (S)-oxetane-2-methylamine disclosed in WO2018 / 109607 is a five-step method starting with (S)-2-((benzyloxy)methyl)oxirane. The first step is a ring expansion step, which expands oxirane to oxetane. In the penultimate step, sodium azide is used to introduce the nitrogen of the amine group, and in the last step, the azide intermediate is reduced to provide the amine group. Azide compounds have the hazards of being unstable, explosive and highly toxic, resulting in the need for a large number of safety measures for the production of this method. Therefore, there is a need for improved methods that are less resource-intensive, cheaper and / or promote more efficient production, and in particular, there is a need for methods that avoid the use of toxic and dangerous azide compounds. Summary of the invention

[0003] The object of the present invention is to avoid the use of azide compounds in the preparation of (S)-oxetane-2-methylamine.

[0004] In order to solve the above technical problems, the present invention provides a method for synthesizing (S)-oxetane-2-methylamine.

[0005] The abbreviations used in the present invention are defined as follows: "DMF" refers to N,N-dimethylformamide; "TsOH" refers to p-toluenesulfonic acid; "THF" refers to tetrahydrofuran; "MsCl" refers to methanesulfonyl chloride; and "TEA" refers to triethylamine.

[0006] On the one hand, the present invention relates to a method for synthesizing (S)-oxetane-2-methylamine, which comprises the following reaction scheme:

[0007]

[0008] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the method comprises: subjecting the compound represented by formula III to an addition reaction to obtain the compound represented by formula IV;

[0009] The compound represented by formula IV is subjected to Gabriel reaction to obtain the compound represented by formula V;

[0010] The compound represented by formula V is liberated with a base to obtain the compound represented by formula VI.

[0011] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the method comprises: mixing and reacting the compound represented by formula III, dichloromethane, triethylamine and methanesulfonyl chloride to obtain the compound represented by formula IV;

[0012] The compound represented by formula IV is reacted with sodium diformylamide, and then an organic phase is taken out, and TsOH is added to the organic phase to react and hydrolyze to obtain a compound represented by formula V;

[0013] The compound represented by formula V is reacted with a base to obtain the compound represented by formula VI.

[0014] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the temperature for the mixed reaction of the compound represented by formula III, dichloromethane, triethylamine and methanesulfonyl chloride is 20 to 30°C;

[0015] The temperature for the reaction of the compound represented by formula IV and sodium diformamide is 50-60°C;

[0016] The temperature for the reaction between the compound represented by formula V and the base is 20-30°C.

[0017] Further, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the base is an inorganic base and / or an organic base;

[0018] The inorganic base is selected from at least one of sodium hydroxide and potassium hydroxide;

[0019] The organic base is selected from at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

[0020] Preferably, in the method for synthesizing (S)-oxetane-2-methylamine provided by the present invention, the base is a combination of the inorganic base and the organic base, and the molar ratio of the inorganic base to the organic base is 3:1 to 2:5.

[0021] The alkali is one of sodium hydroxide and sodium methoxide, or sodium hydroxide and sodium ethoxide, or potassium hydroxide and sodium methoxide, or potassium hydroxide and sodium ethoxide.

[0022] The present invention unexpectedly discovered that in the step of freeing the compound represented by formula V with a base to obtain the compound represented by formula VI, the combination of an inorganic base and an organic base can significantly improve the yield of this step, and in the industrial process, the post-treatment is significantly simplified, and the unit working hours are reduced by 1 / 3 compared with a single base.

[0023] Optionally, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the solution in the synthesis method contains at least one selected from DMF, THF, NMP, DMAc, and DMSO.

[0024] Furthermore, the synthesis method of (S)-oxetane-2-methylamine provided by the present invention includes the following reaction route:

[0025]

[0026] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, it comprises: subjecting (R) glycidol to an addition reaction to obtain a compound of formula I, subjecting the compound of formula I to a ring expansion reaction to obtain a compound of formula II, and subjecting the compound of formula II to an acid-catalyzed hydrolysis reaction to obtain a compound of formula III.

