Synthesis method of sulpiride impurity 2-hydroxy-5-sulfanilamide benzamide

Abstract

The invention is suitable for the technical field of fine chemical engineering, and provides a synthesis method of sulpiride impurity 2-hydroxy-5-sulfanilamide benzamide, which comprises the following specific steps: Step 1, taking salicylic acid as a raw material, taking DMF as a catalyst, and carrying out acylation reaction with thionyl chloride to obtain acylation liquid, and entering the next process; 2, ammoniating the acylation liquid with ammonia water at a low temperature to obtain salicylic acid formamide, and drying to obtain an intermediate 1; 3, TMS-Cl is used for protecting phenolic hydroxyl groups, then chlorosulfonic acid is dropwise added, a chlorosulfonation reaction is carried out, and an intermediate 2 solution is obtained after the reaction is completed; and Step 4, dropwise adding the solution of the intermediate 2 into stronger ammonia water for reaction, carrying out suction filtration, and recrystallizing with ethanol to obtain the sulpiride impurity 2-hydroxy-5-sulfanilamide benzamide. The route synthesis is simple, and the quality can reach 95% or above; in addition, the method has the advantages of cheap and easily available raw materials, mild reaction conditions, low energy consumption, simple process structure, easy operation and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of fine chemicals, and specifically to a synthesis method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide. Background Art

[0002] Sulpiride (sulpiride tablets) is an antipsychotic drug mainly used to treat schizophrenia and depression. It blocks central dopamine receptors, reducing the excessive stimulation of the neurotransmitter dopamine on the brain, thereby alleviating psychotic symptoms such as hallucinations and delusions. In addition, sulpiride also has antidepressant effects, improves cognitive function, enhances memory, and increases alertness.

[0003] There is no report on the synthesis of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide in the existing literature. Therefore, the present invention aims to provide a safe and effective synthesis route. Summary of the Invention

[0004] The object of the present invention is to provide a synthesis method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide to solve the problems in the above background art.

[0005] To achieve the above object, the present invention provides the following technical solution: A synthesis method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide, wherein the 2-hydroxy-5-sulfamoylbenzamide is prepared from salicylic acid as a raw material through acylation, ammoniation, chlorosulfonation, and ammoniation reactions. The specific steps are as follows: Step1, using salicylic acid as a raw material, reacting with thionyl chloride with DMF as a catalyst to obtain an acylation solution, and entering the next process; Step2, ammoniating the acylation solution with ammonia water at low temperature to make it salicylamide, and then drying to obtain intermediate 1; Step3, using TMS-Cl to protect the phenolic hydroxyl group and then dropping in chlorosulfonic acid for chlorosulfonation reaction. After the reaction, an intermediate 2 solution is obtained; Step4, dropping the intermediate 2 solution into concentrated ammonia water for reaction, filtering by suction, and recrystallizing with ethanol to obtain sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide.

[0006] Preferably, in Step1, the dosage of thionyl chloride is 1.1 - 1.5 times that of salicylic acid, and the dosage of the catalyst DMF is 0.1 - 0.3 equivalents.

[0007] Preferably, in Step2, the dosage of ammonia water is 6 - 10 times that of the acylation solution, and the ammoniation temperature is 0 - 5°C.

[0008] Preferably, in Step3, the dosage of TMS-Cl is 1.2 - 1.5 times that of intermediate 1.

[0009] Preferably, the temperature of the chlorosulfonation reaction in Step 3 is 10-55 °C, and the reaction time is 3-24 hours.

[0010] Preferably, the temperature of the ammoniation reaction in Step 4 is -10-25 °C, and the reaction time is 3-10 hours.

[0011] Preferably, in the ethanol crystallization step of Step 4, the amount of ethanol is 0.5-5 times the amount of the wet product.

[0012] The present invention has at least the following beneficial effects: (1) A method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide provided by the present invention uses TMS-Cl to protect the hydroxyl group and effectively reduce the influence of the hydroxyl group on the para-group, enabling the sulfonyl chloride group to be able to normally introduce the amide group. If the hydroxyl group is not protected, it is difficult to synthesize sulfonamide from sulfonyl chloride. And TMS is removed by itself due to the ammoniation in ammonia water and does not need to be treated separately; this synthetic route is simple, and the quality can reach more than 95%; (2) A method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide provided by the present invention has the advantages of cheap and easily available raw materials, mild reaction conditions, low energy consumption, simple process structure and easy operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 It is the synthetic route diagram of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0014] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0015] The present invention provides a method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide, and the synthetic route is as Figure 1 shown, and it is carried out in the following steps in sequence: Step 1: Add salicylic acid and a catalyst into a reaction flask, and then add a certain amount of thionyl chloride; the catalyst is DMF, and by molar ratio, salicylic acid:DMF = (40-60:1); the reaction temperature is 65-70 °C; by molar ratio, salicylic acid:thionyl chloride = 1:(1.3-1.5); the sufficient reaction time is 2-3 h.

