Synthesis method of saborubsa sodium intermediate

Abstract

According to the synthesis method of the saboxada sodium intermediate provided by the invention, the sulfur-containing amino acid or the derivative thereof is added in the reaction, so that the generation of color body impurities can be inhibited, and the qualified saboxada sodium intermediate is prepared. The method is of great significance in improving the quality of the sabolixabate sodium raw material medicine and related preparations and the medication safety.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for synthesizing a sodium sapolisar intermediate. Background Art

[0002] The chemical name of saprolidone sodium is sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate, referred to as SNAC, which is a highly effective penetration enhancer used in the pharmaceutical field. The structural formula of saprolidone sodium is as follows:

[0003]

[0004] N-(8-[2-hydroxybenzoyl]-amino) caprylic acid is a key intermediate for preparing sodium saprolidone (referred to as intermediate A), and can be used to prepare sodium saprolidone by reacting with sodium hydroxide solution.

[0005] Intermediate A is usually prepared by the following method: 2,4-dioxo-1,3-benzoxazinyloctanoic acid ethyl ester (referred to as compound B) is hydrolyzed in a sodium hydroxide aqueous solution and then acidified to obtain the intermediate.

[0006]

[0007] Actual research has found that when ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate is hydrolyzed with sodium hydroxide aqueous solution, a trace amount of pink colored impurities will be produced. This colored impurity cannot be removed by activated carbon adsorption, and it cannot be effectively removed in the subsequent salt-forming reaction, which seriously affects the properties of sodium sapolis. This colored impurity is a trace substance, and the content in the sample is less than one ten-thousandth, but it still affects the color of the sample. Because of its extremely low content, it is difficult to separate by conventional means and its structure is unknown.

[0008] Patent CN101506147B discloses a method for avoiding or reducing the generation of colored impurities when hydrolyzing 2,4-dioxo-1,3-benzoxazinyl octanoate to synthesize N-(8-[2-hydroxybenzoyl]-amino) octanoic acid. One method is to prepare N-(8-[2-hydroxybenzoyl]-amino) octanoic acid by mixing 2,4-dioxo-1,3-benzoxazinyl octanoate with sodium hydroxide, water and one selected from ethylenediaminetetraacetic acid (EDTA), ascorbic acid, NaHSO3 and triphenylphosphine; another method is to prepare N-(8-[2-hydroxybenzoyl]-amino) octanoic acid by mixing 2,4-dioxo-1,3-benzoxazinyl octanoate with sodium hydroxide and pre-boiled water.

[0009] The inventor of the present invention has found that the above-mentioned prior art methods can only inhibit the generation of colored impurities to a certain extent, and the effect is unstable. The use of ethylenediaminetetraacetic acid and triphenylphosphine has no obvious inhibitory effect on the generation of colored impurities. After ascorbic acid is added, pink appears during the reaction process, and then the color gradually changes to light yellow with the reaction time. The final product is yellow, which shows that the generation of colored impurities cannot be completely avoided. Sodium bisulfite has an obvious effect on inhibiting the generation of colored impurities, but its dosage is large. Due to its low toxicity, according to GB 2760-2014, its maximum addition amount in wine and fruit wine shall not be greater than 30mg / kg. The use of a large amount of sodium bisulfite is easy to cause sulfite residues, resulting in certain drug safety risks, and is not suitable for use. The second pre-boiling method is adopted, which will make the production process complicated in workshop production, increase production costs and energy consumption, and do not meet the green and economic production concept. Summary of the invention

[0010] The object of the present invention is to provide a new method for synthesizing pure sapolisar sodium intermediate A and inhibiting the generation of colored impurities. The method has simple process and high safety.

[0011] A method for synthesizing a sodium sapolisar intermediate A comprises the following steps: mixing a compound B with a sulfur-containing amino acid or a derivative thereof, adding a base to carry out a hydrolysis reaction, and obtaining an intermediate A. The base is generally a strong base, such as sodium hydroxide.

[0012]

[0013] This study found that the use of sulfur-containing amino acids or their derivatives can effectively inhibit the generation of colored impurities.

