CN105348184B - Preparation method of sulfasalazine - Google Patents
Preparation method of sulfasalazine Download PDFInfo
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- CN105348184B CN105348184B CN201510834849.3A CN201510834849A CN105348184B CN 105348184 B CN105348184 B CN 105348184B CN 201510834849 A CN201510834849 A CN 201510834849A CN 105348184 B CN105348184 B CN 105348184B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses a preparation method of sulfasalazine. The preparation method comprises the following steps of firstly, carrying out diazotization reaction on sulfapyridine in an aqueous solution dissolved with hydrochloric acid and sodium nitrite to obtain diazonium salt; secondly, performing coupling reaction on the diazonium salt and salicylic acid in a sodium hydroxide aqueous solution to obtain a crude product of sulfasalazine; and thirdly, purifying the crude sulfasalazine. According to the preparation method, sulfapyridine is used as an initial raw material, and diazotization reaction, coupling reaction and purification are sequentially carried out from beginning to end to obtain sulfapyridine. The diazotization reaction-coupling reaction has higher conversion rate and less side reactions, thereby improving the purity of the product and ensuring the yield. In addition, the sulfapyridine is easily available in source, the production cost is reduced, and the method has a large industrial production value.
Description
Technical Field
The invention relates to the technical field of sulfasalazine, in particular to a synthetic method of sulfasalazine.
Background
Sulfasalazine (SASP), also known as 5- [ p- (2-pyridinamidosulfonyl) benzene]Azo salicylic acid. Molecular formula C18H14N4O5S, molecular weight: 398.39. the molecular structural formula is as follows:
SASP is mainly used for treating nonspecific ulcerative colitis, has special affinity to connective tissues, has therapeutic effect by releasing sulfapyridine and 5-aminosalicylic acid from intestinal wall, and can be used for treating rheumatic arthritis. Despite the fact that this product is an old product, the market demand is still great, especially the quality requirements are increasing.
In the prior art, however, few studies on the preparation method thereof have been disclosed. British patent GB 11296655 discloses a synthetic method of sulfasalazine, which takes 4- (4-acetoxyl-3-carbonyl methoxyphenyl azo) -benzenesulfonyl chloride (compound 5) as a starting material, and condenses with 2-aminopyridine under the action of pyridine to generate a compound 6, and then the compound 6 is hydrolyzed under the action of hydrochloric acid to generate 1, wherein the synthetic route is as follows:
the starting material 4- (4-acetoxyl-3-carbonyl methoxy phenyl azo) -benzenesulfonyl chloride of the method is not commercially available at present, is synthesized by a more difficult method and is less in source; in addition, the process is not satisfactory in terms of yield and purity of the product due to the presence of hydrolysis.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing sulfasalazine, which is easy to obtain raw materials and can obtain a purified product with high purity and yield.
The technical problem to be solved by the invention can be realized by the following technical scheme:
a preparation method of sulfasalazine comprises the following steps:
(1) sulfapyridine is diazotized in water solution with dissolved catalyst hydrochloric acid and diazotization reagent sodium nitrite to obtain diazo salt (A) with the reaction formula as follows,
(2) coupling reaction is carried out on the compound A and salicylic acid in sodium hydroxide aqueous solution to obtain crude sulfasalazine (B)
(3) Adding a mixed solution consisting of dimethyl sulfoxide and water into the crude sulfasalazine (B), and then adding alkali to dissolve the mixed solution to form a first solution; the mass ratio of the crude sulfasalazine, dimethyl sulfoxide and water is 1: 6-9: 2-3; the addition amount of the alkali is such that the pH value of the first solution is 8-10;
(4) adding acid into the first solution obtained in the step (3) to adjust the pH value of the first solution to 1-3, preserving heat, cooling to 0-5 ℃, filtering, and obtaining a first crystal at the temperature of 25-35 ℃;
(5) and (3) adding the crude crystals obtained in the step (5) into water, dissolving the crude crystals under the condition of adding alkali to obtain a second solution with the pH value of 8-10, decoloring the second solution, filtering, adding acid to the pH value of 1-3, separating out second crystals at the temperature of 25-35 ℃, and drying the second crystals to obtain a pure sulfasalazine.
In the step (1), the amounts of the catalyst hydrochloric acid and the diazotizing agent sodium nitrite used are not particularly limited in the present invention. For example, preferably, the mass of the hydrochloric acid is 3 to 5 and the mass of the sodium nitrite is 1.06 to 1.14, based on 1 mass of sulfapyridine. In order to provide the yield of the reaction, the reaction temperature is controlled to be 0-5 ℃. Too high a temperature tends to result in a less stable product diazonium salt. At this temperature, the reaction time is preferably 15 to 30 min. The yield hardly continues to increase over a period of 30 min.