[0016] Step 2: Keep the temperature at 0-5 °C for insulation after the ammoniation dropwise addition is completed; the insulation time is 20-30 min.

[0017] Step 3: After the salicylamide is protected with TMS and the chlorosulfonation is completed with heat preservation.

[0018] Step 4: Secondary ammoniation at a temperature control of 0 - 5°C. After the dropping is completed, keep the temperature for heat preservation; the heat preservation time is 2 h to obtain a high-purity sulpiride impurity, 2-hydroxy-5-sulfamoylbenzamide.

[0019] Based on the above technical solution of the synthesis method of a sulpiride impurity, a pharmaceutical intermediate of the present invention, the present invention provides the following partial examples:

[0020] Example 1 A synthesis method of a sulpiride impurity, 2-hydroxy-5-sulfamoylbenzamide, includes the following steps: Step 1: Add salicylic acid and a catalyst into a reaction flask, and then add a certain amount of thionyl chloride; the catalyst is DMF. According to the molar ratio, salicylic acid:DMF = 40:1; the reaction temperature is 65°C; according to the molar ratio, salicylic acid:thionyl chloride = 1:1.3; the sufficient reaction time is 2 h.

[0021] Step 2: Keep the temperature at 0°C for ammoniation. After the dropping is completed, keep the temperature for heat preservation; the heat preservation time is 20 min.

[0022] Step 3: After the salicylamide is protected with TMS and the chlorosulfonation is completed with heat preservation.

[0023] Step 4: Secondary ammoniation at a temperature control of 0°C. After the dropping is completed, keep the temperature for heat preservation; the heat preservation time is 2 h to obtain a high-purity sulpiride impurity, 2-hydroxy-5-sulfamoylbenzamide.

[0024] Example 2 A synthesis method of a sulpiride impurity, 2-hydroxy-5-sulfamoylbenzamide, includes the following steps: Step 1: Add salicylic acid and a catalyst into a reaction flask, and then add a certain amount of thionyl chloride; the catalyst is DMF. According to the molar ratio, salicylic acid:DMF = 50:1; the reaction temperature is 67°C; according to the molar ratio, salicylic acid:thionyl chloride = 1:1.4; the sufficient reaction time is 2.5 h.

[0025] Step 2: Keep the temperature at 3°C for ammoniation. After the dropping is completed, keep the temperature for heat preservation; the heat preservation time is 25 min.

[0026] Step 3: After the salicylamide is protected with TMS and the chlorosulfonation is completed with heat preservation.

[0027] Step 4: Secondary ammoniation at a temperature control of 2°C. After the dropping is completed, keep the temperature for heat preservation; the heat preservation time is 2 h to obtain a high-purity sulpiride impurity, 2-hydroxy-5-sulfamoylbenzamide.

[0028] Example 3 A synthetic method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide, comprising the following steps: Step 1: Add salicylic acid and a catalyst into a reaction flask, and then add a certain amount of thionyl chloride; the catalyst is DMF, and by molar ratio, salicylic acid:DMF = 60:1; the reaction temperature is 70 °C; by molar ratio, salicylic acid:thionyl chloride = 1:1.5; the sufficient reaction time is 3 h.

[0029] Step 2: Keep the temperature controlled at 5 °C and keep warm after the ammoniation dropwise addition ends; the heat preservation time is 30 min.

[0030] Step 3: After the TMS protecting group is added to salicylamide, carry out chlorosulfonation and keep warm.

[0031] Step 4: Carry out secondary ammoniation at a temperature controlled at 5 °C, keep warm after the dropwise addition ends; the heat preservation time is 2 h to obtain a high-purity sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide.

[0032] For the technical solution provided by the present invention, prepare 2-hydroxy-5-sulfamoylbenzamide through experiments and then conduct detections, specifically as follows; I. Experimentally prepare 2-hydroxy-5-sulfamoylbenzamide: 1. Preparation of the acylation solution Add 20 g (0.145 mol) of o-hydroxybenzoic acid into a 100 ml flask, simultaneously drop in 3 drops of DMF, and then add 23 g (0.1933 mol) of thionyl chloride. Stir and heat up to reflux at about 65 - 70 °C. After dissolution and clarification, keep warm for 3 h, and then cool down to 20 °C for standby.

[0033] 2. Add 100 g of concentrated ammonia water (18 - 25%) into another reaction flask, slowly dropwise add the above-mentioned material solution at a temperature controlled at 0 - 5 °C. After dropping, keep warm for 30 min and filter to obtain about 22 g of wet product. After drying, obtain 15 g of intermediate 1. LC: 92% - 95%.