[0027] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, (R) glycidol and vinyl ethyl ether are mixed and reacted, and then p-toluenesulfonic acid is added to react to obtain the compound shown in formula I;

[0028] The compound represented by formula Ⅰ and trimethyl sulfoxide bromide are mixed and reacted to obtain the compound represented by formula Ⅱ;

[0029] The compound represented by formula II, water and acid are mixed to react to obtain the compound represented by formula III;

[0030] The acid used in the acid-catalyzed hydrolysis reaction is selected from one of acetic acid, formic acid, sulfuric acid, hydrochloric acid, propionic acid and butyric acid.

[0031] Furthermore, in the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, the temperature of the mixed reaction of (R) glycidol and vinyl ethyl ether is 0 to 5°C, and the temperature of the reaction of adding p-toluenesulfonic acid is 25 to 30°C;

[0032] The temperature of the mixed reaction of the compound represented by formula I and trimethyl sulfoxide bromide is 60-65°C;

[0033] The temperature for the mixed reaction of the compound represented by formula II, water and acid is 20-30°C.

[0034] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages:

[0035] The invention uses glycidol as a reaction starting material and realizes the synthesis of (S)-oxetane-2-methylamine through a six-step reaction. The starting material is cheap and easy to obtain, no noble metal catalyst is needed, the reaction conditions are mild, and the product is suitable for industrial production. The invention solves the technical problem that the use of azide compounds in the preparation process of synthesizing (S)-oxetane-2-methylamine through a five-step reaction using (S)-2-((benzyloxy)methyl)oxirane as a starting material leads to unsafe production. DETAILED DESCRIPTION

[0036] The technical scheme of the present invention is described below in conjunction with the embodiments, but the present invention is not limited to the following embodiments. The experimental methods and detection methods described in each embodiment are conventional methods unless otherwise specified; the reagents and materials described are all commercially available unless otherwise specified.

[0037] The present invention provides a method for synthesizing (S)-oxetane-2-methylamine, comprising the following reaction route:

[0038]

[0039] In the synthesis method of (S)-oxetane-2-methylamine provided by the present invention, (R) glycidol is used as the starting material, and a total of six steps are included:

[0040] In the first step, (R) glycidol, ethyl vinyl ether and p-toluenesulfonic acid are mixed and subjected to addition reaction to obtain a compound represented by formula I;

[0041] In the second step, the compound represented by formula I, potassium tert-butoxide, trimethyl sulfoxide bromide and an alcohol solvent are mixed to carry out a ring expansion reaction to obtain a compound represented by formula II;

[0042] The third step is to mix the compound represented by formula II with an acid aqueous solution to carry out an acid-catalyzed hydrolysis reaction to obtain a compound represented by formula III;

[0043] The fourth step is to mix the compound represented by formula III with MsCl, TEA and tetrahydrofuran for protection to obtain the compound represented by formula IV;

[0044] The fifth step is to carry out Gabriel reaction of the compound represented by formula IV with sodium diformamide and DMF to obtain the compound represented by formula V;

[0045] In the sixth step, the compound represented by formula V is liberated with a base to obtain the compound represented by formula VI, and the compound represented by formula VI is (S)-oxetane-2-methylamine.

[0046] Illustratively, the method for synthesizing (S)-oxetane-2-methylamine provided by the present invention comprises:

[0047] The first step is to add an aqueous solution of p-toluenesulfonic acid dropwise to (R) glycidol and vinyl ethyl ether at a temperature of 0°C to 5°C, and react at 25°C to 30°C. After the reaction is complete, a saturated aqueous solution of sodium bicarbonate is added to the system to quench, and the organic phase is dried and concentrated to obtain a compound represented by formula I;

[0048] The second step is to dissolve the compound represented by formula I in tert-butanol, add potassium tert-butoxide to the system, control the temperature at 60°C to 65°C, add trimethyl sulfoxide bromide in batches, and after the reaction is complete, filter, extract, dry and concentrate the filtrate to obtain the compound represented by formula II;

[0049] The third step is to add water and acetic acid to the compound represented by formula II, and after the reaction is completed under stirring at 20°C to 30°C, add saturated sodium bicarbonate aqueous solution to the system for quenching, extract, and dry and concentrate the organic phase to obtain the compound represented by formula III;

[0050] The fourth step is to add dichloromethane, triethylamine and methanesulfonyl chloride to the compound represented by formula III under stirring at 20°C to 30°C. After the reaction is complete, water is added to the system to quench the reaction, the liquids are separated, the organic phase is washed with water, dried, concentrated, and recrystallized to obtain the compound represented by formula IV;

[0051] The fifth step is to dissolve the compound represented by formula IV in DMF, add sodium diformamide, stir at 50°C to 60°C until the reaction is complete, add water and ethyl acetate to the system, extract, add TsOH methanol solution to the organic phase, and hydrolyze to obtain the compound represented by formula V;

[0052] Step 6: Add the compound represented by formula V into THF, add base, stir, react completely at 20°C to 30°C, filter, and purify the filtrate by distillation to obtain the compound represented by formula VI.