After the diazotization reaction is finished, the reaction solution may not be subjected to a separation operation. The mixed solution obtained by the reaction may be directly added to the reaction in the next step.
In the step (2), the amount of salicylic acid is 1 to 1.5, preferably 1.3, based on 1 amount of sulfapyridine, for the purpose of increasing the total yield. The amount of sodium hydroxide is adjusted according to the water and the reaction pH. Here, the reaction pH is preferably 10 to 11. The temperature of the coupling reaction is preferably 5 to 10 ℃, and the reaction time at the temperature is 1 to 3 hours.
In the step (2), the method also comprises the step of separating a crude sulfasalazine from a reaction product of the coupling reaction; the separation is specifically as follows: and adding an organic solvent into the coupling reaction product liquid, adding an acid to adjust the pH value to acidity, and then cooling to separate out crystals, wherein the crystals are crude sulfasalazine.
The organic solvent is one or more of THF, DMF and acetone.
And adding an acid to adjust the pH value to be 2.5-3.5.
And then cooling to the temperature of 25-35 ℃ for crystal precipitation.
The acid is hydrochloric acid, sulfuric acid or nitric acid.
In the step (3), the temperature for forming the first solution is 60-80 ℃.
In the above steps (3) and (5), the alkali sodium hydroxide or/and potassium hydroxide is used.
In the step (4), the temperature for heat preservation is 60-80 ℃ and the time is 0.5-2 h.
In the steps (4) and (5), the acid is selected from one or a mixture of two or more of nitric acid, hydrochloric acid and sulfuric acid.
In the step (5), the temperature of the decolorization is 65-75 ℃.
In the step (5), the decolorization is performed by activated carbon, and the amount of the activated carbon is 5-10% of the mass of the first crystal.
In the synthesis method, sulfapyridine is used as an initial raw material, and diazotization reaction and coupling reaction are sequentially carried out from first to second to obtain sulfapyridine. The diazotization reaction-coupling reaction has higher conversion rate and less side reactions, thereby improving the purity of the product and ensuring the yield. Meanwhile, a special purification method is adopted, so that the purity and the yield of the product are further improved. In addition, the sulfapyridine is easily available in source, the production cost is reduced, and the method has a large industrial production value.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example 1
Sulfapyridine and hydrochloric acid (the amount of sulfapyridine is 1) with the mass of 3 are put into a reaction bottle and stirred to be dissolved. The temperature is controlled to 0 ℃, and an aqueous solution prepared by sodium nitrite (based on the mass of sulfapyridine is 1) with the mass of 1.14 is started to drop in for reaction for 30min, so as to obtain a solution containing a diazonium salt intermediate, which is named as A.
Salicylic acid and part of sodium hydroxide (based on the amount of sulfapyridine of 1) were placed in a reaction flask in an amount of 1 part by mass. After controlling the temperature to 5 ℃, slowly dropping the A into the reaction bottle, and simultaneously dropping the residual sodium hydroxide solution to control the pH value of the reaction solution to be 10 so as to start the reaction. The amount of the sodium hydroxide is 2 (based on the mass of sulfapyridine as 1). And stopping the reaction after reacting for 3 hours, adding acetone into the reaction mixed solution, adding hydrochloric acid to adjust the pH value to 2.5, and heating and refluxing for a period of time. Then the temperature is reduced to 25 ℃ to separate out crystals. And filtering the crystals to obtain a crude product of the sulfasalazine.
10g of crude sulfasalazine, 40g of dimethyl sulfoxide and 30g of water are placed into a 250ml flask, sodium hydroxide solid is added until the pH value of the mixed solution is 8, and the mixed solution in the flask is heated to 60 ℃ so as to be fully dissolved. After the solution is dissolved, hydrochloric acid is dripped to adjust the pH value of the solution to 1, the solution is kept at 60 ℃ for 2 hours, then the solution is cooled to 0 ℃ and filtered to obtain crude crystals. Then, adding the crude crystals into water, adding sodium hydroxide solid, heating to 60 ℃, dissolving to ensure that the pH value of the solution is 8, decoloring at 65 ℃ by adopting 5g of activated carbon sequentially from beginning to end, filtering, dropwise adding hydrochloric acid until the pH value is 1 to separate out crystals, and drying the crystals to obtain the pure sulfasalazine.
In this example, 9.25g of pure sulfasalazine was collected, the yield was 92.5%, and the purity by HLPC test was 99.3%.
Example 2
Sulfapyridine and hydrochloric acid (the amount of sulfapyridine is 1) with the mass of 5 are put into a reaction bottle and stirred to be dissolved. Controlling the temperature to 5 ℃, starting to drop an aqueous solution prepared from sodium nitrite (based on the mass of sulfapyridine is 1) with the mass of 1.06, and reacting for 15min to obtain a solution containing a diazonium salt intermediate, which is named as A.
