WO2017197870A1 - 一种氧气氧化合成对羧基苯磺酰胺的方法 - Google Patents

一种氧气氧化合成对羧基苯磺酰胺的方法 Download PDF

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WO2017197870A1
WO2017197870A1 PCT/CN2016/108404 CN2016108404W WO2017197870A1 WO 2017197870 A1 WO2017197870 A1 WO 2017197870A1 CN 2016108404 W CN2016108404 W CN 2016108404W WO 2017197870 A1 WO2017197870 A1 WO 2017197870A1
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oxygen
acetic acid
carboxybenzenesulfonamide
cocatalyst
toluenesulfonamide
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French (fr)
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梁静
杨会会
魏贤勇
宗志敏
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China University of Mining and Technology CUMT
China University of Mining and Technology Beijing CUMTB
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China University of Mining and Technology CUMT
China University of Mining and Technology Beijing CUMTB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom

Definitions

  • the present invention relates to a process for the preparation of p-carboxybenzenesulfonamide, and more particularly to a process for the oxidation of p-carboxybenzenesulfonamide by oxygen oxidation.
  • p-Carboxybenzenesulfonamide (I) is an important pharmaceutical synthetic intermediate for the synthesis of probenecid, harazin, etc., and its sodium salt can also be used as an inhibitor of carbonic anhydrase. Its structural formula is as follows:
  • the p-carboxybenzenesulfonamide is prepared by using p-toluenesulfonamide as a raw material and oxidizing the methyl group to a carboxyl group using an oxidizing agent.
  • the p-methylbenzenesulfonamide aromatic ring contains a strong electron withdrawing group, which is a substrate which is difficult to oxidize. Therefore, its oxidation often uses more than stoichiometric conventional strong oxidizing agents KMnO 4 , Na 2 Cr 2 O 7 , CrO 3 .
  • Li Tao et al. reported the use of cobalt-based pyrazole complexes as catalysts to oxidize toluene with oxygen as an oxidant to prepare benzoic acid, 150 ° C and 1.5 MPa. The reaction was carried out at (150 atm) for 140 minutes, the yield of benzoic acid was up to 75.96%, and the selectivity of benzoic acid was 89.25%.
  • the reaction is carried out under high temperature and high pressure, which is a process of severe energy consumption, and the requirements for equipment are also high; the preparation of the catalyst cobalt-pyrazole complex required for the reaction is cumbersome and costly; the reaction oxidizes the methyl group to the carboxyl group. Further, an intermediate oxidation product such as a methylol group or an aldehyde group is formed, and a product selectivity of a carboxyl group is 89.25%; the reaction condition can oxidize toluene, but when a methyl group is introduced to a strong electron withdrawing sulfonamide group, The base cannot be oxidized to form p-carboxybenzenesulfonamide. In fact, many novel oxidation catalysts can catalyze the oxidation of toluene to benzoic acid, but not the oxidation of p-toluenesulfonamide.
  • the object of the present invention is achieved by using oxygen as an oxidant, oxygen pressure only needs to be maintained at 1 atm, and oxidation by oxygen as an oxidant under the action of a nitroxide type catalyst and a metal salt or a metal oxide promoter.
  • the reaction is carried out in acetic acid; catalytically oxidizing p-toluenesulfonamide to prepare p-carboxybenzenesulfonamide;
  • R 1 and R 2 represent the same group or different groups, and R 1 and R 2 are hydrogen or a C 1 -C 6 alkyl group;
  • the specific process is as follows: in a round bottom flask equipped with a magnetic stirring device, 5 mL of acetic acid, 1 mmol of p-toluenesulfonamide, a catalyst and a cocatalyst are sequentially added, oxygen is introduced, and the pressure is maintained at 1 atm; the amount of the catalyst is used.
  • the molar ratio is 3% to 8% of the amount of p-toluenesulfonamide, and the molar ratio of the cocatalyst is 0.5% to 6% of the amount of p-toluenesulfonamide, and the mixture is stirred at 2 to 12 at 40 to 120 °C.
  • the reaction was stopped, cooled, and acetic acid was distilled off under reduced pressure. The residue was washed successively with water, acetone and dried to give the product p-carboxybenzenesulfonamide.
  • the catalyst used is a free radical catalyst, which is N-hydroxy-2,2,6,6-tetramethylpiperidine, N-hydroxyphthalimide, N-hydroxy sulfonylbenzoyl Amine, N,N-dihydroxystilbenetetramethyleneimide, 1,3,5-trihydroxyisocyanuric acid, N-hydroxy-N-methylbenzamide, 3,5-dinitro-N -hydroxy-N-methylbenzamide or 1-hydroxy-2,2-diphenyl-3-indanone; molar ratio based on p-toluenesulfonamide is only 3% to 8%;
  • the catalyst is cobalt acetate, manganese acetate, copper acetate, iron acetate or manganese dioxide metal salt, the molar ratio based on p-toluenesulfonamide is only 0.5% to 6%, and the conversion ratio of p-toluenesulfonamide is 80.32 ⁇ 99.33%, the yield of the product p-
  • the beneficial effect is that due to the above scheme, the low-cost, environmentally friendly oxygen is used as the oxidant, and the p-toluenesulfonamide is oxidized to the product p-carboxybenzenesulfonamide, the yield is up to 94.05%, and the selectivity is up to 97.65. %, the purity detected by Agilent 1200 high performance liquid chromatography is 92.23 ⁇ 95.35%%, the main product of p-carboxybenzenesulfonamide in the oxidation product, a small amount of 4-hydroxymethylbenzenesulfonamide (II), no 4- Formylbenzenesulfonamide (III) is formed.
