CN118084742A - New preparation method of Iguratimod intermediate - Google Patents
New preparation method of Iguratimod intermediate Download PDFInfo
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- CN118084742A CN118084742A CN202410079684.2A CN202410079684A CN118084742A CN 118084742 A CN118084742 A CN 118084742A CN 202410079684 A CN202410079684 A CN 202410079684A CN 118084742 A CN118084742 A CN 118084742A
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- China
- Prior art keywords
- iguratimod
- methanesulfonamido
- phenoxyanisole
- phenoxyacetophenone
- methoxy
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- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229950003909 iguratimod Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- XZNOAVNRSFURIR-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol Chemical compound FC(F)(F)C(O)(C(F)(F)F)C(F)(F)F XZNOAVNRSFURIR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000011347 resin Substances 0.000 claims abstract description 10
- 229920005989 resin Polymers 0.000 claims abstract description 10
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 8
- HKQJXMJGWKDFTA-UHFFFAOYSA-N n-(5-methoxy-2-phenoxyphenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(OC)=CC=C1OC1=CC=CC=C1 HKQJXMJGWKDFTA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- -1 3-methanesulfonyl-4-phenoxyanisole Chemical compound 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 4
- 238000003912 environmental pollution Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DZXQKWIYTNJLDC-UHFFFAOYSA-N 6-phenoxychromen-4-one Chemical compound O(C1=CC=CC=C1)C=1C=CC2=C(C(C=CO2)=O)C1 DZXQKWIYTNJLDC-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new preparation method of an Iguratimod intermediate, which relates to the technical field of medicines and chemical industry, and is characterized in that 3-methanesulfonamido-4-phenoxyanisole and chloroacetyl chloride are used as raw materials, perfluoro-tertiary butanol is used as a solvent, D72 strong acid macroporous resin is used as a catalyst, and after a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is synthesized, the alpha-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is obtained by reacting with ammonia. The invention greatly improves the yield and purity, overcomes the defects of the prior art in safe production, environmental protection and clean production, has simple route, high reaction safety and convenient post-treatment, effectively reduces the production cost and is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of medicines and chemical industry, in particular to a novel preparation method of an Iguratimod intermediate, namely a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone.
Background
Iguratimod (Iguratimod) is a non-stay anti-inflammatory drug (NSAIDs) with chemical name 3-carboxamide-7-methanesulfonamido 6-phenoxy-4H-1-benzopyran-4-one, CAS registry number: 123663-49-0, a novel disease-modifying drug (DMARDs) developed by the combination of Fushan and Wei-ingredient pharmaceutical company in Japan, is generally used for treating Rheumatoid Arthritis (RA) and osteoarthritis (0A). a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is a key intermediate in the synthesis process of Iguratimod.
Conventionally, for example, "study of synthesis process of Iguratimod (T-614) in volume 14 and 3 of Jiangsu pharmaceutical and clinical study" and "study of synthesis of Iguratimod in volume 15 and 23 of Chinese New drug journal" in 2006, the disclosed preparation method of a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is to use 3-methanesulfonamido-4-phenoxyanisole and aminoacetonitrile hydrochloride as raw materials, aluminum trichloride as catalyst, nitrobenzene as solvent, and to hydrolyze in dilute hydrochloric acid solution after introducing hydrogen chloride to conduct Getman Yikoch reaction. However, the method has low yield and a plurality of problems: firstly, a large amount of aluminum trichloride and hydrogen chloride gas are used, so that a large amount of aluminum-containing acidic wastewater can be generated, the recycling is difficult, the production cost is high, and the environmental pollution is serious; secondly, the mixture of the vapor and the air of the nitrobenzene at the temperature of more than 80 ℃ is explosive, belongs to explosive and highly toxic compounds, has high risk of reaction safety, and also has great harm to human bodies, and the nitrobenzene is used as a solvent, so that the reaction liquid is viscous and difficult to centrifuge during post-treatment, thereby being not beneficial to the subsequent treatment of products and influencing the final purity.
