A substituted oxygen heterocyclic compound and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical chemicals, and specifically relates to a substituted oxygen heterocyclic compound and a preparation method thereof. The present invention uses Compound I and Compound II as reaction raw materials, and prepares a substituted oxygen heterocyclic compound V through an addition reaction, a Grignard reaction, and a hydrolysis reaction. In the Grignard reaction, a Grignard reagent, Compound III, and a mixed solution of HMPA are continuously introduced into a reaction flask in small amounts for reaction. After the Grignard reagent is added to about 40%, the Grignard reagent concentration is reduced to reduce side reactions. A one-pot process is used overall, and the first step reaction is concentrated and directly used in the next step reaction. After the Grignard reaction, the product is obtained by directly adjusting the acid and undergoing a hydrolysis reaction, thereby shortening the process operation process.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemicals, and in particular relates to a substituted oxygen heterocyclic compound and a preparation method thereof. Background Art

[0002] Among four-membered oxygen heterocyclic compounds, the oxetane structure is highly polar and a good hydrogen bond acceptor. Many sedative, hypnotic, and anesthetic drugs contain oxetane structural fragments.

[0003] For example, the novel substituted pyrazole carboxylate derivatives with central nervous system inhibitory effects disclosed in patent CN110724106A also contain oxygen heterocyclic fragments. .

[0004] Patent WO2017181117 discloses a method for preparing oxygen heterocyclic compounds using the Strecker reaction, which comprises reacting ketone and trimethylsilyl cyanide under the catalysis of Lewis acid to obtain the product: .

[0005] Since both the raw materials and the reaction products are four-membered oxygen heterocycles, they are easily decomposed in the presence of Lewis acid, so the yield is low.

[0006] The prior art does not disclose a specific method for synthesizing four-membered oxygen heterocyclic compounds. Therefore, it is of great significance to develop an innovative synthesis method for four-membered oxygen heterocyclic compounds. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a method for preparing a substituted oxygen heterocyclic compound.

[0008] First, the present invention provides a substituted oxygen heterocyclic intermediate compound IV, the structural formula of which is as follows: .

[0009] The present invention provides a method for preparing a substituted oxygen heterocyclic compound, which is prepared by hydrolyzing compound IV. .

[0010] The present invention further provides a method for preparing compound IV, which is prepared by Grignard reaction of compound III with a Grignard reagent. .

[0011] In the Grignard reaction, compound III and the Grignard reagent are added simultaneously in batches, and compound III and the Grignard reagent react continuously in trace amounts.

[0012] The solvent for the Grignard reaction is methyl tert-butyl ether (MTBE), ethyl tert-butyl ether, n-propyl tert-butyl ether, isopropyl tert-butyl ether, and MTBE is more preferred.

[0013] The catalyst for the Grignard reaction is hexamethylphosphoric triamide (HMPA).

[0014] The reaction temperature of the Grignard reaction is -10~10°C.

[0015] In the Grignard reaction, the molar ratio of compound III:Grignard reagent:catalyst is in the range of 1:1.05-1.25:0.05-0.2.

[0016] The present invention also provides a method for preparing compound III, comprising preparing compound III by an addition reaction of compound I and compound II in the presence of a stabilizer. .

[0017] The stabilizer is triethylamine.

[0018] The above-mentioned TMS is trimethylsilyl.

[0019] The technical effect of the present invention is that the first addition reaction is a Strecker reaction, in which the ketone and trimethylsilyl cyanide are catalyzed by a Lewis acid to obtain a product. Because both the raw material and Compound III are four-membered oxygen heterocycles, they are easily decomposed in the presence of a Lewis acid, resulting in a reduced yield. Therefore, the present invention uses triethylamine as a stabilizer to improve the product yield.

[0020] The traditional Grignard reaction has initiation problems and is prone to safety accidents. At the same time, excessive addition of Grignard reagent will cause excessive impurities, resulting in low yield. The present invention adopts a batch-by-batch continuous addition method, which can not only solve the problem of sudden temperature rise causing safety risks, but also reduce the amount of Grignard reagent used and reduce the production of by-products. The present invention uses MTBE solvent instead of common solvents such as tetrahydrofuran and dioxane, and adopts HMPA as a catalyst for Grignard reagent, which can accelerate the reaction speed and prevent heat accumulation. At the same time, it can also reduce the amount of Grignard reagent used, avoiding excessive impurities caused by excessive Grignard reagent, resulting in a decrease in yield.

[0021] In the hydrolysis reaction, the present invention uses low temperature conditions, about 5% dilute hydrochloric acid or dilute sulfuric acid to remove the protecting group, and then uses anhydrous sodium sulfate for drying to reduce the generation of ring-opening impurities.

