A preparation method of high-purity 8-(2-hydroxybenzamido) sodium octanoate

Abstract

This invention relates to a method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate. Salicylate and dimethyl carbonate react under the action of an alkali to generate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione; 2H-benzo[e][1,3]oxazine-2,4(3H)-dione, ethyl 8-bromooctanoate, and an alkali react in a solvent to generate ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate; ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate and lithium salt react in a solvent to generate ethyl 8-(2-hydroxybenzamido)octanoate; ethyl 8-(2-hydroxybenzamido)octanoate and a strong alkali react in a solvent to generate sodium 8-(2-hydroxybenzamido)octanoate. This invention uses dimethyl carbonate instead of ethyl chloroformate, which is genotoxic, or N'N-carbonyldiimidazole, which is difficult to treat in wastewater, for synthesis, and uses lithium salt instead of sodium hydroxide for ring opening, which reduces the generation of impurities and improves the purity of the product.

Description

Technical Field

[0001] This invention relates to a method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate, belonging to the field of pharmaceutical and chemical technology. Background Technology

[0002] Sodium 8-(2-hydroxybenzamido)octanoate, abbreviated as SNAC, is a small-molecule fatty acid derivative that promotes the absorption of carbophosphate compounds and is used to treat gastrointestinal diseases. It enhances drug absorption in gastrointestinal epithelial cells, effectively addressing absorption barriers of orally administered peptide drugs, and is particularly suitable for gastrointestinal diseases caused by malabsorption of diphosphate compounds. Currently, oral SNAC (2.5 mg / day) has been proven effective in treating gastrointestinal diseases caused by malabsorption of diphosphate compounds. It represents a next-generation product for treating gastrointestinal malabsorption of diphosphate compounds, offering higher efficacy and safety than previous medications, and possesses very promising application prospects.

[0003] Chinese patent CN104974060A reports the preparation of SNAC using salicylamide and ethyl chloroformate as raw materials. However, ethyl chloroformate is highly toxic and genotoxic, posing significant risks to humans and the environment. Chinese patent CN108689876B reports the preparation of SNAC using salicylamide and N'N-carbonyldiimidazole as raw materials. However, the use of N'N-carbonyldiimidazole generates wastewater containing imidazole, which is difficult and costly to treat. Therefore, new preparation methods are needed to reduce costs while being more environmentally friendly, making them suitable for industrial production. Furthermore, both Chinese patents CN104974060A and CN108689876B use the strong base sodium hydroxide for the hydrolysis of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, which can cause impurities to form.

[0004] Based on this, the present invention is proposed. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate, the specific technical solution of which is as follows:

[0006] To address the aforementioned technical problems, this invention provides a method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate. This method avoids the use of highly toxic substances, uses dimethyl carbonate instead of ethyl chloroformate or N'N-carbonyldiimidazole to synthesize compound Int1 (structural formula shown in Int1), and uses lithium chloride instead of sodium hydroxide. This not only reduces the generation of impurities but also lowers the production cost, posing less harm to humans and the environment, and is suitable for industrial-scale production. The specific scheme is as follows:

[0007] A method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate, the synthetic route of which is as follows:

[0008]

[0009] Synthesis principle:

[0010] Salicylic acid amide (compound SM1, structural formula shown in formula SM1) and dimethyl carbonate (compound SM2, structural formula shown in formula SM2) react under alkaline conditions to generate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione (compound Int1, structural formula shown in formula Int1). 2H-benzo[e][1,3]oxazine-2,4(3H)-dione and ethyl 8-bromooctanoate react under alkaline conditions to generate 8-[2,4-dioxo-2H-benzo[E][1,3]bromooctanoate. [3]Oxazin-3(4H)-yl]octanoic acid ethyl ester (compound Int2, structural formula as shown in formula Int2), 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoic acid ethyl ester ring-opening under the action of lithium salt to generate 8-(2-hydroxybenzamido)octanoic acid ethyl ester (compound Int3, structural formula as shown in formula Int3), 8-(2-hydroxybenzamido)octanoic acid ethyl ester hydrolyzes under the action of strong base to generate 8-(2-hydroxybenzamido)octanoic acid sodium salt.

