Preparation method of azetidine derivative

Abstract

The invention discloses a preparation method of an azetidine derivative, which comprises the following steps: by taking tert-butyl azetidine-3-yl carbamate as a raw material, carrying out amino protection, nitrogen methylation and catalytic hydrogenolysis debenzylation to obtain a target product tert-butyl (methyl) (azetidine-3-yl methyl) carbamate. The synthetic route is mild in reaction condition, simple and convenient to operate, relatively high in reaction yield in each step, high in product purity, good in total yield and suitable for large-scale production, and can be widely applied to the fields of medicines and organic synthesis as a key intermediate.

Description

Technical Field

[0001] This invention relates to a method for preparing compounds, and more particularly to a method for preparing a nitrogen-containing butane derivative. Background Technology

[0002] Azahexacyclic butanes are important four-membered nitrogen heterocyclic structures, widely used as pharmacophores or key skeletons in bioactive molecules and drugs due to their unique ring strain and electronic properties. Compounds containing azahexacyclic butane structures show significant advantages in modulating the physicochemical properties (such as solubility and metabolic stability) and biological activity of drug molecules.

[0003] (Zyzocyclobut-3-yl)(methyl)carbamate tert-butyl ester is an important azacyclobutane derivative, often used as a key intermediate in the synthesis of complex drug molecules. However, there is a lack of reports on efficient, large-scale synthetic routes for this compound in the current technology. Therefore, developing a short, mild, and high-yield synthetic method is of great significance for promoting the development of related drugs. Summary of the Invention

[0004] Objective of the invention: This invention provides a method for preparing azacyclobutane derivatives, which solves the problems of low yield and difficulty in large-scale production in traditional synthetic routes.

[0005] Technical solution: The present invention provides a method for preparing azacyclic butane derivatives, wherein the azacyclic butane derivatives are tert-butyl(methyl)(azacyclic butane-3-ylmethyl)carbamate, and the reaction route is as follows: ,

[0006] Among them, R1-R6 are Boc, Boc, Cbz, Boc, Cbz, and Boc.

[0007] The above preparation method includes the following steps: Using tert-butylazacyclobutane-3-ylcarbamate as a raw material, through amino protection, nitrogen methylation and catalytic hydrogen debenzylation, the target product tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate was obtained.

[0008] Specifically, the following steps are included: (1) Tert-butylazacyclobutane-3-ylcarbamate and an amine protecting agent are dissolved in a first solvent in the presence of a base and reacted to generate benzyl 3-((tert-butyloxycarbonyl)amino)azacyclobutane-1-carboxylic acid ester.

[0009] (2) The product of step (1) is reacted with an alkylating agent in a second solvent under the action of a strong base to perform nitrogen methylation, generating benzyl 3-((tert-butoxycarbonyl)(methyl)amino)azacyclobutane-1-carboxylic acid ester.

[0010] Step (2) should be carried out under inert gas protection, such as nitrogen protection.

[0011] (3) The product of step (2) is subjected to catalytic hydrogenolysis in a third solvent under the action of a catalyst to remove the benzyl group and obtain tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate.

[0012] In step (1), the amine protecting agent is a benzyl ester reagent and / or a Boc protecting agent.

[0013] The benzyl ester reagent is Cbz-OSu (N-benzyloxycarbonyloxysuccinimide).

[0014] The Boc protecting agent is (Boc)2O (di-tert-butyl dicarbonate).

[0015] The base is N,N-diisopropylethylamine and / or triethylamine.

[0016] In step (2), the strong base is sodium hydrogen.

[0017] The alkylating agent is iodomethane.

[0018] In step (3), the catalyst is Pd / C, and the reaction is carried out in a hydrogen atmosphere.

[0019] In the above steps, the first solvent is DMF, the second solvent is [missing information], and the third solvent is methanol.

[0020] The azacyclic butane derivative prepared by the above method is characterized by the following structural formula: , The azacyclobutane derivative is tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate.

[0021] Beneficial effects: This invention designs two flexible synthetic routes, using readily available azacyclobutane compounds as starting materials, and through key steps such as protection, alkylation, and deprotection, efficiently and with high yield obtains the target product tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate.