[0034] 3. Add 20 g of THF and the above-mentioned dried intermediate 1 into a 250 ml flask. After dissolution, dropwise add 17.8 g of trimethylchlorosilane (TMS-Cl) at a temperature controlled at 10 - 20 °C. After dropping, keep warm and react for 1 h; after the heat preservation ends, drop the obtained reaction solution into 30 g of chlorosulfonic acid under stirring at a temperature controlled at 20 - 40 °C. After adding, heat up to 50 - 55 °C and keep warm for 3 h. After the heat preservation is completed, obtain the reaction solution of intermediate 2, and cool down to 15 - 20 °C for standby.

[0035] Add 250 ml of concentrated ammonia water to a 500 ml reaction flask and cool it to 0 °C. Slowly add the reaction solution of intermediate 2 while controlling the temperature at 0 - 5 °C. After adding, stir for 30 min, then raise the temperature to 20 - 25 °C and keep it warm for 2 h. Filter by suction to obtain about 18 g of wet impure product. After recrystallizing with 3 times the amount of ethanol, about 10 g of wet 2-hydroxy-5-sulfamoylbenzamide can be obtained, and 6 g after drying. LC: 95% - 96%.

[0036] II. Identification of the product: Identification method: Bruker Avance III 400 MHz superconducting nuclear magnetic resonance spectrometer.

[0037] Analysis method: LC (liquid chromatography purity); Shimadzu LC-10AT VP, Shimadzu C-18 chromatographic column, mobile phase: acetonitrile: methanol: aqueous solution of potassium dihydrogen phosphate (6.8 g / L) and sodium octanesulfonate (1 g / L) (adjust the pH value to 3.3 with 10% phosphoric acid) = 10:10:80, detection wavelength 240 nm.

[0038] LC-MS: (m / z) 217 [M + H]; 1H NMR(400MHz,DMSO-d6)δ: 7.21 (d, 1H), 7.26 (d, 1H), 7.68 (s, 1H), 7.93 - 7.98 (s, 2H), 8.31 - 8.35 (s, 2H), 11.20 (s, 1H).

[0039] In summary, the technical solution provided by the present invention uses salicylic acid as the raw material, and reacts with thionyl chloride, TMS-Cl, triethylamine, chlorosulfonic acid, and concentrated ammonia water in the presence of DMF as the catalyst to synthesize the impurity of sulpiride; salicylic acid, DMF, thionyl chloride, and chlorosulfonic acid are all cheap and easily available raw materials, and the reaction can occur almost at room temperature, with low energy consumption. Moreover, the synthesized product is soluble in ethanol and its impurities are easy to separate. The product purity LC is above 95%, and the overall conversion rate of the product is 19.15%.

[0040] The above shows and describes the basic principles, main features and advantages of the present invention. For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and can be implemented in other specific forms without departing from the spirit or basic features of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, it is intended to include all changes falling within the meaning and scope of the equivalent elements of the claims in the present invention.

[0041] Although embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A synthetic method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide, characterized in that, The 2-hydroxy-5-sulfamoylbenzamide is prepared from salicylic acid through acylation, ammoniation, chlorosulfonation, and ammoniation reactions. The specific steps are as follows: Step1: Using salicylic acid as the raw material, carrying out an acylation reaction with thionyl chloride using DMF as the catalyst to obtain an acylated solution, and entering the next process; Step2: Ammoniating the acylated solution with ammonia water at low temperature to make it salicylamide, and then drying to obtain Intermediate 1; Step3: Using TMS-Cl to protect the phenolic hydroxyl group and then dropping in chlorosulfonic acid to carry out a chlorosulfonation reaction. After the reaction, obtain Intermediate 2 solution; Step4: Dropping the Intermediate 2 solution into concentrated ammonia water for reaction, carrying out suction filtration, and recrystallizing with ethanol to prepare sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide.

2. The synthetic method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, wherein: In Step1, the amount of thionyl chloride used is 1.1 - 1.5 times that of salicylic acid, and the amount of catalyst DMF used is 0.1 - 0.3 equivalent.

3. A synthetic method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, characterized in that: In Step2, the amount of ammonia water used is 6 - 10 times that of the acylated solution, and the ammoniation temperature is 0 - 5°C.

4. A method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, characterized in that: In Step3, the amount of TMS-Cl used is 1.2 - 1.5 times that of Intermediate 1.

5. A method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, characterized in that: In Step3, the temperature of the chlorosulfonation reaction is 10 - 55°C, and the reaction time is 3 - 24 hours.

6. A synthetic method of sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, characterized in that: In Step4, the temperature of the ammoniation reaction is -10 - 25°C, and the reaction time is 3 - 10 hours.

7. A method for synthesizing sulpiride impurity 2-hydroxy-5-sulfamoylbenzamide according to claim 1, characterized in that: In the step of ethanol crystallization in Step4, the amount of ethanol is 0.5 - 5 times the amount of the wet product.

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