Salicylic acid and part of sodium hydroxide (based on the amount of sulfapyridine of 1 mass) were placed in a reaction flask with a mass of 1.5. After the temperature is controlled to 10 ℃, the A is slowly dripped into the reaction bottle, and the residual sodium hydroxide solution is dripped simultaneously to control the pH value of the reaction solution to be 11, so that the reaction is started. The amount of the sodium hydroxide is 6 (based on the mass of sulfapyridine as 1). And stopping the reaction after the reaction is carried out for 1 hour. Adding DMF into the reaction mixture, adding sulfuric acid to adjust the pH value to 3.5, and heating and refluxing for a period of time. Then the temperature is reduced to 30 ℃ to separate out crystals. And filtering the crystals to obtain a crude product of the sulfasalazine.
10g of crude sulfasalazine, 90g of dimethyl sulfoxide and 20g of water are placed into a 250ml flask, sodium hydroxide solid is added until the pH value of the mixed solution is 10, and the mixed solution in the flask is heated to 80 ℃ so as to be fully dissolved. After the solution is dissolved, hydrochloric acid is dripped to adjust the pH value of the solution to 3, the solution is kept at 80 ℃ for 0.5h, then the solution is cooled to 5 ℃, and the crude crystal is obtained after filtration. Then, adding the crude crystals into water, adding sodium hydroxide solid, heating to 80 ℃, dissolving to ensure that the pH value of the solution is 10, sequentially decoloring and filtering at 75 ℃ by adopting 10g of activated carbon, dropwise adding hydrochloric acid until the pH value is 3 to separate out crystals, and drying the crystals to obtain the pure sulfasalazine.
In this example, 9.34g of pure sulfasalazine was collected, the yield was 93.4%, and the purity by HLPC test was 99.5%.
Example 3
Sulfapyridine and hydrochloric acid (the amount of sulfapyridine is 1) with the mass of 4 are put into a reaction bottle and stirred to be dissolved. Controlling the temperature to 5 ℃, starting to drop an aqueous solution prepared from sodium nitrite (based on the mass of sulfapyridine is 1) with the mass of 1.10, and reacting for 30min to obtain a solution containing a diazonium salt intermediate, which is named as A.
Salicylic acid and part of sodium hydroxide (based on the amount of sulfapyridine of 1 mass) were placed in a reaction flask with a mass of 1.25. After controlling the temperature to 7 ℃, slowly dropping the A into the reaction bottle, and simultaneously dropping the residual sodium hydroxide solution to control the pH value of the reaction solution to be 10.5 so as to start the reaction. The amount of the sodium hydroxide is 4 (based on the mass of sulfapyridine as 1). And stopping the reaction after reacting for 3 hours. Adding THF into the reaction mixture, adding nitric acid to adjust the pH value to 3, and heating and refluxing for a period of time. Then the temperature is reduced to 30 ℃ to separate out crystals. And filtering the crystals to obtain a crude product of the sulfasalazine.
10g of crude sulfasalazine, 75g of dimethyl sulfoxide and 25g of water are placed into a 250ml flask, sodium hydroxide solid is added until the pH of the mixed solution is 9, and the mixed solution in the flask is heated to 70 ℃ so as to be fully dissolved. After the solution is dissolved, hydrochloric acid is dripped to adjust the pH value of the solution to 2, the solution is kept at 70 ℃ for 1h, then the solution is cooled to 3 ℃, and crude crystals are obtained after filtration. And then, adding the crude crystals into water, adding sodium hydroxide solid, heating to 70 ℃, dissolving to ensure that the pH value of the solution is 9, decoloring and filtering at 70 ℃ by adopting 7.5g of activated carbon in sequence, dropwise adding hydrochloric acid until the pH value is 2 to separate out crystals, and drying the crystals to obtain the pure sulfasalazine.
In this example, 9.46g of pure sulfasalazine was collected, the yield was 94.6%, and the purity by HLPC test was 99.6%.
Example 4
Sulfapyridine and hydrochloric acid (the amount of sulfapyridine is 1) with the mass of 4 are put into a reaction bottle and stirred to be dissolved. The temperature is controlled to 2 ℃, and an aqueous solution prepared by sodium nitrite (based on the mass of sulfapyridine is 1) with the mass of 1.10 is started to drop in for reaction for 20min, so as to obtain a solution containing a diazonium salt intermediate, which is named as A.
Salicylic acid and part of sodium hydroxide (based on the amount of sulfapyridine of 1 mass) were placed in a reaction flask with a mass of 1.3. After controlling the temperature to 7 ℃, slowly dropping the A into the reaction bottle, and simultaneously dropping the residual sodium hydroxide solution to control the pH value of the reaction solution to be 10 so as to start the reaction. The amount of the sodium hydroxide is 4 (based on the mass of sulfapyridine as 1). And stopping the reaction after the reaction is carried out for 1.5 hours. Adding THF into the reaction mixture, adding hydrochloric acid to adjust the pH value to 3, and heating and refluxing for a period of time. Then the temperature is reduced to 30 ℃ to separate out crystals. And filtering the crystals to obtain a crude product of the sulfasalazine.