[0022] In addition, using oxetane as the raw material, the product is obtained through addition reaction, Grignard reaction, and hydrolysis. This is a one-pot process. The first step reaction is concentrated and directly used in the next step. After the Grignard reaction, the acid is directly adjusted and the product is obtained after drying, shortening the process operation process. The yield of this process is 80-85%, which is significantly superior to the traditional Grignard reaction yield of 50-70%. Therefore, this synthetic route is simple to operate, has mild reaction conditions, high yield, and solves the safety issues caused by the Grignard reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Attachment Figure 1 The compound III prepared in Example 1 1 H NMR spectrum.

[0024] Attachment Figure 2 The compound IV prepared in Example 2 1 H NMR spectrum.

[0025] Attachment Figure 3 The compound V prepared in Example 3 1 H NMR spectrum. DETAILED DESCRIPTION

[0026] To further understand the present invention, the following examples provide a detailed description of a substituted oxygen heterocyclic compound and its preparation method. It should be understood that these examples are only intended to further illustrate the features of the present invention and are not intended to limit the scope of the present invention or the scope of the claims.

[0027] Example 1:

[0028]

[0029] Substrate I (83.3 g, 1.16 mol) was added to a dry 1L four-necked flask and dissolved in 250 g of dichloromethane. Triethylamine (12.0 g, 0.12 mol) was slowly added dropwise under nitrogen protection. Compound II (137.3 g, 1.39 mol) was slowly added dropwise under ice bath to control the reaction temperature below 0°C. After the addition was completed, stirring was continued for 30 minutes. The reaction was detected by TLC (iodine colorimetry) to be complete. The diluted reaction solution was quenched with 5.0 g of water. The organic phase was dried with 54.0 g of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 198.5 g of compound III as a light yellow liquid with a yield of 98.0% and a purity of 98.1%. After testing, the attached Figure 1 For compound III 1 H NMR spectrum.

[0030] Example 2:

[0031]

[0032] Material A: Add substrate III (198.5 g, 1.14 mol pure) and HMPA (17.9 g, 0.1 mol) to a dry 2 L four-necked flask. Dissolve it in 1000 g of methyl tert-butyl ether. Under nitrogen protection, control the temperature to 0°C and set the flow rate to 10 ml / min.

[0033] Material B: methylmagnesium bromide in 2-methyltetrahydrofuran (450.0 g, 1.36 mol). The reaction temperature was controlled at 0°C and the flow rate was set at 6 ml / min.

[0034] At the same time, add material A and material B to the reaction flask (the reaction flask was pre-cooled to 0°C after nitrogen replacement 4 times). After 40 minutes of addition, add 250ml of 2-methyltetrahydrofuran solution to material B to dilute the concentration of material B. Set the flow rate of material B to 8ml / min. After the addition of materials A and B, continue the reaction for 30 minutes. The reaction is complete by TLC (iodine color development). Use 10g of saturated ammonium chloride aqueous solution to quench the reaction solution. The organic phase is dried with 134.0g of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 196.7g of compound IV as a light yellow liquid, with a total yield of 86.1% and a purity of 95.6%. After testing, the attached Figure 2 For compound IV 1 H NMR spectrum.

[0035] Equipment model for micro-continuous reactions: Medium-pressure constant-flow pump MP0102D from Shanghai Sanwei Scientific Instrument Co., Ltd.

[0036] Example 3:

[0037]

[0038] Add 200.0g of THF to compound IV to dissolve it, start stirring, use an ice-water bath to cool to below 0°C, slowly add 15.0g of 5% HCl to the reaction flask, continue to keep warm and react for 5 minutes, use TLC to detect the completion of the reaction, dry it with 100.0g of anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a crude compound V. The crude compound V was dissolved in 500.0g of n-heptane, cooled to -5~0°C, and the solid was precipitated and filtered to obtain 111.7g of compound V as a white solid with a purity of 98.9% and a total yield of 84.0%. After testing, the attached Figure 3 For compound V 1 H NMR spectrum.

Claims

1. A method for preparing a substituted oxygen heterocyclic compound, characterized in that: Compound I and compound II are used as reaction raw materials, and are subjected to addition reaction in the presence of stabilizer triethylamine, followed by Grignard reaction and hydrolysis reaction.

2. The preparation method according to claim 1, characterized in that In the Grignard reaction, compound III and the Grignard reagent are added simultaneously and continuously, and compound III and the Grignard reagent react continuously in a micro-flux manner.

3. The preparation method according to claim 1, characterized in that The solvent for the Grignard reaction is methyl tert-butyl ether (MTBE), ethyl tert-butyl ether, n-propyl tert-butyl ether, and isopropyl tert-butyl ether.

4. The preparation method according to claim 1, characterized in that The catalyst for the Grignard reaction is hexamethylphosphoric triamide (HMPA).

5. The preparation method according to claim 1, characterized in that In the Grignard reaction, the molar ratio of compound III:Grignard reagent:catalyst is in the range of 1:1.05-1.25:0.05-0.2.

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