CN117777078A - Method suitable for industrial production of Iguratimod - Google Patents
Method suitable for industrial production of Iguratimod Download PDFInfo
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- CN117777078A CN117777078A CN202311820145.1A CN202311820145A CN117777078A CN 117777078 A CN117777078 A CN 117777078A CN 202311820145 A CN202311820145 A CN 202311820145A CN 117777078 A CN117777078 A CN 117777078A
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- Prior art keywords
- reaction
- iguratimod
- organic solvent
- dosage
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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 51
- 229950003909 iguratimod Drugs 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000009776 industrial production Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 109
- HISHUMDTGXICEZ-UHFFFAOYSA-N 1-chloro-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Cl)C([N+]([O-])=O)=C1 HISHUMDTGXICEZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 12
- 239000004471 Glycine Substances 0.000 claims abstract description 7
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 6
- 239000011592 zinc chloride Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- 239000007787 solid Substances 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- -1 valeric anhydride formate Chemical group 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 13
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 13
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 229960002449 glycine Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 235000009518 sodium iodide Nutrition 0.000 claims description 8
- 150000008064 anhydrides Chemical class 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical group COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical group [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000005751 Copper oxide Substances 0.000 claims description 3
- 229910000431 copper oxide Inorganic materials 0.000 claims description 3
- 230000001335 demethylating effect Effects 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- RDCOMWQFSWWPJG-UHFFFAOYSA-N acetyl acetate;formic acid Chemical group OC=O.CC(=O)OC(C)=O RDCOMWQFSWWPJG-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000006103 sulfonylation Effects 0.000 claims description 2
- 238000005694 sulfonylation reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 60
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 231100000086 high toxicity Toxicity 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 239000011521 glass Substances 0.000 description 24
- 238000005406 washing Methods 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 18
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- QVCYQPIZAWIRIP-UHFFFAOYSA-N 4-methoxy-2-nitro-1-phenoxybenzene Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1OC1=CC=CC=C1 QVCYQPIZAWIRIP-UHFFFAOYSA-N 0.000 description 10
- UOGZDMKXQVZVGO-UHFFFAOYSA-N 5-methoxy-2-phenoxyaniline Chemical compound NC1=CC(OC)=CC=C1OC1=CC=CC=C1 UOGZDMKXQVZVGO-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- NWUBXODWWYGUHS-UHFFFAOYSA-N n-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide;hydrochloride Chemical compound [Cl-].C1=C(C(=O)C[NH3+])C(OC)=CC(NS(C)(=O)=O)=C1OC1=CC=CC=C1 NWUBXODWWYGUHS-UHFFFAOYSA-N 0.000 description 9
- 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 description 7
- OVFGHIVRJWQONU-UHFFFAOYSA-N n-[2-[4-(methanesulfonamido)-2-methoxy-5-phenoxyphenyl]-2-oxoethyl]formamide Chemical compound C1=C(C(=O)CNC=O)C(OC)=CC(NS(C)(=O)=O)=C1OC1=CC=CC=C1 OVFGHIVRJWQONU-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000022244 formylation Effects 0.000 description 3
- 238000006170 formylation reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000003309 Hoesch reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- USJUUYYGHABIBU-UHFFFAOYSA-N methanesulfonamide;hydrochloride Chemical compound Cl.CS(N)(=O)=O USJUUYYGHABIBU-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical group CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method suitable for industrial production of Iguratimod, and relates to the technical field of Iguratimod industrial synthesis production. The invention takes 4-chloro-3-nitroanisole as an initial raw material, and prepares the Iguratimod which accords with clinical medicine through the reaction of the steps 1-8 with high purity and high yield. The invention solves the problems of high toxicity and serious pollution in the prior art, is beneficial to labor protection, reduces the production cost, improves the quality standard and improves the product quality and the economic benefit; meanwhile, the step 1 adopts heavy metal catalysis, so that the reaction is almost quantitatively finished, the product purity is high, and the post-treatment is extremely simple; step 2, palladium-carbon hydrogenation is used for reducing nitro, so that the use of iron powder is reduced, the product purity is high, and the post-treatment is simple; step 3 uses 2-glycine and zinc chloride to catalyze acylation, so that the step of synthesizing intermediates is shortened.