[0011] The specific reaction steps are as follows:

[0012] A method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate includes the following steps:

[0013] Step 1: Salicylic acid amide and dimethyl carbonate react under the action of alkali to generate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione;

[0014] Step 2: 2H-benzo[e][1,3]oxazine-2,4(3H)-dione, ethyl 8-bromooctanoate, and base in a solvent react to generate ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate;

[0015] Step 3: 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate ethyl ester and lithium salt are reacted in a solvent to generate 8-(2-hydroxybenzamido)octanoate ethyl ester;

[0016] Step 4: 8-(2-hydroxybenzamido)octanoate ethyl ester reacts with a strong base in a solvent to produce sodium 8-(2-hydroxybenzamido)octanoate.

[0017] A further improvement is made in step one, where the base used in the reaction is an ethanol solution of sodium ethoxide.

[0018] Further improvements were made in step one, after which purification was carried out: the temperature was first lowered to below 40°C for vacuum filtration, the filter cake was dissolved in an aqueous ethanol solution, the temperature was controlled at 10-20°C and hydrochloric acid was added dropwise to adjust the pH to 3-5, then the temperature was lowered to 0-5°C and kept at that temperature to precipitate crystals, the filter cake was filtered, the filter cake was washed with an aqueous ethanol solution, and the filter cake was dried under vacuum to obtain 2H-benzo[e][1,3]oxazine-2,4(3H)-dione.

[0019] In a further improvement, in step two, the base used in the reaction is potassium carbonate, and the solvent is N,N-dimethylformamide.

[0020] A further improvement is made in step two, after the reaction is completed, purification is carried out: first, the filtrate is filtered, ethyl acetate and water are added to the filtrate for extraction and separation, the organic phase is concentrated, cooled to 10-20℃, n-heptane is added dropwise, and then the temperature is lowered to 0-5℃ and kept warm to precipitate crystals. The filtrate is filtered, the filter cake is washed with n-heptane, and the filter cake is dried to obtain ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate.

[0021] A further improvement is made in step three, where the lithium salt is one of lithium chloride, lithium bromide, lithium iodide, lithium sulfate, lithium carbonate, lithium acetate, lithium nitrate, and lithium phosphate. Preferably, lithium chloride or lithium bromide is used; more preferably, lithium chloride is used.

[0022] A further improvement is made in step three, after the reaction is completed, purification is carried out: first, the mixture is concentrated under reduced pressure, and after the concentration is completed, the temperature is lowered to 20-30℃ for filtration. The filter cake is washed with water and dried to obtain ethyl 8-(2-hydroxybenzamido)octanoate.

[0023] In a further improvement, in step four, the strong base is one or more of sodium hydroxide and potassium hydroxide, the solvent is isopropanol and water, and the reaction temperature is 30-40℃.

[0024] A further improvement is made in step four, after the reaction is completed, purification is carried out: the temperature is first lowered to 0-5℃ for filtration, the filter cake is washed with isopropanol, and the filter cake is dried under vacuum to obtain high-purity sodium 8-(2-hydroxybenzamido)octanoate.

[0025] In a further improvement, in step three, the reflux reaction temperature is 80±2℃, and the solvents are ethanol and water, with a volume ratio of ethanol to water of 2:1.

[0026] The beneficial effects of this invention are:

[0027] 1) First step reaction: replacing ethyl chloroformate or N'N-carbonyldiimidazole with dimethyl carbonate to synthesize compound Int1 not only avoids the use of genotoxic ethyl chloroformate, but also avoids the use of N'N-carbonyldiimidazole, which is difficult to treat wastewater, thus conforming to green chemistry process.

[0028] 2) The third reaction step: Replacing sodium hydroxide with lithium chloride or lithium bromide to open the ring reduces the generation of impurities and improves the purity of the product; it also reduces the production cost and has less harm to humans and the environment, making it suitable for industrial-scale production. Attached Figure Description

[0029] Figure 1 The LC chromatogram of compound Int1 in Example 1;

[0030] Figure 2 MS chromatogram of compound Int1 in Example 1;

[0031] Figure 3 The LC chromatogram of compound Int2 in Example 1;

[0032] Figure 4 MS chromatogram of compound Int2 in Example 1;

[0033] Figure 5 The LC chromatogram of compound Int3 in Example 1;

[0034] Figure 6 MS chromatogram of compound Int3 in Example 1;

[0035] Figure 7 The LC diagram of SNAC in Example 1;

[0036] Figure 8 The image shows the MS plot of the SNAC in Example 1;

[0037] Figure 9 The LC chromatogram of compound Int3 in Example 2;

[0038] Figure 10 This is an LC chromatogram of the product from Example 3.