In the prior art, researches on a preparation method of a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone, such as a preparation method of an Iguratimod intermediate IV of patent application CN107162942A, and the like, can reduce environmental pollution and harm to human bodies to a certain extent by adopting nitromethane instead of nitrobenzene as a solvent for preparing the a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone, improve the yield and purity of the product, but the reaction safety in the prior art is still general, for example, nitromethane still belongs to explosive compounds, and meanwhile, the prior art still has the problems of difficult recycling and high production cost due to the fact that a large amount of aluminum trichloride and hydrogen chloride gas are also used, is unfavorable for industrialized popularization and application, and has limited improvement on the environmental pollution.
For this reason, a new technical solution is needed to solve the above technical problems.
Disclosure of Invention
The invention aims to provide a novel preparation method of an Iguratimod intermediate, namely a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone, so as to solve the technical problems that the prior art provided by the background art is still general in reaction safety, difficult to recycle and high in production cost, is not beneficial to industrialized popularization and application and has limited improvement on environmental pollution while improving the yield and purity.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A new preparation method of an Iguratimod intermediate, which is prepared by taking 3-methanesulfonamido-4-phenoxyanisole and chloroacetyl chloride as raw materials and perfluoro-tertiary butanol as a solvent and D72 strong acid macroporous resin as a catalyst, and carrying out a reflux reaction with ammonia after synthesizing a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone, wherein the reaction equation of the new preparation method is as follows:
，
。
Further, the reflux time is 5-10 hours, the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to perfluoro-tert-butanol is 1:8.0-12, the molar ratio of 3-methanesulfonyl-4-phenoxyanisole to chloroacetyl chloride is 1:1.1-1.3, the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to D72 strong acid macroporous resin is 1:0.01-0.05, and the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to 10% ammonia ethanol solvent is 1:5-10.
Compared with the prior art, the invention has the beneficial effects that:
1. According to the invention, 3-methanesulfonamido-4-phenoxyanisole and chloroacetyl chloride are used as raw materials, perfluoro-tert-butanol is used as a solvent, D72 strong acid macroporous resin is used as a catalyst, a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is synthesized, a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is reacted with ammonia to obtain a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone, in the whole process, chloroacetyl chloride is used for performing Friedel-crafts reaction instead of aminoacetonitrile hydrochloride, perfluoro-tert-butanol is used for replacing nitrobenzene and nitromethane as a solvent, D72 strong acid macroporous resin is used as a catalyst, the defects of the prior art in safe production, environmental protection and clean production are overcome while the yield and purity are greatly improved, the route is simple, the reaction safety is high, the post-treatment is convenient, the production cost is effectively reduced, and the method is suitable for large-scale production.
2. Before the reaction of the alpha-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone and ammonia, the catalyst D72 can be filtered out by only carrying out conventional filtering operation, and then the solvent perfluoro-tert-butanol can be distilled out by normal pressure evaporation, so that the whole process is simpler, the post-treatment is simpler and more convenient, the catalyst and the solvent are recycled, and the production cost is further reduced.
Detailed Description
The following examples are intended to further illustrate the invention and are not intended to limit the application of the invention.
Example 1
15G of 3-methanesulfonamido-4-phenoxyanisole, 180g of perfluoro-tertiary butanol and 0.8g of D72 strong acid macroporous resin are added into a 250ml tetrafluoro reaction bottle, 7.4g of chloracetyl chloride is slowly added dropwise at 0 ℃ under the protection of nitrogen, the reaction is continued for 10 hours after 1 hour, the catalyst is filtered out, 150g of 10% ammonia ethanol solvent is added after the filtrate is distilled out of perfluoro-tertiary butanol at normal pressure, the reflux reaction is carried out for 5 hours, the feed liquid is cooled to 0 ℃, the filtration is carried out, the obtained solid is dried at 60 ℃ for 5 hours under vacuum, and the 16.7 ga-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is obtained, the content is 98.3 percent, and the yield is 95.4 percent, and the melting point is 167-169 ℃.
1H NMR(CDCl3,500MHZ) 3.07(3H,S,CH3SO2 ) 3.97 (3H, s, aromatic hydrogen), 4.30 (2H, d, COCH 2), 6.95-7.33 (5H, m, aromatic hydrogen), 7.39-7.54 (2H, s, aromatic hydrogen), 8.65 (2H, s, NH 2),9.24(1H,S,SO2 NH).
