CN115677599A - Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine - Google Patents
Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 36
- VELRBZDRGTVGGT-UHFFFAOYSA-N 6-methoxypyrimidin-4-amine Chemical compound COC1=CC(N)=NC=N1 VELRBZDRGTVGGT-UHFFFAOYSA-N 0.000 claims abstract description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 19
- 230000008025 crystallization Effects 0.000 claims description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012265 solid product Substances 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- 238000005008 domestic process Methods 0.000 abstract description 2
- 239000007810 chemical reaction solvent Substances 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 230000007794 irritation Effects 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 206010028470 Mycoplasma infections Diseases 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 201000005485 Toxoplasmosis Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 4- (p-acetoxyaminobenzenesulfonylamino) -6-methoxypyrimidine Chemical compound 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606807 Glaesserella parasuis Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 201000006509 pleuropneumonia Diseases 0.000 description 1
- 239000002602 strong irritant Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to a treatment method in the field of chemistry, and particularly relates to a method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine. Under the action of a solvent, 4-acetamido benzene sulfonyl chloride and 4-amino-6-methoxyl pyrimidine react to generate 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine; the solvent is dichloromethane, tetrahydrofuran or N, N-dimethylformamide. The invention adopts a new reaction solvent to prepare the 4- (p-acetamido-benzene sulfonamide) -6-methoxyl pyrimidine, and compared with the prior domestic process, the invention improves the environmental protection level, reduces the pollution to the environment, improves the utilization efficiency of the solvent, improves the yield and reduces the cost.
Description
Technical Field
The invention belongs to a treatment method in the field of chemistry, and particularly relates to a method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine.
Background
4- (p-acetamido-benzenesulfonamide) -6-methoxypyrimidine, english name: 4- (p-acetoxyaminobenzenesulfonylamino) -6-methoxypyrimidine, CAS No.: 4049-01-8, molecular formula: c 13 H 14 N 4 O 4 S, molecular weight: 322, is a key intermediate for preparing the sulfanilamide-6-methoxyl pyrimidine sodium.
The sulfa-6-methoxyl pyrimidine sodium is a sulfa drug with the strongest in vivo and in vitro antibacterial action, has stronger inhibition effect on most gram-positive bacteria and gram-negative bacteria, and has slower drug resistance on the drug by bacteria. The compound is mainly used for various diseases (such as high fever, streptococcicosis, haemophilus parasuis disease, toxoplasmosis, pig edema disease, eperythrozoonosis, infectious pleuropneumonia, pasteurella pneumonia and the like) caused by sensitive bacteria, toxoplasmosis and eperythrozoonosis and mixed infection thereof, and 4- (p-acetaminophenylsulfonamide) -6-methoxypyrimidine is a key intermediate for preparing the compound, and the structural formula is as follows:
at present, the synthesis of 4- (p-acetamido-benzene-sulfonamide) -6-methoxyl pyrimidine is reported to be less, the invention patent CN108276346 reports that 4-amino-6-methoxyl pyrimidine and N-acetanilide react with chlorosulfonic acid under the condition that carbon tetrachloride is used as a solvent to directly generate the 4- (p-acetamido-benzene-sulfonamide) -6-methoxyl pyrimidine in a one-pot method, although the operation steps are simplified, the route uses a solvent of carbon tetrachloride, basically belongs to a forbidden solvent in the drug synthesis, and simultaneously uses chlorosulfonic acid with high irritation as a sulfonation reagent, so that the irritation is strong, and the corrosivity in industrial production is high. The invention patent CN 105294576 reports that 4-amino-6-methoxypyrimidine reacts with 4-p-acetamido benzene sulfonyl chloride under the condition that pyridine is used as a solvent, then the obtained product is directly put into the next hydrolysis reaction without separation, the method can avoid using chlorosulfonic acid with strong irritation, but pyridine is used as a solvent in a large amount, the environment protection pressure is high due to the strong irritation taste of the pyridine, the next hydrolysis reaction can be carried out without post treatment, and after the pyridine is mixed with water, the pyridine and the water are subjected to azeotropic distillation, so that the difficulty is brought to the recovery of the pyridine. In patent CN 101565418, 4-amino-6-methoxypyrimidine reacts with 4-p-acetamido benzene sulfonyl chloride under the condition that pyridine is used as a solvent, and the 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine is obtained by separation, but the yield is only 53%, so that the pyridine is used as the solvent, and the method is large in irritation, not beneficial to industrial production, and low in yield.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine, which can obtain a product with high yield, is safe and environment-friendly, has lower cost and is simple to operate, and overcomes the defects of the existing 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine in China.