[0014] Furthermore, the sulfur-containing amino acid or its derivative is an amino acid or its derivative containing a carbon-sulfur bond.

[0015] Further, the molar ratio of the sulfur-containing amino acid or its derivative to compound B is not less than 0.01%. Further, the molar ratio of the sulfur-containing amino acid or its derivative to compound B is 0.01% to 1%.

[0016] Furthermore, the sulfur-containing amino acid or its derivative is selected from one or more of cysteine ​​or cysteine ​​derivatives and salts thereof, methionine and salts thereof. The cysteine ​​derivative can be acetylcysteine, cysteine ​​esters, such as cysteine ​​methyl ester, cysteine ​​ethyl ester, etc.

[0017] The sulfur-containing amino acid or its derivative has high biological safety, is suitable for the synthesis of drug intermediates, and has a wide source, low price, and is easy to obtain.

[0018] Furthermore, the sulfur-containing amino acid or its derivative is preferably an amino acid or its derivative with a thiol group.

[0019] Cysteine, acetylcysteine, and cysteine ​​methyl ester are all amino acids or amino acid derivatives with sulfhydryl groups, which are easily soluble in water under acidic conditions. The residue can be removed by washing with water, and no potential harm will be caused to the pharmaceutical application of the product. The reaction environment of the synthesis method of the present invention does not need to be deoxygenated. In actual operation, nitrogen protection is not required, the equipment requirements are not high, and the process is simple and economical. The reaction solvent does not need to be deoxygenated, and purified water can be selected, and operations such as deoxygenation or boiling are not required, which is conducive to energy saving.

[0020] Furthermore, the molar ratio of the compound B to sodium hydroxide is 1:2-10.

[0021] Furthermore, after the hydrolysis reaction is completed, dilute hydrochloric acid is added to adjust the pH value to 1-3, and the mixture is filtered, and the filter cake is rinsed with a solvent and dried to obtain a white to off-white solid, which is the intermediate A. Preferably, the solvent is water.

[0022] Beneficial effects of the present invention:

[0023] 1. The synthesis method of the sodium saprolidone intermediate A of the present invention comprises adding a sulfur-containing amino acid when compound B reacts with sodium hydroxide, which can effectively inhibit the generation of colored impurities during the reaction process. The process of the present invention is simple and does not require nitrogen protection, process water deoxygenation and other operations. The sulfur-containing amino acid or its derivative is cheap and easy to obtain, and has high biological safety.

[0024] 2. The intermediate A prepared by the synthesis method of the present invention is used to prepare sapolisan sodium to obtain pure, white sapolisan sodium. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The left side is the reaction liquid of comparative example 1, and the right side is the reaction liquid of embodiment 1.

[0026] Figure 2 The following are photos of the reaction solutions of Example 2 and Comparative Example 1, wherein the left side is the reaction solution of Comparative Example 1, and the right side is the reaction solution of Example 2.

[0027] Figure 3 The following are photos of the reaction solutions of Example 5 and Comparative Example 1, wherein the left side is the reaction solution of Comparative Example 1, and the right side is the reaction solution of Example 5. DETAILED DESCRIPTION

[0028] The present application is further described in detail below through specific examples. The following examples are only used to further illustrate the present application and should not be construed as limiting the present application.

[0029] The reagents and raw materials used in the present invention are all commercially available.

[0030] The specific embodiments and comparative examples of the present invention are as follows:

[0031] In the synthesis method of the sodium sapolisar intermediate A of the present invention, the amount of materials used is measured in molar equivalent.