  • the oxidant used is oxygen, which not only reduces the cost, but also the by-product after oxidation is water, which is environmentally friendly, and is removed by vacuum distillation after the reaction is completed.
  • Acetic acid and acetic acid can be recycled, and the residue can be separated by washing with water and acetone, thereby separating the product from the catalyst, the cocatalyst and the by-product, and the post-treatment is simple and convenient.
  • the method has mild reaction conditions and is carried out under normal pressure (oxygen pressure maintained at 1 atm) at a medium temperature (40 to 120 ° C), and has high conversion rate and high selectivity, high product purity, and good industrial application prospect.
  • the invention Compared with the traditional oxidation method, the invention has the essential feature that the method uses low-cost oxygen as an oxidant, greatly reduces the cost, and the by-product is water, and has no pollution to the environment; the reaction only needs to maintain oxygen pressure. 1atm can efficiently oxidize p-methylbenzenesulfonamide to p-carboxybenzenesulfonamide, mild conditions, avoid the use of high temperature and high pressure equipment, and reduce energy consumption. It is an ideal green synthesis method for p-carboxybenzenesulfonamide. Industrial application prospects.
  • the reaction is a catalytic oxidation process.
  • the amount of catalyst and cocatalyst is small. Compared with the raw material p-toluenesulfonamide, the amount of catalyst is only 3% to 8%, and the amount of cocatalyst is 0.5% to 6%.
  • the washing of the water and the washing of a small amount of acetone can realize the separation of the catalyst, the cocatalyst, the by-products and the product, and the operation is simple and convenient.
  • the reaction has a relatively high selectivity and conversion rate.
  • the reaction oxidizes the methyl group to a carboxyl group, and only a very small amount of p-toluenesulfonamide is oxidized to 4-hydroxymethylbenzenesulfonamide without 4-formylbenzenesulfonate.
  • the formation of amides Under the optimized conditions, the conversion of p-toluenesulfonamide can reach 99.33%, the yield of p-carboxybenzenesulfonamide can reach 94.05%, and the selectivity can reach 94.68%.
  • the reaction conditions are mild, the reaction is carried out under normal pressure (1 atm) and medium temperature (40 ⁇ 120 ° C), the equipment requirements are simple, avoiding the disadvantages that must be carried out under high temperature and high pressure when using oxygen for oxidation, reducing energy consumption Easy to industrialize and promote applications.
  • the method comprises the steps of: preparing a p-carboxybenzenesulfonamide by catalytic oxidation of p-toluenesulfonamide under the action of a nitroxide type catalyst and a metal salt or a metal oxide cocatalyst, using oxygen as an oxidant:
  • R 1 and R 2 represent the same group or different groups, and R 1 and R 2 are hydrogen or a C 1 -C 6 alkyl group.
  • the catalyst used in the method is a nitrogen oxide radical type catalyst; the promoter is various metal salts and metal oxides, the oxidant is oxygen; and the oxidation reaction uses acetic acid as a solvent at normal pressure (1 atm) and medium temperature (40 to 120 ° C). Under conditions; catalytic oxidation of p-toluenesulfonamide to p-carboxybenzenesulfonamide.
  • the catalyst may be N-hydroxy-2,2,6,6-tetramethylpiperidine, N-hydroxyphthalimide, N-hydroxy sulfonyl benzoimide, N, N. -dihydroxystilbenetetramethyleneimide, 1,3,5-trihydroxyisocyanuric acid, N-hydroxy-N-methylbenzamide, 3,5-dinitro-N-hydroxy-N- Methyl benzamide or 1-hydroxy-2,2-diphenyl-3-fluorenone; the structural formula of the above catalyst is as follows:
  • the metal salt or metal oxide cocatalyst may be cobalt acetate, manganese acetate, copper acetate, iron acetate or manganese dioxide;
  • the reactant used is p-toluenesulfonamide, and the benzene ring containing an electron withdrawing substituent is difficult to undergo oxidation reaction itself; therefore, when the sulfonamide group is substituted with an electron donor group such as a methoxy group or an acetamide group, the oxidation reaction is carried out. More likely to happen.
  • acetic acid, p-toluenesulfonamide, a catalyst and a cocatalyst are sequentially added; the molar ratio of the catalyst is 3% to 8% of the amount of p-toluenesulfonamide, and the cocatalyst
  • the molar ratio is 0.5% to 6%
  • oxygen is supplied, the oxygen pressure is maintained at 1 atm, and the reaction is stopped after stirring for 2 to 12 hours at 40 to 120 ° C.
  • the acetic acid is removed under reduced pressure, and the solvent acetic acid can be repeatedly used, and the residue is used.
  • the residual acetic acid and the cocatalyst were washed repeatedly with water, and the residue was washed with a small amount of acetone to remove the catalyst and a small amount of by-products, and the filter cake was dried to obtain the product p-carboxybenzenesulfonamide.
