Process for the preparation of a casanthranol

Abstract

The application discloses a preparation method of cardolan, and comprises the following steps: 1) adding 2-hydroxybenzamide and an inorganic base into water as a solvent to react; and 2) adding ethyl chloroformate, heating and ring closing to obtain cardolan. The application has the advantages that water is used as the solvent, which is beneficial to an environment-friendly reaction, ethyl chloroformate is added at room temperature, and the operation is simple and the energy consumption is low; meanwhile, the product with high quality and high yield is prepared in one step.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation methods of Kasaran, in particular to a preparation method of Kasaran. Background Art

[0002] Kasalan (chemical name: benzo[e][1,3]oxazine-2,4-dione) is an important intermediate in the synthesis of sodium 8-(2-hydroxybenzamido)octanoate. Sodium 8-(2-hydroxybenzamido)octanoate, abbreviated as SNAC, is an amino acid derivative absorption enhancer that can promote the oral absorption of various protein-based drug solutions, such as heparin and human growth hormone. It can also be used to treat gastrointestinal diseases and has promising application prospects.

[0003] Patent publication number CN104974060A describes a synthesis method for preparing benzo[e][1,3]oxazine-2,4-dione by reacting 2-hydroxybenzamide with ethyl chloroformate in acetonitrile as a solvent, catalyzed by pyridine, and then heating the reaction temperature to 124°C. This method, with a yield of only approximately 85%, requires high temperatures, and the use of a mixed solvent of acetonitrile and pyridine increases costs and is environmentally unsuitable for scale-up production.

[0004] Patent publication number CN108689876A describes a synthesis method for preparing benzo[e][1,3]oxazine-2,4-dione by reacting 2-hydroxybenzamide with carbonyldiimidazole using DMF as a solvent. While this method offers mild reaction conditions and a yield of up to 97.9%, the use of DMF as a solvent is environmentally unfriendly, carbonyldiimidazole is expensive, and the byproduct imidazole can cause water pollution, making wastewater treatment difficult and costly, making it unsuitable for industrial production.

[0005] Patent publication number CN112661662A describes a synthesis method: using acetonitrile as a solvent, 2-hydroxybenzamide reacts with oxalyl chloride to prepare benzo[e][1,3]oxazine-2,4-dione, with a yield of 93.2%. Oxalyl chloride used in this method is highly toxic and reacts with water to produce the toxic gas carbon monoxide. The use of acetonitrile as a solvent also makes it unsuitable for industrial production. Patent publication number CN113795482A describes a synthesis method: using ethanol as a solvent, 2-hydroxybenzamide reacts with diethyl carbonate in the presence of sodium ethoxide, and the temperature is raised to 80°C to prepare kasaran, with a yield of 90%. This method uses expensive sodium ethoxide, a large excess of diethyl carbonate, and requires ethanol as a solvent for both the reaction and crystallization, which increases the number of steps and makes it unsuitable for industrial production.

[0006] Patent publication number CN111269193A describes a synthetic method for preparing benzo[e][1,3]oxazine-2,4-dione by reacting 2-hydroxybenzamide with phosgene in the presence of pyridine at a temperature of 50°C. While this method is simple to operate, the phosgene used is a highly toxic substance, posing operational safety risks and high production risks. Furthermore, the use of pyridine, which has a foul odor, is environmentally unfriendly and unsuitable for industrial production. The inventors tested the method using the safer triphosgene instead of phosgene, but failed to obtain the desired results described in the patent.

[0007] Patent publication number CN115260116A improves upon patent CN104974060, describing a synthesis method: using ethanol as the solvent, 2-hydroxybenzamide reacts with ethyl chloroformate in the presence of triethylamine as an acid-binding agent, heating the reaction temperature to 85°C to produce benzo[e][1,3]oxazine-2,4-dione with a yield of 94.5%. This method solves the problem of residual ethyl chloroformate, but requires high-temperature reflux to evaporate the solvent before the reaction is complete, resulting in high energy consumption. Furthermore, the use of ethanol and triethylamine poses recycling issues, increasing operational safety and quality risks, making it unsuitable for industrial production. Summary of the Invention

[0008] In order to overcome the above-mentioned shortcomings of the prior art of using organic solvents, which lead to serious environmental pollution and complicated processes, the present invention provides a method for preparing kasaran. The method has the advantages of using water as a solvent, which is conducive to an environmentally friendly reaction, and adding ethyl chloroformate at room temperature, which is simple to operate and has low energy consumption. At the same time, high-quality and high-yield products can be prepared in one step.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] A method for preparing Kashalan comprises the following steps:

[0011] 1) First, 2-hydroxybenzamide and an inorganic base are added to water as a solvent to react;

[0012] 2) Add ethyl chloroformate and heat to close the ring to obtain Kasaran.