[0022] The synthetic route provided by this invention is rationally designed and highly flexible, and can be selected according to the availability of starting materials. The reaction conditions are mild and the operation is simple. The yields of each step are high, the product purity is high, and the overall yield is good. It is suitable for large-scale production and can be widely used as a key intermediate in the fields of pharmaceuticals and organic synthesis. Attached Figure Description

[0023] Figure 1 The ¹H NMR spectrum of benzyl 3-((tert-butoxycarbonyl)amino)azacyclobutane-1-carboxylic acid ester in Example 1 of the present invention; Figure 2 The ¹H NMR spectrum of 3-((tert-butoxycarbonyl)(methyl)amino)azacyclobutane-1-carboxylic acid ester in Example 1 of the present invention; Figure 3 The ¹H NMR spectrum of tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate in Example 1 of the present invention; Detailed Implementation Example 1

[0024] The synthesis of tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate from tert-butylazacyclobutane-3-ylcarbamate includes the following steps: Step A1: Synthesis of benzyl 3-((tert-butoxycarbonyl)amino)azacyclobutane-1-carboxylic acid ester Cbz-OSu (2.2 g, 8.7 mmol) and DIEA (2.25 g, 17.4 mmol) were added to a DMF (20 mL) solution of tert-butylazacyclobutane-3-ylcarbamate (1 g, 5.8 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with DCM (3 × 60 mL). The organic phases were combined, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give a white solid product (1.7 g, 96% yield).

[0025] ¹H NMR (400 MHz, DMSO-d6): δ ppm: 7.40-7.27 (m, 5H), 5.03 (s, 2H), 4.72 (s, 1H), 4.04 (d, J=29.3 Hz, 4H), 1.39 (s, 9H). LC-MS: m / z [M+H]⁺ = 307.3. Step A2: Synthesis of benzyl 3-((tert-butoxycarbonyl)(methyl)amino)azacyclobutane-1-carboxylic acid ester At 0 °C, NaH (444 mg, 60%, 11.1 mmol) was added to a 20 mL THF solution of the product from step A1 (1.7 g, 5.6 mmol). After stirring at room temperature for 10 min, CH3I (1.58 g, 11.1 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h under nitrogen protection. After the reaction was complete, the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (3 × 80 mL). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give a colorless oily product (1.47 g, 83% yield).

[0026] ¹H NMR (400 MHz, DMSO-d6): δ ppm: 7.40-7.27 (m, 5H), 5.03 (s, 2H), 4.72 (s, 1H), 4.04 (d, J = 29.3 Hz, 4H), 2.82 (s, 3H), 1.39 (s, 9H). LC-MS: m / z [M+H]⁺ = 321.2. Step A3: Synthesis of tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate Pd / C (150 mg, 10%) was added to a MeOH (15 mL) solution of the product from step A2 (1.47 g, 4.6 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to give the target product (850 mg, 99% yield) as a colorless oil.

[0027] ¹H NMR (400 MHz, CDCl3): δppm: 4.80 (s, 1H), 3.77-3.67 (m, 4H), 2.89 (s, 3H), 1.44 (s, 9H). LC-MS: m / z [M+H]⁺ = 187.1.

Claims

1. A method for preparing a nitrogen-containing butane derivative, characterized in that, The azacyclobutane derivative is tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate, and its reaction route is as follows: ， Among them, R1-R6 are Boc, Boc, Cbz, Boc, Cbz, and Boc.

2. The preparation method according to claim 1, characterized in that, The steps include: using tert-butylazacyclobutane-3-ylcarbamate as a raw material, subjecting it to amino protection, nitrogen methylation, and catalytic hydrogen debenzylation to obtain the target product tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate.

3. The preparation method according to claim 1 or 2, characterized in that, Specifically, the following steps are included: (1) Tert-butylazacyclobutane-3-ylcarbamate and an amine protecting agent are dissolved in a first solvent in the presence of a base and reacted to generate benzyl 3-((tert-butyloxycarbonyl)amino)azacyclobutane-1-carboxylic acid ester; (2) The product of step (1) is reacted with an alkylating agent in a second solvent under the action of a strong base to perform nitrogen methylation, generating benzyl 3-((tert-butoxycarbonyl)(methyl)amino)azacyclobutane-1-carboxylic acid ester; (3) The product of step (2) is subjected to catalytic hydrogenolysis in a third solvent under the action of a catalyst to remove the benzyl group and obtain tert-butyl(methyl)(azacyclobutane-3-ylmethyl)carbamate.

4. The preparation method according to claim 3, characterized in that: In step (1), the amine protecting agent is a benzyl ester reagent and / or a Boc protecting agent.

5. The preparation method according to claim 4, characterized in that: The benzyl ester reagent is Cbz-OSu.

6. The preparation method according to claim 4, characterized in that: The Boc protecting agent is (Boc)₂O.

7. The preparation method according to claim 3, characterized in that: In step (2), the strong base is sodium hydrogen.

8. The preparation method according to claim 3, characterized in that: The alkylating agent is iodomethane.

9. The preparation method according to claim 3, characterized in that: In step (3), the catalyst is Pd / C, and the reaction is carried out in a hydrogen atmosphere.

10. The azacyclic butane derivative prepared by the method according to any one of claims 1-9, characterized in that, Its structural formula is as follows: ， The azacyclobutane derivative is (zazacyclobut-3-yl)(methyl)carbamate tert-butyl ester.

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