  • the yield of the product p-carboxybenzenesulfonamide was 70.83 to 94.05%, and the purity was 92.23 to 95.35% by analytical analysis by Agilent 1200 high performance liquid chromatography.
  • the oxidation reaction is highly selective, and only a small amount of p-toluenesulfonamide is oxidized to 4-hydroxymethylbenzenesulfonamide (II), and no 4-formylbenzenesulfonamide (III) is formed.
  • R 1 and R 2 in 4-hydroxymethylbenzenesulfonamide (II) and 4-formylbenzenesulfonamide (III) represent the same group or different groups, and R 1 and R 2 are hydrogen or C 1 -C 6 alkyl.
  • the reactant used in the reaction contains an electron withdrawing group sulfonamide group, which is a substrate which is difficult to be oxidized, and therefore the reaction is equally applicable to the oxidation of other aromatic hydrocarbon side chains containing an electron withdrawing group or an electron donating group.
  • the reaction uses oxygen as the oxidant, but the oxygen is weak when used alone. Therefore, it is the key of the present invention to select a suitable catalytic system to increase the activity of oxygen.
  • the catalyst used in the present invention is a nitroxide-type oxidizing agent N-hydroxy-2,2,6,6-tetramethylpiperidine, N-hydroxyphthalimide, N-hydroxyl-sulfonylbenzophenone Imide, N,N-dihydroxystilbenetetramethyleneimide, 1,3,5-trihydroxyisocyanuric acid, N-hydroxy-N-methylbenzamide, 3,5-dinitro -N-hydroxy-N-methylbenzamide, 1-hydroxy-2,2-diphenyl-3-indolone, etc.
  • the cocatalyst is cobalt acetate, manganese acetate, copper acetate, iron acetate, manganese dioxide Such as a metal salt or a metal oxide; the catalytic system is used in a small amount, and the catalytic efficiency is high.
  • the p-toluenesulfonamide: catalyst: cocatalyst 100:3 to 8:0.5 to 6, the atmospheric pressure (oxygen pressure) can be achieved. Maintaining at 1 atm) oxygen oxidizes p-methylbenzenesulfonamide to p-carboxybenzenesulfonamide, and the conversion of p-toluenesulfonamide is up to 99.33%.
  • the yield of the product p-carboxybenzenesulfonamide is up to 94.05%; and after the reaction is completed, the separation and purification of p-carboxybenzenesulfonamide can be achieved by simple filtration, washing and drying.
  • Example 1 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.06 mmol of N-hydroxy sulfonylbenzamide, 0.03 mmol of manganese dioxide, add 25 mL of reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain The oxygen pressure was 1 atm, and the temperature was raised to 80 ° C for 6 hours. After the reaction was completed, it was cooled to room temperature. The manganese dioxide is filtered off, the acetic acid is removed under reduced pressure, and the acetic acid can be recycled.
  • the residue was washed with water to remove residual acetic acid, washed with a small amount of acetone to remove N-hydroxy sulfonylbenzamide and a small amount of p-hydroxymethylbenzenesulfonamide, and the filter cake was dried to obtain p-carboxybenzenesulfonamide in a yield of 81.86. %, the conversion of p-toluenesulfonamide was 86.32%, the selectivity to p-carboxybenzenesulfonamide was 94.83%, and the purity of the product was 94.20% by Agilent 1200 high performance liquid chromatography.
  • Example 2 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.03 mmol of N,N-dihydroxystilbenetetramethyleneimide, 0.06 mmol of manganese acetate, add 25 mL of reaction flask, add 5 mL of acetic acid, and introduce oxygen. The oxygen pressure was maintained at 1 atm, and the temperature was raised to 120 ° C for 2 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid and co-catalyst manganese acetate, and a small amount of acetone is washed to remove N,N-dihydroxystilbenetetramethyleneimide and a small amount of p-hydroxymethylbenzenesulfonamide, and the filter cake is dried to obtain
  • the yield of p-carboxybenzenesulfonamide was 70.83%
  • the conversion of p-toluenesulfonamide was 80.32%
  • the selectivity to p-carboxybenzenesulfonamide was 88.18%.
  • the purity of the product was analyzed by Agilent 1200 high performance liquid chromatography. It is 92.23%.
  • Example 3 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.08 mmol of N-hydroxyphthalimide, 0.04 mmol of copper acetate, add 25 mL of reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain oxygen pressure. It was 1 atm, and the temperature was raised to 40 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled. The residue is repeatedly washed with water to remove residual acetic acid and cocatalyst copper acetate.
  • Example 4 Weigh 1 mmol of p-carboxybenzenesulfonamide, 0.05 mmol of 3,5-dinitro-N-hydroxy-N-methylbenzamide, 0.05 mmol of iron acetate, add to a 25 mL reaction flask, and add 5 mL of acetic acid. Oxygen was supplied, the oxygen pressure was maintained at 1 atm, and the temperature was raised to 100 ° C for 6 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid and cocatalyst iron acetate, and a small amount of acetone is washed to remove 3,5-dinitro-N-hydroxy-N-methylbenzamide and a small amount of p-hydroxymethylbenzenesulfonamide, filter cake.
  • p-carboxybenzenesulfonamide can be obtained in a yield of 74.25%, the conversion of p-toluenesulfonamide is 82.43%, and the selectivity to p-carboxybenzenesulfonamide is 90.08%.