10g of crude sulfasalazine, 70g of dimethyl sulfoxide and 30g of water are placed into a 250ml flask, sodium hydroxide solid is added until the pH of the mixed solution is 9, and the mixed solution in the flask is heated to 80 ℃ so as to be fully dissolved. After the solution is dissolved, hydrochloric acid is dripped to adjust the pH value of the solution to 1, the solution is kept at 80 ℃ for 2 hours, then the solution is cooled to 0 ℃ and filtered to obtain crude crystals. And then, adding the crude crystals into water, adding sodium hydroxide solid, heating to 80 ℃, dissolving to ensure that the pH value of the solution is 9, then sequentially decoloring and filtering at 70 ℃ by adopting 7g of activated carbon, dropwise adding hydrochloric acid until the pH value is 1, precipitating crystals, and drying the crystals to obtain the pure sulfasalazine.
In this example, 9.54g of pure sulfasalazine was collected, the yield was 95.4%, and the purity by HLPC test was 99.7%.
Since the numerical ranges of the various process parameters involved in the present invention are not necessarily all represented in the above examples, one skilled in the art can fully envision that the present invention can be practiced with any number falling within the above numerical ranges, including any combination of specific values within the numerical ranges. Here, for the sake of brevity, the embodiment giving specific values in a certain numerical range or ranges is omitted, and this should not be construed as an insufficient disclosure of the technical solution of the present invention.
The applicant states that the present invention is illustrated by the above examples to show the detailed process equipment and process flow of the present invention, but the present invention is not limited to the above detailed process equipment and process flow, i.e. it does not mean that the present invention must rely on the above detailed process equipment and process flow to be implemented. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (1)
1. A preparation method of sulfapyridine is characterized in that sulfapyridine and hydrochloric acid with the mass of 1 of sulfapyridine and the mass of 4 are put into a reaction bottle, stirred to be dissolved, the temperature is controlled to 2 ℃, aqueous solution prepared by sodium nitrite with the mass of 1.10 of sulfapyridine and the mass of 1 of sulfapyridine is started to be dropped, and the aqueous solution is reacted for 20min to obtain solution containing diazonium salt intermediate, which is named as A; adding salicylic acid with the mass of 1.3 and sodium hydroxide with the mass of sulfapyridine of 1 into a reaction bottle, slowly dropping the A into the reaction bottle after controlling the temperature to 7 ℃, simultaneously dropping the residual sodium hydroxide solution to control the pH value of the reaction solution to be 10, starting the reaction, and stopping the reaction after the sodium hydroxide with the mass of sulfapyridine of 1 to 4 reacts for 1.5 hours; adding THF into the reaction mixed solution, adding hydrochloric acid to adjust the pH value to 3, and heating and refluxing for a period of time; then cooling to 30 ℃ to precipitate crystals; filtering the crystal to obtain a crude product of sulfasalazine;
putting 10g of crude sulfasalazine, 70g of dimethyl sulfoxide and 30g of water into a 250ml flask, adding sodium hydroxide solid until the pH value of the mixed solution is 9, and heating to ensure that the mixed solution in the flask is heated to 80 ℃ so as to be fully dissolved; after the solution is dissolved, dropwise adding hydrochloric acid to adjust the pH value of the solution to 1, preserving the temperature at 80 ℃ for 2 hours, then cooling to 0 ℃, and filtering to obtain a crude crystal; then, adding the crude crystals into water, adding sodium hydroxide solid, heating to 80 ℃, dissolving to ensure that the pH value of the solution is 9, then sequentially decoloring and filtering at 70 ℃ by adopting 7g of activated carbon, dropwise adding hydrochloric acid until the pH value is 1 to precipitate crystals, drying the crystals to obtain a pure sulfasalazine product, and collecting 9.54g of the pure sulfasalazine product, wherein the yield is 95.4%, and the purity is 99.7% by HLPC test.
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| CN108218769A (en) * | 2018-02-27 | 2018-06-29 | 苏州逸纪杰电子科技有限公司 | A kind of preparation method of sulfasalazine |
| CN110818625A (en) * | 2019-12-09 | 2020-02-21 | 苏州黄河制药有限公司 | Preparation method of sulfasalazine |
| CN111303022A (en) * | 2020-04-02 | 2020-06-19 | 杨玉成 | Preparation method of sulfasalazine |
| CN115010660A (en) * | 2022-07-15 | 2022-09-06 | 天和药业股份有限公司 | Preparation method of sulfasalazine |
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