A method for preparing benzo[e][1,3]oxazine-2,4-dione

Abstract

The present invention provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, the method comprising the following steps: in a base and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst, the reaction temperature is 110-140°C, and the time is 4-8h to obtain benzo[e][1,3]oxazine-2,4-dione. The oxalic acid diester is a dibasic ester of oxalic acid and a fatty alcohol containing 1-4 carbon atoms, specifically one or more of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and its isomers, dibutyl oxalate and its isomers, preferably dimethyl oxalate. The catalyst is a nitrogen-containing organic base, specifically a nitrogen-containing heterocyclic compound and its derivatives, including N,N-dimethylaminopyridine, 2-methylpyridine or pyridine, preferably N,N-dimethylaminopyridine. The base is an alkali metal salt of the fatty alcohol corresponding to the oxalic acid diester. The method has cheap raw materials, avoids corrosion to metal equipment, reduces the manufacturing cost of production equipment, and the preparation method is simple to operate. The purity of the obtained product reaches more than 97%, and the yield is as high as more than 82%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compounds, and specifically relates to a method for preparing benzo[e][1,3]oxazine-2,4-dione. Background Art

[0002] Benzo[e][1,3]oxazine-2,4-dione (CAS 2037-95-8) is a key intermediate for the synthesis of sodium 8-(2-hydroxybenzamido)octanoate (SNAC, CAS 203787-91-1). SNAC is a new type of absorption enhancer. As an oral drug excipient, it can help prepare oral preparations of various drugs, such as vitamin B12 (CN101952241) and semaglutide (CN105377306).

[0003] The most commonly used starting material for the synthesis of benzo[e][1,3]oxazine-2,4-dione is salicylamide (2-hydroxybenzamide). Literature and patents report a variety of different reaction pathways involving different reaction raw materials for salicylamide cyclization. Early reaction routes used highly toxic raw materials such as ethyl chloroformate, phosgene, and isocyanate (Chemische Berichte, 1902, vol. 35, p3649). In the late 1990s, scientific and technological workers made improvements to it, using safer oxalyl chloride (Pharmazie, 1995, vol. 50, No. 2, p150-151), phenyl chloroformate derivatives (Journal of the American Chemical Society, 1992, vol. 114, No. 27, p10715-10721), and carbonyldiimidazole (Liebigs Annalen der Chemie, 1981, No. 8, p1513-1514). In recent years, there are also reports on process upgrades using oxalyl chloride and carbonyldiimidazole (CN112661662, CN108689876), as well as the use of a new reaction raw material, di-tert-butyl dicarbonate (CN114195730).

[0004] Among them, the reaction mechanism of oxalyl chloride to synthesize benzo[e][1,3]oxazine-2,4-dione (Pharmazie, 1995, vol.50, No.2, p150-151) is as follows:

[0005]

[0006] This method uses hydrogen chloride gas caused by acyl chloride to corrode metal equipment. The raw materials of other existing synthesis methods are generally expensive. It is of great significance to seek safer and more economical reaction raw materials. Summary of the invention

[0007] In order to solve the problems of the prior art, the present invention provides a method for preparing benzo[e][1,3]oxazine-2,4-dione.

[0008] The specific technical solutions of the present invention are as follows:

[0009] The present invention provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, which is characterized by comprising the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain benzo[e][1,3]oxazine-2,4-dione.

[0010] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the oxalic acid diester is a dibasic ester of oxalic acid and a fatty alcohol containing 1 to 4 carbon atoms.

[0011] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the dibasic ester of oxalic acid and a fatty alcohol containing 1 to 4 carbon atoms is one or more of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and its isomers, dibutyl oxalate and its isomers, preferably dimethyl oxalate.

[0012] The method for preparing benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical feature: the catalyst is a nitrogen-containing organic base.

[0013] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the nitrogen-containing organic base is a nitrogen-containing heterocyclic compound and its derivatives.

[0014] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the nitrogen-containing heterocyclic compound and its derivatives are N,N-dimethylaminopyridine, 2-methylpyridine or pyridine, preferably N,N-dimethylaminopyridine.

[0015] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical feature: the base is an alkali metal salt of a fatty alcohol corresponding to an oxalic acid diester.

[0016] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical feature: the alkali metal salt of the oxalic acid diester corresponding to the fatty alcohol is a sodium salt or a potassium salt.

[0017] The method for preparing benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical feature: the organic solvent is an aprotic organic solvent with a relatively high boiling point.

[0018] The method for preparing benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical feature: the aprotic organic solvent with a relatively high boiling point is toluene or xylene.