  • the product is subjected to Agilent 1200 high performance liquid phase. The purity of the chromatographic analysis was 93.12%.
  • Example 5 Weigh 1 m mol of p-carboxybenzenesulfonamide, 1-hydroxy-2,2-diphenyl-3-indanone 0.06 mmol, cobalt acetate 0.005 mmol, add 25 mL reaction flask, add 5 mL of acetic acid, Oxygen was supplied, the oxygen pressure was maintained at 1 atm, and the temperature was raised to 100 ° C for 8 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate, and a small amount of acetone is washed to remove 1-hydroxy-2,2-diphenyl-3-indolone and the like and a small amount of p-hydroxymethylbenzenesulfonamide, and the filter cake is dried.
  • the p-carboxybenzenesulfonamide was obtained in a yield of 73.45%
  • the conversion of p-toluenesulfonamide was 82.12%
  • the selectivity to p-carboxybenzenesulfonamide was 89.44%.
  • the product was analyzed by Agilent 1200 high performance liquid chromatography to detect a purity of 95.20%.
  • Example 6 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.06 mmol of 1,3,5-trihydroxyisocyanuric acid, 0.03 mmol of manganese dioxide, add 25 mL of reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain The oxygen pressure was 1 atm, and the temperature was raised to 90 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature. Filtration removes manganese dioxide, and the filtrate removes acetic acid under reduced pressure, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid, and a small amount of acetone is washed to remove 1,3,5-trihydroxyisocyanuric acid and a small amount of p-hydroxymethylbenzenesulfonamide, and the filter cake is dried to obtain p-carboxybenzenesulfonamide. 90.76%, the conversion of p-toluenesulfonamide was 93.24%, the selectivity to p-carboxybenzenesulfonamide was 97.34%, and the purity of the product was 95.15% by Agilent 1200 high performance liquid chromatography.
  • Example 7 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.06 mmol of N-hydroxy-2,2,6,6-tetramethylpiperidine, 0.03 mmol of manganese dioxide, add to a 25 mL reaction flask, and add 5 mL of acetic acid. Oxygen was supplied, the oxygen pressure was maintained at 1 atm, and the temperature was raised to 100 ° C for 10 hours. The reaction was completed and cooled to room temperature. Manganese dioxide is removed by filtration, and the filtrate is removed under reduced pressure, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid, and a small amount of acetone is washed to remove N-hydroxy-2,2,6,6-tetramethylpiperidine and a small amount of p-hydroxymethylbenzenesulfonamide, and the filter cake is dried to obtain a carboxyl group.
  • the yield of benzenesulfonamide was 72.87%
  • the conversion of p-toluenesulfonamide was 80.88%
  • the selectivity to p-carboxybenzenesulfonamide was 90.10%
  • the purity of the product was 95.35 by Agilent 1200 high performance liquid chromatography. %.
  • Example 8 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.06 mmol of N-hydroxy-N-methylbenzamide, 0.01 mmol of cobalt acetate, add 25 mL of reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain oxygen. The pressure was 1 atm, and the temperature was raised to 100 ° C for 12 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled. The residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate.
  • Example 9 Weigh 1 m mol of p-carboxybenzenesulfonamide, 1-hydroxy-2,2-diphenyl-3-indanone 0.06 mmol, cobalt acetate 0.02 mmol, add 25 mL reaction flask, add 5 mL of acetic acid, Oxygen was supplied, the oxygen pressure was maintained at 1 atm, and the temperature was raised to 100 ° C for 10 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate, and a small amount of acetone is washed to remove 1-hydroxy-2,2-diphenyl-3-indanone and a small amount of p-hydroxymethylbenzenesulfonimide, filter cake.
  • p-carboxybenzenesulfonamide can be obtained in a yield of 84.14%, the conversion of p-toluenesulfonamide is 89.12%, and the selectivity to p-carboxybenzenesulfonamide is 94.41%.
  • the product is subjected to Agilent 1200 high performance liquid phase. The purity of the chromatographic analysis was 95.32%.
  • Example 10 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.05 mmol of N-hydroxy sulfonylbenzamide, 0.02 mmol of cobalt acetate, add to a 25 mL reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain oxygen. The pressure was 1 atm, and the temperature was raised to 80 ° C for 12 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled. The residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate.
  • Example 11 Weigh 1 m mol of p-carboxybenzenesulfonamide, 3,5-dinitro-N-hydroxy-N-methylbenzamide 0.05 mmol, cobalt acetate 0.01 mmol, add 25 mL reaction flask, add acetic acid 5 mL, oxygen was introduced, the oxygen pressure was maintained at 1 atm, and the temperature was raised to 100 ° C for 10 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled.
  • the residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate, and a small amount of acetone is washed to remove 3,5-dinitro-N-hydroxy-N-methylbenzamide and a small amount of p-hydroxymethylbenzenesulfonimide.
  • the filter cake is dried to obtain p-carboxybenzenesulfonamide, the yield is 94.05%, the conversion of p-toluenesulfonamide is 99.33%, and the selectivity to p-carboxybenzenesulfonamide is 94.68%.
  • the product is highly efficient by Agilent 1200. The purity of the liquid chromatograph was 95.14%.