[0032] Table 1 Reaction conditions of the examples

[0033]

[0034] Table 2 Reaction conditions of comparative examples

[0035]

[0036] Example 1

[0037] Add 5.0g (15.0mmol, 1.0eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 0.25mg (0.0015mmol, 0.01%eq) cysteine ​​hydrochloride, and 24.0g (60.0mmol, 4.0eq) 10% sodium hydroxide solution into a 250mL three-necked flask and reflux for 3-4h. Take a photo of the reaction solution and record it as follows: Figure 1 After the reaction is completed, the temperature is lowered to 20-30°C, 3M dilute hydrochloric acid is carefully added dropwise while stirring to adjust the pH value to 1-3, stirred for 0.5-1h and then filtered, the filter cake is washed with 2×200mL purified water, and the filter cake is dried at 55-60°C for 12-16h to obtain 4.0g of off-white solid, with a yield of 95%.

[0038] Example 2

[0039] Add 5.0g (15.0mmol, 1.0eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 2.6mg (0.015mmol, 0.1%eq) cysteine ​​hydrochloride, and 24.0g (60.0mmol, 4.0eq) 10% sodium hydroxide solution into a 250mL three-necked flask and reflux for 3-4h. Take a photo of the reaction solution and record it as follows: Figure 2 After the reaction is completed, the temperature is lowered to 20-30°C, 3M dilute hydrochloric acid is carefully added dropwise under stirring to adjust the pH to 1-3, stirred for 0.5-1h and then filtered, the filter cake is washed with 2×200mL purified water, and the filter cake is dried at 55-60°C for 12-16h to obtain 4.0g of off-white solid, with a yield of 95%.

[0040] Example 3

[0041] 5.0 g (15.0 mmol, 1.0 eq) of ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 25 mg (0.15 mmol, 1.0% eq) of cysteine ​​hydrochloride, and 24.0 g (60.0 mmol, 4.0 eq) of 10% sodium hydroxide solution were added to a 250 mL three-necked flask and refluxed for 3 to 4 hours. After the reaction was completed, the temperature was lowered to 20 to 30°C, and 3 M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1 to 3. After stirring for 0.5 to 1 hour, the mixture was filtered and washed with 2 × 200 mL of purified water. The filter cake was dried at 55 to 60°C with air blast for 12 to 16 hours to obtain 4.0 g of off-white solid with a yield of 95%.

[0042] Example 4

[0043] 5.0 g (15.0 mmol, 1.0 eq) of ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 0.25 mg (0.0015 mmol, 0.01% eq) of acetylcysteine, and 24.0 g (60.0 mmol, 4.0 eq) of 10% sodium hydroxide solution were added to a 250 mL three-necked flask and refluxed for 3 to 4 hours. After the reaction was completed, the temperature was lowered to 20 to 30°C, and 3M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1 to 3. After stirring for 0.5 to 1 hour, the mixture was filtered and washed with 2×200 mL of purified water. The filter cake was dried at 55 to 60°C with air blast for 12 to 16 hours to obtain 4.0 g of off-white solid with a yield of 95%.

[0044] Example 5

[0045] Add 5.0g (15.0mmol, 1.0eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 2.5mg (0.015mmol, 0.1%eq) acetylcysteine, and 24.0g (60.0mmol, 4.0eq) 10% sodium hydroxide solution to a 250mL three-necked flask and reflux for 3-4h. Take a photo of the reaction solution and record it as follows: Figure 3 After the reaction is completed, the temperature is lowered to 20-30°C, 3M dilute hydrochloric acid is carefully added dropwise under stirring to adjust the pH to 1-3, stirred for 0.5-1h and then filtered, the filter cake is washed with 2×200mL purified water, and the filter cake is dried at 55-60°C for 12-16h to obtain 4.0g of off-white solid, with a yield of 95%.

[0046] Example 6

[0047] 5.0 g (15.0 mmol, 1.0 eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 2.3 mg (0.015 mmol, 0.1% eq) methionine, and 24.0 g (60.0 mmol, 4.0 eq) 10% sodium hydroxide solution were added to a 250 mL three-necked flask and refluxed for 3 to 4 hours. After the reaction was completed, the temperature was lowered to 20 to 30°C, and 3M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1 to 3. After stirring for 0.5 to 1 hour, the mixture was filtered and washed with 2×200 mL purified water. The filter cake was dried at 55 to 60°C with air blast for 12 to 16 hours to obtain 4.0 g of off-white solid with a yield of 95%.