[0019] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the molar ratio of 2-hydroxybenzamide, oxalic acid diester and catalyst is 1:(1.2-2):(0.2-0.1), and the base is 2% of the molar amount of 2-hydroxybenzamide.

[0020] The preparation method of benzo[e][1,3]oxazine-2,4-dione provided by the present invention also has the following technical characteristics: the reaction temperature is 110-140° C. and the reaction time is 4-8 hours.

[0021] Functions and Effects of the Invention

[0022] The preparation method of the present invention adopts oxalic acid diester as reaction raw material, under the premise of not reducing safety (even safer than most reaction raw materials of prior art), compared with prior art, such raw materials can reduce production cost, especially dimethyl oxalate has better economy. In addition, the method provided by the present invention avoids the corrosion of metal equipment by hydrogen chloride gas caused by using acyl chloride, thereby reducing the manufacturing cost of production equipment. Finally, the preparation method is simple to operate, and the purity of the obtained product reaches more than 97%, and the yield is up to more than 82%. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the HPLC chart of 2-hydroxybenzamide, the raw material used in Example 1 of the present invention.

[0024] Figure 2 This is the HPLC chart of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention.

[0025] Figure 3 This is a HPLC chart of a mixture of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention and the raw material 2-hydroxybenzamide used.

[0026] Figure 4 This is the infrared spectrum of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0027] The terms used in the present invention, unless otherwise specified, generally have the meanings that are commonly understood by those of ordinary skill in the art.

[0028] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0029] The reagents used in the following examples were purchased from common commercial channels, and the experimental operations and experimental conditions not specified were referred to the conventional operations and conventional conditions in the art.

[0030] The specific implementation of the present invention is described below in conjunction with embodiments and drawings.

[0031] <Example 1>

[0032] This embodiment provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, which comprises the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain benzo[e][1,3]oxazine-2,4-dione, and the specific process is as follows:

[0033] In a 500mL four-necked reaction bottle, add 2-hydroxybenzamide (13.7g, 0.1mol, 1.0equiv), toluene (50mL), N,N-dimethylaminopyridine (2.63g, 0.02mol, 0.2equiv) at room temperature, stir, add dimethyl oxalate (14.2g, 0.12mol, 1.2equiv), then add sodium methoxide (0.11g, 0.002mol) and gradually heat to 110°C. , stirred at this temperature for 6 hours, stopped the reaction, added 150 mL of ethyl acetate, washed with 1% dilute hydrochloric acid 3 times (200 mL×3), the solution was concentrated in vacuo at 30-40°C to obtain a residue, toluene (80 mL) was added to the residue, heated to 100°C, stirred for 2 hours, cooled to 25°C, filtered to obtain a white crystalline solid, washed with 25 mL of toluene, and then washed with 25 mL of 1% dilute hydrochloric acid, the yield was 82.7%, and the product HPLC purity was >97%. The reaction mechanism is shown in the following formula:

[0034]

[0035] Figure 1 This is the HPLC chart of 2-hydroxybenzamide, the raw material used in Example 1 of the present invention. Retention time: 4.821 min.

[0036] Figure 2 This is the HPLC chart of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention. Retention time: 4.688 min.

[0037] Figure 3 It is an HPLC chart of a mixture of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention and the raw material 2-hydroxybenzamide used.

[0038] Figure 4 is the infrared spectrum of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 of the present invention. Figure 4 It can be seen that the structure of benzo[e][1,3]oxazine-2,4-dione prepared in Example 1 is consistent with its theoretical structure.

[0039] <Example 2>

[0040] This embodiment provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, which comprises the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain benzo[e][1,3]oxazine-2,4-dione, and the specific process is as follows:

[0041] In a 500mL four-necked reaction bottle, add 2-hydroxybenzamide (13.7g, 0.1mol, 1.0equiv), toluene (50mL), N,N-dimethylaminopyridine (2.63g, 0.02mol, 0.2equiv) at room temperature, stir, add dimethyl oxalate (14.2g, 0.12mol, 1.2equiv), then add sodium methoxide (0.11g, 0.002mol) and gradually heat to 110°C, stir at this temperature for 6h, and stop. Stop the reaction, add acetic acid (0.12 g, 0.002 mol), then add ethyl acetate 150 mL, wash with 1% dilute hydrochloric acid 3 times (200 mL × 3), and concentrate the solution in vacuo at 30-40 ° C to obtain a residue. Add toluene (80 mL) to the residue, raise the temperature to 100 ° C, stir for 2 h, cool to 25 ° C, filter and obtain a white crystalline solid, wash with 25 mL of toluene, and then wash with 25 mL of 1% dilute hydrochloric acid. The yield is 78.4%, and the product HPLC purity is >97%.