  • Example 12 Weigh 1 m mol of p-carboxybenzenesulfonamide, 0.06 mmol of 1,3,5-trihydroxyisocyanuric acid, 0.02 mmol of cobalt acetate, add to a 25 mL reaction flask, add 5 mL of acetic acid, and pass oxygen to maintain oxygen. The pressure was 1 atm, and the temperature was raised to 100 ° C for 10 hours. The reaction was completed and cooled to room temperature. The filtrate is decompressed to remove acetic acid, and acetic acid can be recycled. The residue is repeatedly washed with water to remove residual acetic acid and cocatalyst cobalt acetate.

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Abstract

一种氧气氧化合成对羧基苯磺酰胺的方法，属于制备对羧基苯磺酰胺的方法。该方法以氧气为氧化剂，氧气压仅需维持在1atm，在氮氧自由基型催化剂及金属盐或金属氧化物助催化剂的作用下，以氧气为氧化剂，氧化反应在乙酸中进行；催化氧化对甲基苯磺酰胺制备对羧基苯磺酰胺；工艺：在装有磁力搅拌装置的圆底烧瓶中，依次加入5mL的乙酸、1mmol的对甲基苯磺酰胺、催化剂和助催化剂，通入氧气，并维持压力为1atm；催化剂的用量摩尔比为对甲基苯磺酰胺用量的3％～8％，助催化剂的用量摩尔比为对甲基苯磺酰胺用量的0.5％～6％，在40～120℃条件下，搅拌2～12小时后停止反应，冷却，减压蒸馏除去乙酸，残渣依次用水洗、丙酮洗涤，干燥得到产物对羧基苯磺酰胺。优点：条件温和，产率高。

Description

一种氧气氧化合成对羧基苯磺酰胺的方法 技术领域
本发明涉及一种制备对羧基苯磺酰胺的方法，特别是一种氧气氧化合成对羧基苯磺酰胺的方法。
背景技术
对羧基苯磺酰胺(I)是重要的医药合成中间体，用于合成丙磺舒、哈拉腙等，其钠盐还可用于碳酸酐酶的抑制剂，其结构式如下所示：
Figure PCTCN2016108404-appb-000001
对羧基苯磺酰胺的制备以对甲基苯磺酰胺为原料，使用氧化剂将甲基氧化为羧基。但对甲基苯磺酰胺芳环上含有强吸电子基团，是较难氧化的底物，因此它的氧化往往使用超过化学计量的传统强氧化剂KMnO4、Na2Cr2O7、CrO3、NaIO4等，这些氧化剂反应后以更低的价态存在于反应体系中,不仅增加了产物分离提纯的难度,而且排放的废液也给环境带来了恶劣的影响，同时还存在腐蚀设备、效率低等弊端，不符合绿色化学的要求。
以往使用氧气做氧化剂氧化芳烃侧链往往需要在高温高压的条件下进行，如李涛等报道了采用钴基吡唑配合物作为催化剂，以氧气为氧化剂催化氧化甲苯制备苯甲酸，150℃和1.5Mpa(150atm)下反应140分钟，苯甲酸的产率最高达75.96％，苯甲酸的选择性达89.25％。该反应在高温高压下进行，是一个严重耗能的过程，对设备要求也较高；反应所需催化剂钴基吡唑配合物制备较为繁琐，成本较高；该反应除了将甲基氧化为羧基，还会生成羟甲基、醛基等中间氧化产物，生成羧基的产物选择性为89.25％；该反应条件能将甲苯氧化，但当甲基对位引入强吸电子基磺酰胺基后，甲基不能被氧化生成对羧基苯磺酰胺，事实上很多新型的氧化催化剂能够催化甲苯氧化为苯甲酸，但是不能催化对甲基苯磺酰胺的氧化。
发明内容
本发明的目的是要提供一种价格低廉、环境友好、温和高效的氧气氧化合成对羧基苯磺酰胺的方法。
本发明的目的是这样实现的：该方法以氧气为氧化剂，氧气压仅需维持在1atm，在氮氧自由基型催化剂及金属盐或金属氧化物助催化剂的作用下，以氧气为氧化剂，氧化反应在乙酸中进行；催化氧化对甲基苯磺酰胺制备对羧基苯磺酰胺；
Figure PCTCN2016108404-appb-000002
R1和R2代表相同基团或不同基团，R1和R2为氢或C1-C6的烷基；
具体工艺过程如下：在装有磁力搅拌装置的圆底烧瓶中，依次加入5mL的乙酸、1mmol的对甲基苯磺酰胺、催化剂和助催化剂，通入氧气，并维持压力为1atm；催化剂的用量摩尔比为对甲基苯磺酰胺用量的3％～8％，助催化剂的用量摩尔比为对甲基苯磺酰胺用量的0.5％～6％，在40～120℃条件下，搅拌2～12小时后停止反应，冷却，减压蒸馏除去乙酸，残渣依次用水洗、丙酮洗涤，干燥得到产物对羧基苯磺酰胺。
所使用的催化剂为自由基型催化剂，为N-羟基-2，2，6，6-四甲基哌啶、N-羟基邻苯二甲酰亚胺、N-羟基邻磺酰苯甲酰亚胺、N,N-二羟基均苯四甲二酰亚胺、1,3,5-三羟基异氰尿酸、N-羟基-N-甲基苯甲酰胺、3,5-二硝基-N-羟基-N-甲基苯甲酰胺或1-羟基-2，2-二苯基-3-吲哚酮；基于对甲基苯磺酰胺摩尔比仅为3％～8％；所使用的助催化剂为乙酸钴、乙酸锰、乙酸铜、乙酸铁或二氧化锰金属盐，基于对甲基苯磺酰胺的摩尔比仅为0.5％～6％，对甲基苯磺酰胺的转化率为80.32～99.33％，产物对羧基苯磺酰胺的产率为70.83～94.05％，选择性最高为97.65％；催化剂和助催化剂反应完毕后均可通过洗涤除去。