[0039] Figure 11 This is an LC chromatogram of the product from Example 4. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0041] Example 1

[0042] Step 1: Weigh 20g of salicylamide and 39.4g of dimethyl carbonate into a 500ml three-necked flask and stir mechanically for 30min. Dissolve 12.6g of sodium ethoxide in 200ml of anhydrous ethanol and add it to the 500ml three-necked flask. Heat to reflux and maintain the temperature for 3h. After the reaction is complete, cool to below 40℃ and filter. Dissolve the filter cake in 200ml of 50% ethanol aqueous solution. Adjust the pH to 3-5 by adding 2mol / L dilute hydrochloric acid dropwise while maintaining the temperature at 10-20℃. Then cool to 0-5℃ and maintain the temperature for 2h to allow crystallization. Filter and wash the filter cake with 20ml of 50% ethanol aqueous solution. Dry the filter cake under vacuum at 60℃ for 4h to obtain 20.3g of compound Int1, which is an off-white solid. The yield was 90.3%, the purity was 99.86%, and the molecular weight of 2H-benzo[e][1,3]oxazine-2,4(3H)-dione was 163.13. LC-MS analysis showed the molecular weight to be 162.37. (See attached image.) Figure 1 , 2 It is consistent with the target compound (2H-benzo[e][1,3]oxazine-2,4(3H)-dione).

[0043] Step 2: Weigh 16.3g of 2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 100ml of N,N-dimethylformamide into a 250ml three-necked flask. After dissolving by mechanical stirring, add 26.4g of ethyl 8-bromooctanoate and 16.6g of potassium carbonate. Incubate at 30-35℃ for 4 hours. After the reaction is complete, filter the solution and transfer the filtrate to a 500ml three-necked flask. Then add 100ml of ethyl acetate and 200ml of water for extraction and separation. Concentrate the organic phase to half its volume and cool to 10-20℃. Add 100ml of n-heptane dropwise, then reduce the temperature further. The mixture was kept at 0-5℃ for 2 hours to allow crystals to crystallize. After filtration, the filter cake was washed with 20 ml of n-heptane and dried under vacuum at 80℃ for 5 hours to obtain 30.2 g of compound Int2, a white solid with a yield of 92.16% and a purity of 99.91%. The molecular weight of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate was 333.38, and LC-MS analysis showed a molecular weight of 334.51. (See attached image). Figure 3 , 4 It is consistent with the target compound (ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate).

[0044] Step 3: Weigh 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 5 g of lithium chloride, 200 ml of ethanol, and 100 ml of water into a 500 ml three-necked flask. Stir and heat to reflux, and maintain the reaction temperature for 4 h. After the reaction is complete, concentrate under reduced pressure to remove ethanol. After concentration, cool to 20-30 °C and filter. Wash the filter cake with 20 ml of water. Dry the filter cake under vacuum at 70 °C for 5 h to obtain 14.1 g of compound Int3, with a yield of 93.7% and a purity of 99.70%. The molecular weight of ethyl 8-(2-hydroxybenzamido)octanoate is 307.38, and the molecular weight measured by LC-MS is 306.56. See [link to LC-MS analysis]. Figure 5 , 6 It is consistent with the target compound (ethyl 8-(2-hydroxybenzamido)octanoate).

[0045] Step 4: Weigh 12.3 g of ethyl 8-(2-hydroxybenzamido)octanoate, 4 g of sodium hydroxide, 200 ml of isopropanol, and 20 ml of water into a 500 ml three-necked flask. Stir and heat to 30-40 °C, maintain the temperature for 5 h. After the reaction, cool to 0-5 °C and filter. Wash the filter cake with 20 ml of isopropanol. Dry the filter cake under vacuum at 50 °C for 5 h to obtain 11.5 g of sodium 8-(2-hydroxybenzamido)octanoate (SNAC). Yield 94.8%, purity 99.66%; the molecular weight of 8-(2-hydroxybenzamido)octanoate is 279.33, and LC-MS analysis showed 278.55, consistent with the target compound. See [link to LC-MS analysis]. Figure 5 , 6 .