In order to achieve the technical aim, the invention adopts the following technical scheme:
a method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine is characterized in that 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine is generated by the reaction of 4-acetamido benzene sulfonyl chloride and 4-amino-6-methoxyl pyrimidine under the action of a solvent;
the solvent is dichloromethane, tetrahydrofuran or N, N-dimethylformamide, and the mass of the added solvent is 4-6 times of that of 4-amino-6-methoxypyrimidine.
Further, the synthetic route is as follows:
adding 4-amino-6-methoxypyrimidine (MD for short) into a solvent, adding p-acetamidobenzenesulfonyl chloride (SCL for short) under stirring, dropwise adding an acid-binding agent, adding a polar crystallization solvent after the reaction is finished, crystallizing and stirring until a large amount of solid is separated out, cooling, continuing crystallizing, filtering, washing and drying to obtain a white solid product.
Furthermore, 4-amino-6-Methoxypyrimidine (MD) is added into a solvent, p-acetamido-benzenesulfonyl chloride (SCL) is added under the stirring condition, an acid-binding agent is dropwise added, condensation reaction is carried out for 2-6 hours at 10-30 ℃, a polar crystallization solvent is added in batches after the reaction, crystallization is carried out for 2-6 hours until solid is separated out, the temperature is reduced to 0-20 ℃, crystallization time is continued for 2-6 hours, and a white solid product is obtained after filtration, washing and drying.
The acid-binding agent is pyridine, 2-methylpyridine, triethylamine or piperidine; the molar weight of the added compound is 1 to 2 times of that of the 4-amino-6-methoxypyrimidine.
The crystallization solvent is methanol, ethanol, isopropanol or acetone; the adding amount is 6-10 times of the mass of the 4-amino-6-methoxyl pyrimidine; adding crystallization solvent in 2-4 batches, with the interval of 8-10min.
The dosage ratio of the 4-amino-6-methoxypyrimidine to the p-acetamido benzene sulfonyl chloride is 1.0-1.
And filtering after crystallization, washing the precipitate by using a crystallization solvent, and drying in vacuum (50 ℃ reduced pressure vacuum) after washing to obtain the 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine with the purity of more than 99%.
The invention has the beneficial effects that:
compared with the prior domestic process, the preparation method of the 4- (p-acetamido benzene sulfonamide) -6-methoxypyrimidine avoids the use of chlorosulfonic acid and pyridine which are strong irritant solvents, and avoids the use of carbon tetrachloride which is a solvent, the invention replaces pyridine with dichloromethane which is a common low-toxicity solvent and the like as a solvent, can achieve better reaction effect only by using a catalytic amount of acid-binding agent, greatly reduces the use amount of pyridine, simultaneously has thorough reaction of condensation reaction in a solvent system, has less impurities and obviously higher yield than the prior process, and has higher product purity after the product is separated.
Detailed Description
The following examples are presented to further illustrate embodiments of the present invention, and it should be understood that the embodiments described herein are for purposes of illustration and explanation only and are not intended to limit the invention.
The method for preparing the 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine has the advantages of high product yield, safe and environment-friendly used solvent, easy recovery, simple and convenient operation and contribution to large-scale production.
Example 1:
adding 50.0g of 4-amino-6-methoxypyrimidine into 200.0g of dichloromethane, stirring at 15 ℃ to dissolve, adding 100.0g of p-acetamidobenzenesulfonyl chloride, starting to dropwise add 31.6g of pyridine, reacting at 30 ℃ for 2 hours, after the reaction is finished, adding 100g of methanol into each batch at an interval of 10min, carrying out crystallization and stirring for 2 hours until a large amount of solid is separated out, cooling to 0 ℃, continuing to crystallize for 2 hours, filtering, washing, and drying to obtain 121.0g of white solid 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine, wherein the yield is 93.9%, and the product purity is 99.2% (HPLC).
Example 2:
adding 50.0g of 4-amino-6-methoxypyrimidine into 250.0g of tetrahydrofuran, stirring and dissolving at 20 ℃, adding 100.0g of p-acetamidobenzene sulfonyl chloride, starting to dropwise add 40.4g of triethylamine, reacting at 10 ℃ for 2 hours, after the reaction is finished, adding 300.0g of ethanol in batches (100 g of ethanol is added in three batches at intervals of 8 min), crystallizing and stirring for 2 hours until a large amount of solid is separated out, cooling to 0 ℃, continuing to crystallize for 2 hours, filtering, washing, and drying to obtain 120.5g of 4- (p-acetamidobenzene sulfonamide) -6-methoxypyrimidine as a white solid, wherein the yield is 93.5%, and the product purity is 99.0% (HPLC).