有益效果，由于采用了上述方案，使用价格低廉、环境友好的氧气为氧化剂，对甲基苯磺酰胺被氧化为产物对羧基苯磺酰胺，产率最高可达94.05％，选择性最高可达97.65％，通过Agilent 1200型高效液相色谱仪分析检测纯度为92.23～95.35％％，氧化产物中对羧基苯磺酰胺为主产物，有少量4-羟甲基苯磺酰胺(II)，无4-甲酰基苯磺酰胺(III)形成。
Figure PCTCN2016108404-appb-000003
本方法与传统的对甲基苯磺酰胺氧化过程相比，所使用的氧化剂为氧气，不但降低了成本，而且氧化后的副产物为水，对环境无污染，反应完毕后经过减压蒸馏除去乙酸，乙酸可回收利用，残渣依次用水洗、丙酮洗涤，即可实现产物与催化剂和助催化剂、副产物的分离，后处理简单方便。
本方法反应条件温和，在常压(氧气压维持1atm)中温(40～120℃)下进行，且具有高转化率和高选择性，产物纯度高，具有良好的工业应用前景。
本发明与传统的氧化法相比其实质性的特点是：该方法以价格低廉的氧气为氧化剂，极大降低了成本，且副产物为水，对环境无污染；该反应仅需维持氧气压在1atm就可以高效氧化对甲基苯磺酰胺为对羧基苯磺酰胺，条件温和，避免了高温高压设备的使用，降低了能耗，是一种理想的对羧基苯磺酰胺的绿色合成方法，具有工业应用前景。
优点：
1、反应是一个催化氧化过程，催化剂和助催化剂的用量少，相对于原料对甲基苯磺酰胺，催化剂用量仅为3％～8％，助催化剂用量为0.5％～6％，经过简单的水洗、少量丙酮洗涤就可以实现催化剂、助催化剂、副产物和产物的分离，操作简便。
2、不使用传统的强氧化剂，使用氧气为氧化剂，不但极大降低了成本，且副产物为 水，对环境没有危害，是一个环境友好的过程；
3、反应具有相当高的选择性和转化率，反应将甲基氧化为羧基，仅有极少量对甲基苯磺酰胺被氧化为4-羟甲基苯磺酰胺，无4-甲酰基苯磺酰胺的生成。在最优化的条件下，对甲基苯磺酰胺的转化率可达99.33％，对羧基苯磺酰胺的产率可达94.05％，选择性可达94.68％。
4、反应条件温和，反应在常压(1atm)和中温(40～120℃)下进行，对设备要求简单，避免了以往使用氧气进行氧化时必须在高温高压下进行的弊端，降低了能耗，易于工业化推广应用。
具体实施方式
该方法在氮氧自由基型催化剂和金属盐或金属氧化物助催化剂的作用下，以氧气为氧化剂，催化氧化对甲基苯磺酰胺制备对羧基苯磺酰胺：
Figure PCTCN2016108404-appb-000004
R1和R2代表相同基团或不同基团，R1和R2为氢或C1-C6的烷基。
本方法中使用的催化剂为氮氧自由基型催化剂；助催化剂为各种金属盐和金属氧化物，氧化剂为氧气；氧化反应以乙酸为溶剂在常压(1atm)和中温(40～120℃)条件下进行；催化氧化对甲基苯磺酰胺氧化为对羧基苯磺酰胺。
所述的催化剂可以是N-羟基-2，2，6，6-四甲基哌啶、N-羟基邻苯二甲酰亚胺、N-羟基邻磺酰苯甲酰亚胺、N,N-二羟基均苯四甲二酰亚胺、1,3,5-三羟基异氰尿酸、N-羟基-N-甲基苯甲酰胺、3,5-二硝基-N-羟基-N-甲基苯甲酰胺或1-羟基-2，2-二苯基-3-吲哚酮；上述催化剂的结构式如下：
Figure PCTCN2016108404-appb-000005
Figure PCTCN2016108404-appb-000006
所述的金属盐或金属氧化物助催化剂可以是乙酸钴、乙酸锰、乙酸铜、乙酸铁或二氧化锰；
所使用的反应物为对甲基苯磺酰胺，含有吸电子取代基的苯环，本身难于发生氧化反应；因此当磺酰胺基置换为甲氧基、乙酰胺基等给电子基时，氧化反应更易发生。
具体工艺过程如下：
在装有磁力搅拌装置的圆底烧瓶中，依次加入乙酸、对甲基苯磺酰胺、催化剂、助催化剂；催化剂的用量摩尔比为对甲基苯磺酰胺用量的3％～8％，助催化剂的用量摩尔比为0.5％～6％，通入氧气，维持氧气压为1atm，在40～120℃条件下，搅拌2～12小时后停止反应，减压除去乙酸，溶剂乙酸可反复使用，残渣用水反复洗涤除残余乙酸和助催化剂，残渣再用少量丙酮洗涤除去催化剂及少量副产物，滤饼干燥后即得产物对羧基苯磺酰胺。
产物对羧基苯磺酰胺的产率为70.83～94.05％，通过Agilent 1200型高效液相色谱仪分析检测纯度为92.23～95.35％％。该氧化反应选择性高，仅有少量对甲基苯磺酰胺被氧化为4-羟甲基苯磺酰胺(II)，并无4-甲酰基苯磺酰胺(III)的生成。
Figure PCTCN2016108404-appb-000007
4-羟甲基苯磺酰胺(II)和4-甲酰基苯磺酰胺(III)中的R1和R2代表相同基团或不同基团，R1和R2为氢或C1-C6的烷基。
该反应所使用的反应物含有吸电子基团磺酰胺基，是较难被氧化的底物，因此该反应同样适用于其他含有吸电子基团或给电子基团的芳烃侧链的氧化。
该反应采用氧气为氧化剂，但氧气单独使用时氧化能力较弱，因此选择合适的催化体系提高氧气的活性是本发明的关键。本发明所使用的催化剂为氮氧自由基型氧化剂N-羟基-2，2，6，6-四甲基哌啶、N-羟基邻苯二甲酰亚胺、N-羟基邻磺酰苯甲酰亚胺、N,N-二羟基均苯四甲二酰亚胺、1,3,5-三羟基异氰尿酸、N-羟基-N-甲基苯甲酰胺、3,5-二硝基-N-羟基-N-甲基苯甲酰胺、1-羟基-2,2-二苯基-3-吲哚酮等，助催化剂为乙酸钴、乙酸锰、乙酸铜、乙酸铁、二氧化锰等金属盐或金属氧化物；该催化体系用量少，催化效率高，对甲基苯磺酰胺：催化剂：助催化剂＝100：3～8：0.5～6时，可实现常压下(氧气压维持在1atm)氧气将对甲基苯磺酰胺氧化为对羧基苯磺酰胺，对甲基苯磺酰胺的转化率最高可达99.33％， 产物对羧基苯磺酰胺的产率最高可达94.05％；并且反应完毕后通过简单的过滤、洗涤、干燥即可实现对羧基苯磺酰胺的分离纯化。