[0013] Preferably, the inorganic base comprises an alkali metal compound.

[0014] Preferably, the alkali metal compound includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium phosphate, and sodium phosphate.

[0015] Preferably, a catalyst is further added in step 1), and the catalyst includes one or more of 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine (DMAP), 2,4,6-trimethylpyridine and 2,3,5-trimethylpyridine.

[0016] Preferably, the mass ratio of the 2-hydroxybenzamide to the catalyst is 1:0% to 10.0%.

[0017] Preferably, the molar ratio of the 2-hydroxybenzamide to the inorganic base is 1:1.01-3.0.

[0018] Preferably, the molar ratio of the 2-hydroxybenzamide to the ethyl chloroformate is 1:1.01-2.0.

[0019] Preferably, the mass ratio of the 2-hydroxybenzamide to the water is 1:2.0-10.0.

[0020] Preferably, the temperature of the ring-closure reaction is 30-100°C.

[0021] Preferably, the heat preservation reaction time is 0.5 to 5 hours.

[0022] The beneficial effects of the present invention are as follows: (1) the present invention adopts 2-hydroxybenzamide and ethyl chloroformate to react in water under the action of an inorganic base, and obtains a product with a yield of up to 98.5% to 99.5% and a purity of 99.9% to 100.0% (liquid chromatography). Water is used as a solvent, which is conducive to becoming an environmentally friendly reaction. The addition of ethyl chloroformate at room temperature is simple to operate and has low energy consumption. At the same time, high-quality and high-yield products can be prepared in one step; (2) in order to promote the complete reaction of 2-hydroxybenzamide, a slightly excessive amount of ethyl chloroformate is added. In the ring-closing stage, The temperature of the section is 50-80°C, and a small amount of residual ethyl chloroformate can react with water, thereby removing the residual ethyl chloroformate in the product and eliminating the drug toxicity caused by the inclusion of genotoxic ethyl chloroformate; (3) Water is green and environmentally friendly as a solvent, and there is no solvent recovery and reuse, thereby reducing operational safety risks and quality risks, and also achieving energy saving and consumption reduction and low cost; (4) The green and environmentally friendly process of the invention has easy-to-obtain raw materials, smooth process, simple post-processing, low industrialization cost, is conducive to industrial production, and can effectively improve the economic and social benefits of the enterprise. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The preparation method of Kashalan of the present invention is as follows: 1 H-NMR spectrum;

[0024] Figure 2 This is the HPLC spectrum of Example 1 of the method for preparing Kasaran of the present invention;

[0025] Figure 3 This is the HPLC spectrum of Example 2 of the preparation method of Kasaran of the present invention;

[0026] Figure 4 This is the HPLC spectrum of Example 3 of the method for preparing Kasalan of the present invention;

[0027] Figure 5 This is the HPLC spectrum of Example 4 of the method for preparing Kasaran of the present invention;

[0028] Figure 6 This is the HPLC spectrum of Example 5 of the method for preparing Kasaran of the present invention;

[0029] Figure 7 This is the HPLC spectrum of Example 6 of the method for preparing Kasaran of the present invention;

[0030] Figure 8 This is the HPLC spectrum of Example 7 of the method for preparing Kasaran of the present invention; DETAILED DESCRIPTION

[0031] The present invention is further described below with reference to the accompanying drawings and specific examples. The raw materials and equipment used in the following specific examples of the present invention are all known products and were obtained by purchasing commercial products. In the present invention, yield = molar yield * content.