[0053] Example 1

[0054] This example provides the preparation of (S)-oxetane-2-methylamine

[0055] Add (R) glycidol (100g, 1.35mol) and ethyl vinyl ether (146.02g, 2.02mol) to a 1000mL three-necked flask, start stirring, cool to 0°C, add p-toluenesulfonic acid (2.32g, 0.01mol) in batches, react at 30°C for 4h, after the reaction is complete, add saturated sodium bicarbonate aqueous solution (300g) to the system, stir for 1h, stand for separation, take the organic phase, dry the organic phase with anhydrous magnesium sulfate (20g) for 2h, filter, and concentrate the filtrate under reduced pressure to constant weight to obtain the compound shown in formula I (179g, yield: 90%). MS (M+1) + =147.10.

[0056] Add tert-butanol: 2000mL, potassium tert-butoxide (153.5g, 1.37mol) to the reaction bottle, add the compound shown in formula I (100g, 0.68mol), start stirring, add trimethyl sulfoxide bromide (353.06g, 2.04mol), raise the temperature to 70°C, react for 10h, filter after the reaction is complete, collect the filtrate, and concentrate under reduced pressure to a remaining 100mL, add water: 250mL, extract with ethyl acetate: 500mL, dry the organic phase with anhydrous magnesium sulfate 50g for 2h, filter, and concentrate the filtrate under reduced pressure to constant weight to obtain the compound shown in formula II (100g, yield: 91.7%) MS (M+1) + =161.11.

[0057] Add water: 270mL, acetic acid (31.1g, 0.52mol), compound shown in formula II (100g, 0.62mol) to the reaction bottle, start stirring, react at 30°C for 12h, after the reaction is complete, add sodium bicarbonate to adjust the system pH to 9, add ethyl acetate: 500mL for extraction, dry the organic phase with anhydrous magnesium sulfate: 20g for 2h, and concentrate the organic phase under reduced pressure to constant weight to obtain the compound shown in formula III (50g, yield: 91.5%) MS (M+1) + =89.05.

[0058] Add the compound of formula III (50 g, 0.57 mol) to the reaction bottle, add dichloromethane: 250 mL, start stirring, add triethylamine (86.06 g, 0.86 mol), methanesulfonyl chloride (78.35 g, 0.68 mol), react for 6 hours, after the reaction is complete, add 100 mL of water, stand and separate, take the organic phase, wash the organic phase with saturated sodium chloride aqueous solution twice, dry it with anhydrous magnesium sulfate, and concentrate the organic phase to constant weight to obtain the compound of formula IV (60 g, yield: 90.6%). MS (M+1) + =167.03.

[0059] Add the compound represented by formula IV (50 g, 0.43 mol) to the reaction bottle, add DMF: 250 mL, sodium diformamide (61.3 g, 0.65 mol), start stirring, heat to 60 ° C, react for 10 hours, after the reaction is complete, stop heating, cool to 30 ° C, add 200 mL of water and 100 mL of ethyl acetate to the system, stir for 30 minutes, stand for stratification, take the organic phase, add 30% TsOH methanol solution to the organic phase, stir for 2 hours, filter, and obtain a white solid compound represented by formula V (83.6 g, yield 75%) MS (M+1) + =88.2.

[0060] Add the compound represented by formula V (50 g, 0.19 mol), THF 250 mL, sodium methoxide (11.3 g, 0.21 mol), sodium hydroxide (4.2 g, 0.105 mol) to the reaction bottle, stir for 2 h, filter, rinse the solid with THF once, concentrate the filtrate under reduced pressure to a remaining 50 mL, and purify by reduced pressure distillation to obtain a colorless transparent liquid compound represented by formula VI (10 g, yield: 60.4%). Nuclear magnetic data: 1H NMR (300 MHz, CDCl3): S4.78 (1H, m), δ4.66 (1H, m), δ4·47 (1H, m), δ2·86 (2H, d, J=5.1 Hz), 2.59 (1H, m), δ2·43 (1H, m), 1.62 (2H, brs). MS (M+1) +=88.2.