实施例1：称取1m mol的对羧基苯磺酰胺，N-羟基邻磺酰苯甲酰亚胺0.06mmol，二氧化锰0.03mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至80℃反应6小时，反应完毕，冷却至室温。过滤滤除二氧化锰，滤液减压除去乙酸，乙酸可回收利用。残渣水洗除去残留的乙酸，用少量丙酮洗涤除去N-羟基邻磺酰苯甲酰亚胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率81.86％，对甲基苯磺酰胺的转化率为86.32％,生成对羧基苯磺酰胺的选择性为94.83％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为94.20％。
实施例2：称取1m mol的对羧基苯磺酰胺，N,N-二羟基均苯四甲二酰亚胺0.03mmol，乙酸锰0.06mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至120℃反应2小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸锰，少量丙酮洗涤除去N,N-二羟基均苯四甲二酰亚胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率70.83％，对甲基苯磺酰胺的转化率为80.32％,生成对羧基苯磺酰胺的选择性为88.18％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为92.23％。
实施例3：称取1m mol的对羧基苯磺酰胺，N-羟基邻苯二甲酰亚胺0.08mmol，乙酸铜0.04mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至40℃反应12小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸铜，少量丙酮洗涤除去N-羟基邻苯二甲酰亚胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率72.81％，对甲基苯磺酰胺的转化率为81.55％,生成对羧基苯磺酰胺的选择性为89.28％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为94.42％。
实施例4：称取1mmol的对羧基苯磺酰胺，3,5-二硝基-N-羟基-N-甲基苯甲酰胺0.05mmol，乙酸铁0.05mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应6小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸铁，少量丙酮洗涤除去3,5-二硝基-N-羟基-N-甲基苯甲酰胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率74.25％，对甲基苯磺酰胺的转化率为82.43％,生成对羧基苯磺酰胺的选择性为90.08％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为93.12％。
实施例5：称取1m mol的对羧基苯磺酰胺，1-羟基-2，2-二苯基-3-吲哚酮0.06mmol，乙酸钴0.005mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应8小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去1-羟基-2，2-二苯基-3-吲哚酮等和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率73.45％，对甲基苯磺酰胺的转化率为82.12％,生成对羧基苯磺酰胺的选择性为89.44％， 产品经Agilent 1200型高效液相色谱仪分析检测纯度为95.20％。
实施例6：称取1m mol的对羧基苯磺酰胺，1,3,5-三羟基异氰尿酸0.06mmol，二氧化锰0.03mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至90℃反应12小时，反应完毕，冷却至室温。过滤，除去二氧化锰，滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸，少量丙酮洗涤除去1,3,5-三羟基异氰尿酸和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率90.76％，对甲基苯磺酰胺的转化率为93.24％,生成对羧基苯磺酰胺的选择性为97.34％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为95.15％。
实施例7：称取1m mol的对羧基苯磺酰胺，N-羟基-2，2，6，6-四甲基哌啶0.06mmol，二氧化锰0.03mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应10小时，反应完毕，冷却至室温。过滤除去二氧化锰，滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸，少量丙酮洗涤除去N-羟基-2，2，6，6-四甲基哌啶和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率72.87％，对甲基苯磺酰胺的转化率为80.88％,生成对羧基苯磺酰胺的选择性为90.10％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为95.35％。