[0048] Example 7

[0049] 5.0 g (15.0 mmol, 1.0 eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 22.4 mg (0.15 mmol, 1.0% eq) methionine, and 24.0 g (60.0 mmol, 4.0 eq) 10% sodium hydroxide solution were added to a 250 mL three-necked flask and refluxed for 3 to 4 hours. After the reaction was completed, the temperature was lowered to 20 to 30°C, and 3M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1 to 3. After stirring for 0.5 to 1 hour, the mixture was filtered and washed with 2×200 mL purified water. The filter cake was dried at 55 to 60°C with air blast for 12 to 16 hours to obtain 4.0 g of off-white solid with a yield of 95%.

[0050] Comparative Example 1

[0051] Add 5.0 g (15.0 mmol, 1.0 eq) of ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate and 24.0 g (60.0 mmol, 4.0 eq) of 10% sodium hydroxide solution into a 250 mL three-necked flask and reflux for 3 to 4 hours. Take a photo of the reaction solution and record it as follows: Figure 1 After the reaction is completed, the temperature is lowered to 20-30°C, 3M dilute hydrochloric acid is carefully added dropwise under stirring to adjust the pH to 1-3, stirred for 0.5-1h and then filtered, the filter cake is washed with 2×200mL purified water, and the filter cake is dried at 55-60°C for 12-16h to obtain 4.0g of pink solid, with a yield of 95%.

[0052] Comparative Example 2

[0053] Add 5.0g (15.0mmol, 1.0eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 5.0mg (0.015mmol, 0.1%eq) disodium ethylenediaminetetraacetate, and 24.0g (60.0mmol, 4.0eq) 10% sodium hydroxide solution into a 250mL three-necked flask and reflux for 3-4h. After the reaction is complete, cool to 20-30°C, carefully add 3M dilute hydrochloric acid dropwise while stirring to adjust the pH to 1-3, stir for 0.5-1h, filter by suction, wash the filter cake with 2×200mL purified water, and dry the filter cake at 55-60°C with air for 12-16h to obtain 4.0g light pink solid with a yield of 95%.

[0054] Comparative Example 3

[0055] 5.0g (15.0mmol, 1.0eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 26.4mg (0.15mmol, 1.0%eq) ascorbic acid, 24.0g (60.0mmol, 4.0eq) 10% sodium hydroxide solution were added to a 250mL three-necked flask and refluxed for 3-4h. After the reaction was completed, the temperature was lowered to 20-30°C, and 3M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1-3. After stirring for 0.5-1h, the filter cake was filtered and washed with 2×200mL purified water. The filter cake was dried at 55-60°C with air blast for 12-16h to obtain 4.0g of light yellow solid with a yield of 95%.

[0056] Comparative Example 4

[0057] 5.0 g (15.0 mmol, 1.0 eq) ethyl 2,4-dioxo-1,3-benzoxazinyloctanoate, 3.9 mg (0.015 mmol, 0.1% eq) triphenylphosphine, and 24.0 g (60.0 mmol, 4.0 eq) 10% sodium hydroxide solution were added to a 250 mL three-necked flask and refluxed for 3 to 4 hours. After the reaction was completed, the temperature was lowered to 20 to 30°C, and 3M dilute hydrochloric acid was carefully added dropwise under stirring to adjust the pH to 1 to 3. After stirring for 0.5 to 1 hour, the mixture was filtered and washed with 2×200 mL purified water. The filter cake was dried at 55 to 60°C with air for 12 to 16 hours to obtain 4.0 g of a pink solid with a yield of 95%.

[0058] Experimental Example 1

[0059] The properties of the intermediate A obtained in the examples and comparative examples were examined. The results are shown below.