[0032] The chemical name of Kasaran in the present invention is benzo[e][1,3]oxazine-2,4-dione (also known as 2H-benzo[e][1,3]oxazine-2,4(3H)-dione), CAS: 2037-95-8, and it is a white or light gray crystalline powder. This product is insoluble in water but soluble in sodium hydroxide solution. The structural formula is shown below:

[0033]

[0034] Example 1: A method for preparing kasaran comprises the following steps: 207.6 g (99%, 1.5 mol) of 2-hydroxybenzamide, 2.06 g (99%) of 4-dimethylaminopyridine, 66.7 g of sodium hydroxide (99.0%, 1.65 mol) and 620 g of water are added to a 2000 ml three-necked flask in sequence, and after stirring for half an hour, 179.9 g (99.5%, 1.65 mol) of ethyl chloroformate is added. After the addition is completed, the mixture is heated to 50° C. and kept in the reaction mixture for 2 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and filtered. The filter cake is washed with 100 g of water and then dried in a forced air drying oven at 70° C. for 12 hours to obtain 243.8 g of white solid kasaran. Yield: 99.5%, content (external standard method): 99.8%, purity detected by HPLC: 99.98%, HPLC spectrum as shown in FIG. Figure 2The H-NMR spectrum is shown in Figure 1. 1 The H-NMR spectrum is shown in Figure 1. Figure 1 The H-NMR spectrum is shown in Figure 1.

[0035] 1 H-NMR (400 MHz, DMSO) 12.05 (s, 1H) 7.93-7.91 (d, 1H) 7.80-7.76 (t, 1H) 7.42-7.37 (m, 2H).

[0036] Example 2: A preparation method of caroxazone, comprising the following steps:

[0037] A 2000ml three-necked flask was charged with 207.6g (99%, 1.5mol) 2-hydroxybenzamide, 4.1g (99%) 2-methylpyridine, 149.1g sodium acetate (99.0%, 1.8mol) and 830g water, stirred for half an hour, then added 196.3g (99.5%, 1.8mol) ethyl chloroformate, heated to 80°C for 3 hours, after the reaction was completed, the reaction liquid was cooled to room temperature, filtered, the filter cake was washed with 100g water, and then dried in a blast drying oven at 70°C for 12 hours, to obtain 243.5g white solid caroxazone, yield: 98.7%, content: 99.1%, HPLC purity: 99.96%, the HPLC spectrum is shown in Figure 1. Figure 3

[0038] Example 3: A preparation method of caroxazone, comprising the following steps:

[0039] A 2000ml three-necked flask was charged with 207.6g (99%, 1.5mol) 2-hydroxybenzamide, 4.1g (99%) 2-methylpyridine, 149.1g sodium acetate (99.0%, 1.8mol) and 830g water, stirred for half an hour, then added 196.3g (99.5%, 1.8mol) ethyl chloroformate, heated to 80°C for 3 hours, after the reaction was completed, the reaction liquid was cooled to room temperature, filtered, the filter cake was washed with 100g water, and then dried in a blast drying oven at 70°C for 12 hours, to obtain 243.5g white solid caroxazone, yield: 98.7%, content: 99.1%, HPLC purity: 99.96%, the HPLC spectrum is shown in Figure 1. Figure 4

[0040] ​​Example 4: A method for preparing kasaran comprises the following steps: 207.6 g (99%, 1.5 mol) of 2-hydroxybenzamide, 10.3 g (99%) of 2,4,6-trimethylpyridine, 418.8 g of potassium carbonate (99.0%, 3.0 mol) and 1038 g of water are added to a 2000 ml three-necked flask in sequence, 179.9 g (99.5%, 1.65 mol) of ethyl chloroformate is added at room temperature, and after the addition is completed, the temperature is raised to 60° C. and the reaction is kept incubated for 1.5 hours. After the reaction is completed, the reaction solution is cooled to room temperature and filtered. The filter cake is washed with 100 g of water and then dried in a forced air drying oven at 70° C. for 12 hours to obtain 243.8 g of white solid kasaran, with a yield of 98.8%, a content of 99.1%, a purity of 99.97% detected by HPLC, and the HPLC spectrum is as shown in FIG. Figure 5 shown.