实施例8：称取1m mol的对羧基苯磺酰胺，N-羟基-N-甲基苯甲酰胺0.06mmol，乙酸钴0.01mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应12小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去N-羟基-N-甲基苯甲酰胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率84.62％，对甲基苯磺酰胺的转化率为90.23％,生成对羧基苯磺酰胺的选择性为93.78％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为93.42％。
实施例9：称取1m mol的对羧基苯磺酰胺，1-羟基-2,2-二苯基-3-吲哚酮0.06mmol，乙酸钴0.02mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应10小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去1-羟基-2,2-二苯基-3-吲哚酮和少量的对羟甲基苯磺酰亚胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率84.14％，对甲基苯磺酰胺的转化率为89.12％,生成对羧基苯磺酰胺的选择性为94.41％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为95.32％。
实施例10：称取1m mol的对羧基苯磺酰胺，N-羟基邻磺酰苯甲酰亚胺0.05mmol，乙酸钴0.02mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至80℃反应12小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去N-羟基邻磺酰苯甲酰亚胺和少量的对羟甲基苯磺酰胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率81.89％，对甲基苯磺酰胺的转化率为87.65％,生成对羧基苯磺酰胺的选择性为93.43％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为94.20％。
实施例11：称取1m mol的对羧基苯磺酰胺，3,5-二硝基-N-羟基-N-甲基苯甲酰胺0.05mmol，乙酸钴0.01mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应10小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去3,5-二硝基-N-羟基-N-甲基苯甲酰胺和少量的对羟甲基苯磺酰亚胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率94.05％，对甲基苯磺酰胺的转化率为99.33％,生成对羧基苯磺酰胺的选择性为94.68％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为95.14％。
实施例12：称取1m mol的对羧基苯磺酰胺，1,3,5-三羟基异氰尿酸0.06mmol，乙酸钴0.02mmol，加入25mL反应瓶中，加入乙酸5mL，通入氧气，维持氧气压为1atm，升温至100℃反应10小时，反应完毕，冷却至室温。滤液减压除去乙酸，乙酸可回收利用。残渣反复水洗，除去残留的乙酸和助催化剂乙酸钴，少量丙酮洗涤除去1,3,5-三羟基异氰尿酸和少量的对羟甲基苯磺酰亚胺，滤饼干燥，即可得到对羧基苯磺酰胺，产率85.62％，对甲基苯磺酰胺的转化率为87.68％，生成对羧基苯磺酰胺的选择性为97.65％，产品经Agilent 1200型高效液相色谱仪分析检测纯度为93.44％。

Claims (2)

  1. 一种氧气氧化合成对羧基苯磺酰胺的方法，其特征是：该方法以氧气为氧化剂，氧气压仅需维持在1atm，在氮氧自由基型催化剂及金属盐或金属氧化物助催化剂的作用下，以氧气为氧化剂，氧化反应在乙酸中进行；催化氧化对甲基苯磺酰胺制备对羧基苯磺酰胺；
    Figure PCTCN2016108404-appb-100001
    R1和R2代表相同基团或不同基团，R1和R2为氢或C1-C6的烷基；
    具体工艺过程如下：在装有磁力搅拌装置的圆底烧瓶中，依次加入5mL的乙酸、1mmol的对甲基苯磺酰胺、催化剂和助催化剂，通入氧气，并维持压力为1atm；催化剂的用量摩尔比为对甲基苯磺酰胺用量的3％～8％，助催化剂的用量摩尔比为对甲基苯磺酰胺用量的0.5％～6％，在40～120℃条件下，搅拌2～12小时后停止反应，冷却，减压蒸馏除去乙酸，残渣依次用水洗、丙酮洗涤，干燥得到产物对羧基苯磺酰胺。
  2. 根据权利要求1所述的一种氧气氧化合成对羧基苯磺酰胺的方法，其特征是：所使用的催化剂为自由基型催化剂，为N-羟基-2，2，6，6-四甲基哌啶、N-羟基邻苯二甲酰亚胺、N-羟基邻磺酰苯甲酰亚胺、N,N-二羟基均苯四甲二酰亚胺、1,3,5-三羟基异氰尿酸、N-羟基-N-甲基苯甲酰胺、3,5-二硝基-N-羟基-N-甲基苯甲酰胺或1-羟基-2，2-二苯基-3-吲哚酮；基于对甲基苯磺酰胺摩尔比仅为3％～8％；所使用的助催化剂为乙酸钴、乙酸锰、乙酸铜、乙酸铁或二氧化锰金属盐，基于对甲基苯磺酰胺的摩尔比仅为0.5％～6％，对甲基苯磺酰胺的转化率为80.32～99.33％，产物对羧基苯磺酰胺的产率为70.83～94.05％，选择性最高为97.65％；催化剂和助催化剂反应完毕后均可通过洗涤除去。
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