[0060] Table 3 Properties of Intermediate A in Examples and Comparative Examples

[0061] sample Product properties Example 1 Off-white solid Example 2 Off-white solid Example 3 Off-white solid Example 4 Off-white solid Example 5 Off-white solid Example 6 Off-white solid Example 7 Off-white solid Comparative Example 1 Pink solid Comparative Example 2 Light pink solid Comparative Example 3 Light yellow solid Comparative Example 4 Pink solid

[0062] The intermediates obtained in Examples 1 to 7 were off-white in color. The intermediates A obtained in Comparative Examples 1, 2, and 4 were pink in color, and the intermediate obtained in Comparative Example 3 was light yellow in color.

[0063] Experimental Example 2

[0064] The reaction solutions of the hydrolysis reactions of the examples and comparative examples were taken for solution stability investigation, and the changes in solution color over time at room temperature were observed.

[0065] Table 4 Stability study data of the reaction solution of the embodiment

[0066]

[0067] Table 5 Stability investigation data of comparative example reaction solution

[0068]

[0069] Experimental Example 3

[0070] 1. Prepare saprolizate sodium using the intermediate A obtained in Example 1. The operation is as follows:

[0071] Add 4.0g of intermediate A (14.39mmol, 1.00eq) and 60ml of isopropanol into a 100ml three-necked flask, stir at 45-50°C until dissolved, pass through a 0.45μm filter element, slowly add sodium hydroxide aqueous solution (587mg of sodium hydroxide (14.68mmol, 1.02eq) dissolved in 2.3g of purified water) to the filtrate while keeping it warm at 45-50°C and stirring, slowly cool to room temperature and stir for 3h, filter with suction, wash the filter cake with a small amount of isopropanol, dry it with air at 45°C for 4h, and then dry it in vacuo at 80°C overnight to obtain the finished product of sodium saprolite.

[0072] Table 6 Yield and properties of sodium sapolis prepared in Example

[0073] Intermediate A Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Yield 92.0％ 92.0％ 92.0％ 92.0％ 92.0％ 92.0％ 92.0％

[0074] Experimental results: The sodium sapolisar prepared by using the intermediate A prepared in the example is off-white and does not require recrystallization.

[0075] 2. Take the intermediate A obtained in the comparative example to prepare sodium sapolis, and the operation is the same as above, but the obtained sodium sapolis has color, comparative examples 1, 2, and 4 are light pink, and comparative example 4 is light yellow. It is necessary to perform recrystallization operation to remove color on the intermediate A. Recrystallization leads to a decrease in product yield, and the yield is shown in Table 7.

[0076] Table 7 Yield and properties of sodium sapolis prepared in comparative example

[0077]

[0078] The above contents are further detailed descriptions of the present application in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present application is limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application, which should be deemed to fall within the scope of protection of the present application.

Claims

1. A method for synthesizing a sodium sapolisar intermediate A, characterized in that: The structure of the intermediate A is shown below: The synthesis method comprises the following steps: Compound B is mixed with a sulfur-containing amino acid or a derivative thereof, and a base is added to cause a hydrolysis reaction to obtain an intermediate A.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the sulfur-containing amino acid or its derivative to compound B is not less than 0.01%.

3. The synthesis method according to claim 2, characterized in that The molar ratio of the sulfur-containing amino acid or its derivative to compound B is 0.01% to 1%.

4. The synthesis method according to any one of claims 1 to 3, characterized in that The sulfur-containing amino acid or its derivative is selected from one or more of cysteine ​​or cysteine ​​derivatives and salts thereof, methionine and salts thereof.

5. The synthesis method according to claim 4, characterized in that The sulfur-containing amino acid or its derivative is selected from one or more of cysteine ​​hydrochloride, acetylcysteine, cysteine ​​methyl ester hydrochloride, and methionine.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The base is a strong base.

7. The synthesis method according to claim 6, characterized in that The strong base is sodium hydroxide, and the molar ratio of the compound B to sodium hydroxide is 1:2-10.

8. The synthesis method according to any one of claims 1 to 7, characterized in that: After the hydrolysis reaction is completed, dilute hydrochloric acid is added to adjust the pH value to 1-3, and the mixture is filtered, and the filter cake is washed with a solvent and dried to obtain a white to off-white solid.

9. The synthesis method according to claim 8, characterized in that The solvent is water.

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