[0046] Example 2

[0047] 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 6 g of lithium bromide, 200 ml of ethanol, and 100 ml of water were weighed into a 500 ml three-necked flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the ethanol. After concentration, the mixture was cooled to 20-30 °C and filtered. The filter cake was washed with 20 ml of water and dried under vacuum at 70 °C for 5 h to obtain 14.0 g of compound Int3, with a yield of 93.6% and a purity of 99.63%. Figure 9 As shown.

[0048] Example 3

[0049] 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 11 g of potassium carbonate, 200 ml of ethanol, and 100 ml of water were weighed into a 500 ml three-necked flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 4 h. A sample was taken for HPLC analysis. At 46.8 min, the impurity content was 4.68%. The LC chromatogram is shown below. Figure 10 .

[0050] Example 4

[0051] 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 6 g of sodium hydroxide, 200 ml of ethanol, and 100 ml of water were weighed into a 500 ml three-necked flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 4 h. A sample was taken for HPLC analysis. At 41.4 min, the impurity content was 7.58%. The LC chromatogram is shown below. Figure 11 .

[0052] Example 5

[0053] 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 6 g of sodium chloride, 200 ml of ethanol, and 100 ml of water were weighed into a 500 ml three-necked flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 4 h. Samples were taken for testing. Conclusion: Ring-opening failed, and the reaction could not proceed.

[0054] Example 6

[0055] 16.67 g of ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate, 6 g of potassium chloride, 200 ml of ethanol, and 100 ml of water were weighed into a 500 ml three-necked flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 4 h. Samples were taken for testing. Conclusion: Ring-opening failed, and the reaction could not proceed.

[0056] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate, characterized in that, Includes the following steps: Step 1: Salicylic acid amide and dimethyl carbonate react under the action of alkali to generate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione; Step 2: 2H-benzo[e][1,3]oxazine-2,4(3H)-dione, ethyl 8-bromooctanoate, and base in a solvent react to generate ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate; Step 3: 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate ethyl ester and lithium salt are reacted in a solvent to generate 8-(2-hydroxybenzamido)octanoate ethyl ester; Step 4: 8-(2-hydroxybenzamido)octanoate ethyl ester reacts with a strong base in a solvent to produce sodium 8-(2-hydroxybenzamido)octanoate; In step three, the lithium salt is one of lithium chloride, lithium bromide, lithium iodide, lithium sulfate, lithium carbonate, lithium acetate, lithium nitrate, and lithium phosphate.

2. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step one, the base used in the reaction is an ethanol solution of sodium ethoxide.

3. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step one, after the reaction is completed, the temperature is lowered to below 40°C for filtration. The filter cake is dissolved in an ethanol-water solution. The temperature is controlled at 10-20°C and hydrochloric acid is added dropwise to adjust the pH to 3-5. Then the temperature is lowered to 0-5°C and kept at that temperature to allow crystallization. The filter cake is then filtered, washed with an ethanol-water solution, and dried under vacuum to obtain 2H-benzo[e][1,3]oxazine-2,4(3H)-dione.

4. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step two, the base used in the reaction is potassium carbonate, and the solvent is N,N-dimethylformamide.

5. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step two, after the reaction is complete, the mixture is filtered, and the filtrate is extracted with ethyl acetate and water. The organic phase is concentrated, cooled to 10-20℃, and n-heptane is added dropwise. Then, the mixture is cooled to 0-5℃ and kept at this temperature to allow crystallization. The mixture is filtered, and the filter cake is washed with n-heptane. After drying, the filter cake yields ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazine-3(4H)-yl]octanoate.

6. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step three, after the reaction is completed, the mixture is concentrated under reduced pressure. After concentration, the temperature is lowered to 20-30℃ for filtration. The filter cake is washed with water and dried to obtain ethyl 8-(2-hydroxybenzamido)octanoate.

7. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step four, the strong base is one or more of sodium hydroxide and potassium hydroxide, and the solvent is isopropanol and water; the reaction temperature is 30-40℃.

8. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step four, after the reaction is completed, the temperature is lowered to 0-5℃ for filtration. The filter cake is washed with isopropanol and then dried under vacuum to obtain high-purity sodium 8-(2-hydroxybenzamide)octanoate.

9. The method for preparing high-purity sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that: In step three, the reaction temperature is 80±2℃; the solvents are ethanol and water, with a volume ratio of ethanol to water of 2:1.

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