Example 2
15G of 3-methanesulfonamido-4-phenoxyanisole, 120g of perfluoro-tert-butanol and 0.2g of D72 strong acid macroporous resin are added into a 250ml tetrafluoro reaction bottle, 6.2g of chloracetyl chloride is slowly added dropwise at 0 ℃ under the protection of nitrogen, the reaction is continued for 5 hours after 1 hour, the catalyst is filtered out, 75g of 10% ammonia ethanol solvent is added after the perfluoro-tert-butanol is distilled out from the filtrate under normal pressure, the reflux reaction is carried out for 5 hours, the feed liquid is cooled to 0 ℃, the filtration is carried out, the obtained solid is dried at 60 ℃ for 5 hours under vacuum, and the 16.6 ga-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is obtained, the content of which is 98.5 percent, and the yield is 95 percent, and the melting point of which is 167-169 ℃.
Example 3
15G of 3-methanesulfonamido-4-phenoxyanisole, 150g of perfluoro-tertiary butanol and 0.4g of D72 strong acid macroporous resin are added into a 250ml tetrafluoro reaction bottle, 6.8g of chloracetyl chloride is slowly added dropwise under the protection of nitrogen at 0 ℃ for 1 hour, the reaction is continued for 10 hours, the catalyst is filtered out, 112g of 10% ammonia ethanol solvent is added after the perfluoro-tertiary butanol is distilled out from the filtrate under normal pressure, the reflux reaction is carried out for 7.5 hours, the feed liquid is cooled to 0 ℃ and filtered, the obtained solid is dried at 60 ℃ for 5 hours under vacuum, and the content of 16.9 ga-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is 98.9%, the yield is 96.6%, and the melting point is 167-169 ℃.
Claims (9)
1. A novel preparation method of an Iguratimod intermediate is characterized in that 3-methanesulfonamido-4-phenoxyanisole and chloroacetyl chloride are used as raw materials, perfluoro-tertiary butanol is used as a solvent, D72 strong acid macroporous resin is used as a catalyst, and after a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is synthesized, the mixture and ammonia are subjected to reflux reaction to obtain the Iguratimod intermediate, namely a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone.
2. A novel process for the preparation of an Iguratimod intermediate according to claim 1, characterized in that the reaction equation of the novel process is as follows:
。
3. The novel preparation method of the Iguratimod intermediate according to claim 1, wherein the mass ratio of the 3-methanesulfonamide-4-phenoxyanisole to the perfluoro-tert-butanol is 1:8.0-12.
4. The novel preparation method of the Iguratimod intermediate according to claim 1, wherein the molar ratio of the 3-methanesulfonamide-4-phenoxyanisole to the chloroacetyl chloride is 1:1.1-1.3.
5. The novel preparation method of the Iguratimod intermediate according to claim 1, wherein the mass ratio of the 3-methanesulfonamide-4-phenoxyanisole to the D72 strong acid macroporous resin is 1:0.01-0.05.
6. The novel process for preparing an Iguratimod intermediate according to claim 1, characterized in that the ammonia is an ethanol solvent of 10% ammonia.
7. The novel preparation method of the Iguratimod intermediate according to claim 6, wherein the mass ratio of the 3-methanesulfonamide-4-phenoxyanisole to the ethanol solvent of 10% ammonia is 1:5-10.
8. The novel process for preparing Iguratimod intermediate according to claim 1, wherein the reaction temperature of the novel process is 0 to 20 ℃.
9. The novel process for preparing an Iguratimod intermediate according to claim 1, characterized in that the reflux time is 5 to 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410079684.2A CN118084742A (en) | 2024-01-19 | 2024-01-19 | New preparation method of Iguratimod intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410079684.2A CN118084742A (en) | 2024-01-19 | 2024-01-19 | New preparation method of Iguratimod intermediate |
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| Publication Number | Publication Date |
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| CN118084742A true CN118084742A (en) | 2024-05-28 |
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|---|---|---|---|
| CN202410079684.2A Pending CN118084742A (en) | 2024-01-19 | 2024-01-19 | New preparation method of Iguratimod intermediate |
Country Status (1)
| Country | Link |
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| CN (1) | CN118084742A (en) |
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- 2024-01-19 CN CN202410079684.2A patent/CN118084742A/en active Pending
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