[0041] Example 5: A method for preparing Kasaran, comprising the following steps:

[0042] 207.6 g (99%, 1.5 mol) of 2-hydroxybenzamide, 0.21 g (99%) of 4-methylpyridine, 210.8 g of potassium carbonate (99.0%, 1.51 mol) and 2076 g of water were added to a 3000 ml three-necked flask in sequence, and 164.69 g (99.5%, 1.51 mol) of ethyl chloroformate was added at room temperature. After the addition was completed, the temperature was raised to 100° C. and the reaction was kept warm for 0.5 hour. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with 100 g of water and then dried in a forced air drying oven at 70° C. for 12 hours to obtain 241.03 g of white solid casaran, with a yield of 97.2%, an assay content of 98.6%, and a purity of 99.95% as determined by HPLC. The HPLC spectrum is shown in FIG. Figure 6 shown.

[0043] Example 6: A method for preparing Kasaran, comprising the following steps:

[0044] In a 2000 ml three-necked flask, 207.6 g (99%, 1.5 mol) of 2-hydroxybenzamide, 20.97 g (99%) of 2,3,5-trimethylpyridine, 481.8 g of sodium carbonate (99.0%, 4.5 mol) and 415 g of water were added in sequence. 217.04 g (99.5%, 1.65 mol) of ethyl chloroformate was added at room temperature. After the addition was complete, the temperature was raised to 30°C and kept for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with 100 g of water and then dried in a forced air drying oven at 70°C for 12 hours to obtain 242.5 g of white solid Kasaran. The yield was 97.6%, the content was 98.4%, and the purity was 99.98% as determined by HPLC. The HPLC spectrum is shown in FIG. Figure 7 shown.

[0045] Example 7: A method for preparing Kasaran, comprising the following steps:

[0046] 207.6 g (99%, 1.5 mol) of 2-hydroxybenzamide, 121.2 g of sodium hydroxide (99.0%, 3.0 mol) and 600 g of water were added to a 2000 ml three-necked flask in sequence, and 217.04 g (99.5%, 1.65 mol) of ethyl chloroformate was added at room temperature. After the addition was completed, the temperature was raised to 70°C and kept for reaction for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with 100 g of water and then dried in a forced air drying oven at 70°C for 12 hours to obtain 234.2 g of white solid casaran. The yield was 95.3%, the content was 99.5%, and the purity was 99.97% as determined by HPLC. The HPLC spectrum is shown in FIG. Figure 8 shown.

[0047] The above description is only a preferred embodiment of the present invention and does not limit the scope of patent protection of the present invention. Any equivalent structural transformation made by using the contents of the description and drawings of the present invention, directly or indirectly applied to other related technical fields, is also included in the scope of protection of the present invention.

Claims

1. A method for preparing Kasaran, characterized in that: The following steps are involved: 1) First, 2-hydroxybenzamide and an inorganic base are added to water as a solvent to react; 2) adding ethyl chloroformate and heating to close the ring to obtain Kasaran; The inorganic base includes an alkali metal compound, and the alkali metal compound includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium phosphate, and sodium phosphate.

2. The method for preparing Kasaran according to claim 1, wherein: In step 1), a catalyst is further added, and the catalyst includes one or more of 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine and 2,3,5-trimethylpyridine.

3. The method for preparing Kasaran according to claim 2, wherein: The mass ratio of the 2-hydroxybenzamide to the catalyst is 1:0% to 10.0%.

4. The method for preparing Kasaran according to claim 1 or 2, wherein: The molar ratio of the 2-hydroxybenzamide to the inorganic base is 1:1.01-3.

0.

5. The method for preparing Kasaran according to claim 1 or 2, wherein: The molar ratio of the 2-hydroxybenzamide to the ethyl chloroformate is 1:1.01-2.

0.

6. The method for preparing Kasaran according to claim 1 or 2, wherein: The mass ratio of the 2-hydroxybenzamide to the water is 1:2.0-10.

0.

7. The method for preparing Kasaran according to claim 1 or 2, wherein: The temperature of the ring-closure reaction is 30-100°C.

8. The method for preparing Kasaran according to claim 1 or 2, wherein: In the temperature-raising ring closing, after the temperature is raised, the reaction is continued at the temperature for 0.5 to 5 hours.

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