Example 3:
adding 50.0g of 4-amino-6-methoxypyrimidine into 300.0g of N, N-dimethylformamide, stirring at 25 ℃ to dissolve, adding 100.0g of p-acetamidobenzene sulfonyl chloride, after the addition is finished, beginning to dropwise add 37.2g of 2-methylpyridine to react at 30 ℃ for 2h, after the reaction is finished, adding 300.0g of acetone in batches (adding 150g in two batches at an interval of 10 min), crystallizing and stirring for 2h until a large amount of solid is separated out, cooling to 0 ℃, continuing to crystallize for 2h, filtering, washing, and drying to obtain 119.0g of white solid 4- (p-acetamidobenzene sulfonamide) -6-methoxypyrimidine, wherein the yield is 92.4%, and the product purity is 99.3% (HPLC).
Claims (7)
1. A method for preparing 4- (p-acetamido-benzenesulfonamide) -6-methoxypyrimidine, comprising: under the action of a solvent, 4-acetamido benzene sulfonyl chloride and 4-amino-6-methoxyl pyrimidine react to generate 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine;
the solvent is dichloromethane, tetrahydrofuran or N, N-dimethylformamide, and the mass of the added solvent is 4-6 times of that of 4-amino-6-methoxypyrimidine.
2. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 1, characterized in that: adding 4-amino-6-methoxyl pyrimidine into a solvent, adding p-acetamido benzenesulfonyl chloride under stirring, dropwise adding an acid-binding agent, after the reaction is finished, adding a polar crystallization solvent, performing crystallization and stirring until a large amount of solids are separated out, cooling, continuing crystallization, filtering, washing, and drying to obtain a white solid product.
3. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 2, characterized in that: adding 4-amino-6-methoxypyrimidine into a solvent, adding p-acetamidobenzenesulfonyl chloride under stirring, dropwise adding an acid-binding agent, carrying out condensation reaction at 10-30 ℃ for 2-6 hours, adding a polar crystallization solvent in batches after the reaction, carrying out crystallization stirring for 2-6 hours until a solid is separated out, cooling to 0-20 ℃, continuing crystallization for 2-6 hours, filtering, washing and drying to obtain a white solid product.
4. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 3, characterized in that: the acid-binding agent is pyridine, 2-methylpyridine, triethylamine or piperidine; wherein the added molar weight is 1 to 2 times of the molar weight of the 4-amino-6-methoxypyrimidine.
5. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 3, characterized in that: the crystallization solvent is methanol, ethanol, isopropanol or acetone; the adding amount is 6-10 times of the mass of the 4-amino-6-methoxyl pyrimidine; adding crystallization solvent in 2-4 batches, with the interval of 8-10min.
6. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 3, characterized in that: the dosage ratio of the 4-amino-6-methoxyl pyrimidine to the p-acetamido benzene sulfonyl chloride is 1.0-1.
7. The process for preparing 4- (p-acetamidobenzenesulfonamide) -6-methoxypyrimidine according to claim 3, characterized in that: and filtering after crystallization, washing the precipitate by using a crystallization solvent, and drying in vacuum after washing to obtain the 4- (p-acetamido benzene sulfonamide) -6-methoxyl pyrimidine with the purity of more than 99%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110869055.6A CN115677599A (en) | 2021-07-30 | 2021-07-30 | Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine |
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| CN202110869055.6A CN115677599A (en) | 2021-07-30 | 2021-07-30 | Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine |
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| CN202110869055.6A Pending CN115677599A (en) | 2021-07-30 | 2021-07-30 | Method for preparing 4- (p-acetamido benzene sulfonamide) -6-methoxy pyrimidine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2410793A (en) * | 1940-03-01 | 1946-11-05 | American Cyanamid Co | Sulfonamido pyrimidines |
| CN101565418A (en) * | 2008-04-23 | 2009-10-28 | 华东理工大学 | Amide derivative and purpose thereof |
| CN107325057A (en) * | 2017-08-04 | 2017-11-07 | 吴赣药业（苏州）有限公司 | A kind of preparation method of the dimethoxypyridin of sulfanilamide (SN) 2,6 |
-
2021
- 2021-07-30 CN CN202110869055.6A patent/CN115677599A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2410793A (en) * | 1940-03-01 | 1946-11-05 | American Cyanamid Co | Sulfonamido pyrimidines |
| CN101565418A (en) * | 2008-04-23 | 2009-10-28 | 华东理工大学 | Amide derivative and purpose thereof |
| CN107325057A (en) * | 2017-08-04 | 2017-11-07 | 吴赣药业（苏州）有限公司 | A kind of preparation method of the dimethoxypyridin of sulfanilamide (SN) 2,6 |
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