[0042] <Example 3>

[0043] This embodiment provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, which comprises the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain benzo[e][1,3]oxazine-2,4-dione, and the specific process is as follows:

[0044] In a 500mL four-necked reaction bottle, 2-hydroxybenzamide (13.7g, 0.1mol, 1.0equiv), xylene (50mL), and 2-methylpyridine (0.93g, 0.01mol, 0.1equiv) were added at room temperature, stirred, diethyl oxalate (29.3g, 0.2mol, 2equiv) was added, and sodium ethoxide (0.14g, 0.002mol) was added and the temperature was gradually raised to 140°C. The mixture was stirred at this temperature for 6 h, the reaction was stopped, 150 mL of ethyl acetate was added, and the mixture was washed with 1% dilute hydrochloric acid for 3 times (200 mL × 3). The solution was concentrated in vacuo at 30-40 ° C to obtain a residue. Toluene (80 mL) was added to the residue, the mixture was heated to 100 ° C, stirred for 2 h, cooled to 25 ° C, and filtered to obtain a white crystalline solid. The solid was washed with 25 mL of toluene and then with 25 mL of 1% dilute hydrochloric acid. The yield was 72.9%, and the product HPLC purity was >97%.

[0045] <Example 4>

[0046] This embodiment provides a method for preparing benzo[e][1,3]oxazine-2,4-dione, which comprises the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain benzo[e][1,3]oxazine-2,4-dione, and the specific process is as follows:

[0047] In a 500mL four-necked reaction bottle, 2-hydroxybenzamide (13.7g, 0.1mol, 1.0equiv), toluene (50mL), pyridine (1.58g, 0.02mol, 0.2equiv) were added at room temperature, stirred, dimethyl oxalate (17.8g, 0.15mol, 1.5equiv) was added, and potassium methoxide (0.14g, 0.002mol) was added, and the temperature was gradually raised to 110°C. The mixture was stirred at this temperature for 8h, and the reaction was stopped. 150mL of ethyl acetate was added, and the mixture was washed with 1% dilute hydrochloric acid 3 times (200mL×3). The solution was concentrated in vacuo at 30-40°C to obtain a residue. Toluene (80mL) was added to the residue, and the temperature was raised to 100°C. The mixture was stirred for 2h, cooled to 25°C, and filtered to obtain a white crystalline solid. The solid was washed with 25mL of toluene and then with 25mL of 1% dilute hydrochloric acid. The yield was 61.5%, and the product had a HPLC purity of >97%.

[0048] The above is a detailed description of the embodiments, which is convenient for those skilled in the art to correctly understand and use the present invention. Any improvements or modifications to the technical solutions obtained by those skilled in the art based on the present invention on the basis of the prior art, without innovative work, only through analysis, analogy or limited enumeration, etc., should be within the scope of protection determined by the claims.

Claims

1. A method for preparing benzo[e][1,3]oxazine-2,4-dione, characterized in that: The method comprises the following steps: in an alkali and an organic solvent, 2-hydroxybenzamide and an oxalic acid diester react under the action of a catalyst to obtain the benzo[e][1,3]oxazine-2,4-dione, wherein the oxalic acid diester is one or more of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and its isomers, and dibutyl oxalate and its isomers; The catalyst is a nitrogen-containing organic base; the base is an alkali metal salt of a fatty alcohol corresponding to an oxalic acid diester; the organic solvent is an aprotic organic solvent with a relatively high boiling point; the molar ratio of the 2-hydroxybenzamide, the oxalic acid diester and the catalyst is 1:(1.2-2):(0.2-0.1), and the base is 2% of the molar amount of the 2-hydroxybenzamide; the reaction temperature is 110-140°C, and the reaction time is 4-8h.

2. The method for preparing benzo[e][1,3]oxazine-2,4-dione according to claim 1, characterized in that: The nitrogen-containing organic base is a nitrogen-containing heterocyclic compound and its derivatives.

3. The method for preparing benzo[e][1,3]oxazine-2,4-dione according to claim 2, characterized in that: The nitrogen-containing heterocyclic compound and its derivatives are N,N-dimethylaminopyridine, 2-methylpyridine or pyridine.

4. The method for preparing benzo[e][1,3]oxazine-2,4-dione according to claim 3, characterized in that: The alkali metal salt of the oxalic acid diester corresponding to the fatty alcohol is a sodium salt or a potassium salt.

5. The method for preparing benzo[e][1,3]oxazine-2,4-dione according to claim 4, characterized in that: The aprotic organic solvent with a relatively high boiling point is toluene or xylene.

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