[0061] When preparing the compound represented by formula IV, using the same amount but different types of bases, the yield and unit working hours of the compound represented by formula IV are shown in the following table.

[0062]

[0063] Example 2

[0064] Add the compound represented by formula V (50 g, 0.19 mol), THF 250 mL, sodium methoxide (5.65 g, 0.105 mol), sodium hydroxide (4.2 g, 0.105 mol) to the reaction bottle, stir for 2 h, filter, rinse the solid with THF once, concentrate the filtrate under reduced pressure to a remaining 50 mL, and purify by reduced pressure distillation to obtain a colorless transparent liquid compound represented by formula VI (9.10 g, yield: 55%). Nuclear magnetic data: 1H NMR (300 MHz, CDCl3): S4.78 (1H, m), δ4.66 (1H, m), δ4·47 (1H, m), δ2·86 (2H, d, J=5.1 Hz), 2.59 (1H, m), δ2·43 (1H, m), 1.62 (2H, brs). MS (M+1) + =88.2.

[0065] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. All other embodiments obtained without creative work and related deductions and substitutions made by ordinary technicians in the field under the conditions of the concept of the present invention belong to the scope of protection of the present invention.

Claims

1. A method for synthesizing (S)-oxetane-2-methylamine, characterized in that: The following reaction routes are included: ； The compound represented by formula III, dichloromethane, triethylamine and methanesulfonyl chloride are mixed and reacted to obtain the compound represented by formula IV; The compound represented by formula IV is reacted with sodium diformylamide, and then an organic phase is taken out, and TsOH is added to the organic phase to react and hydrolyze to obtain a compound represented by formula V; The compound represented by formula V is reacted with a base to obtain the compound represented by formula VI; The alkali is sodium hydroxide and sodium methoxide, and the molar ratio of the sodium hydroxide to the sodium methoxide is 2:

1.

2. The method for synthesizing (S)-oxetane-2-methylamine according to claim 1, characterized in that: The temperature of the mixed reaction of the compound represented by formula III, dichloromethane, triethylamine and methanesulfonyl chloride is 20-30°C; The temperature for the reaction of the compound represented by formula IV and sodium diformamide is 50-60° C.; The temperature for the reaction between the compound represented by formula V and the base is 20-30°C.

3. The method for synthesizing (S)-oxetane-2-methylamine according to any one of claims 1 to 2, characterized in that: The following reaction routes are included: 。 4. The method for synthesizing (S)-oxetane-2-methylamine according to claim 3, characterized in that: include: The compound of formula I is prepared by subjecting (R) glycidol to an addition reaction, the compound of formula I is prepared by a ring expansion reaction to obtain a compound of formula II, and the compound of formula II is prepared by an acid-catalyzed hydrolysis reaction to obtain a compound of formula III.

5. The method for synthesizing (S)-oxetane-2-methylamine according to claim 4, characterized in that: (R) glycidol and vinyl ethyl ether are mixed and reacted, and then p-toluenesulfonic acid is added to react to obtain a compound represented by formula I; The compound represented by formula Ⅰ and trimethyl sulfoxide bromide are mixed and reacted to obtain the compound represented by formula Ⅱ; The compound represented by formula II, water and acid are mixed to react to obtain the compound represented by formula III; The acid used in the acid-catalyzed hydrolysis reaction is selected from one of acetic acid, formic acid, sulfuric acid, hydrochloric acid, propionic acid and butyric acid.

6. The method for synthesizing (S)-oxetane-2-methylamine according to claim 5, characterized in that: The temperature of the mixed reaction of (R) glycidol and vinyl ethyl ether is 0-5°C, and the temperature of the reaction of adding p-toluenesulfonic acid is 25-30°C; The temperature of the mixed reaction of the compound represented by formula I and trimethyl sulfoxide bromide is 60-65°C; The temperature for the mixed reaction of the compound represented by formula II, water and acid is 20-30°C.

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