Description
Technical Field
The invention belongs to the technical field of industrial synthesis production of Iguratimod, and particularly relates to a method suitable for industrial production of Iguratimod.
Background
Iguratimod (Iguratimod), formula C 17 H 14 N 2 O 6 S, molecular weight 374.38, trade name Aidexin, chemical name N- [3- (carboxamide) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]The chemical structural formula of the methanesulfonamide is as follows:
currently, four main synthetic routes for Iguratimod are described in detail in chemistry select2020,5,13916-13918 for route one, route two and route three mentioned in this invention:
the synthesis route I is as follows:
taking 4-chloro-3-nitroanisole as shown in formula 2 as a starting material, taking sodium hydride as alkali, and nucleophilic substitution of a product generated by the reaction of phenol and 4-chloro-3-nitroanisole to generate 4-phenoxy-3-nitroanisole; reducing into 4-phenoxy-3-aminoanisole in a reaction system of iron powder and hydrochloric acid; then reacting with methanesulfonyl chloride to generate 4-phenoxy-3-methanesulfonylaminoanisole shown in formula 3; under the catalysis of anhydrous aluminum trichloride, 4-phenoxy-3-methanesulfonamido anisole shown in the formula 3 in the previous step reacts with aminoacetonitrile hydrochloride to generate N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride shown in the formula 4; formylating with mixed anhydride in weak alkaline system to form N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide shown in the formula 5; selectively demethylating in an anhydrous aluminum trichloride, sodium iodide and acetonitrile system to produce N- [4- (2-formamidoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide shown in formula 6; finally, the Iguratimod is reacted with DMFDMA to produce the final product Iguratimod shown in the formula 1. The whole process comprises 7 chemical reactions in total, namely nucleophilic substitution reaction, nitro reduction, methanesulfonylation, houben-Hoesch reaction, formylation, methoxy demethylation and cyclization, and has more reaction steps and long product period.
The synthesis route II is as follows:
carrying out Friedel-crafts acylation reaction on 4-phenoxy-3-methanesulfonamido anisole shown in a formula 3 and acetyl chloride under the catalysis of anhydrous aluminum trichloride, and heating to 110 ℃ after the reaction is finished to carry out demethylation to obtain an intermediate acetyl product shown in a formula 7; at room temperature, 70% HClO was used 4 Treating a stirred suspension of an acetyl product in triethyl orthoformate, and filtering and washing a crystal precipitate generated by the reaction by using diethyl ether to obtain an intermediate pyrone of a formula 8; the intermediate pyrone of the formula 8 is hydrogenated and reduced into the intermediate cyclic ketone of the formula 9 under the catalysis of palladium carbon; intermediate 9Cyclic ketones and Br 2 Bromination reaction is carried out, and product solid is recrystallized through toluene to obtain intermediate bromide in the formula 10; intermediate bromide and NaN 3 Amination is carried out in DMF to obtain an amination product of formula 11, and the obtained amination product of formula 11 is reacted with formylating agent to obtain the target product Iguratimod of formula 1. The whole process is subjected to 6 steps of reactions, more impurities are generated by bromination, the catalyst required by hydrogenation is expensive, and the middle process also uses inflammable and explosive substances sodium azide, so that the method is not beneficial to industrial production and safety of operators.
The synthesis route III:
4-phenoxy-3-methanesulfonamido anisole shown in the formula 3 and N-methyl formanilide are subjected to Wilsmeier-Hake reaction formylation in phosphorus oxychloride to generate a compound shown in the formula 16, the compound shown in the formula 16 is subjected to demethylation under the action of boron tribromide to obtain a compound shown in the formula 17, the compound shown in the formula 17 and bromoacetonitrile are subjected to condensation reaction to obtain a compound shown in the formula 18, the compound shown in the formula 18 is subjected to cyclization reaction under the action of DBU to obtain a compound shown in the formula 19, and the compound shown in the formula 19 is subjected to formylation to obtain the Iguratimod shown in the formula 1 as a final product. The route has 5 steps of reactions, the intermediate process uses low-temperature conditions (-20 ℃), and the utilization rate of the adopted chemical reagent is not high, which is not beneficial to industrial production.
The synthesis route is four:
acetylate an intermediate of formula 7 and Br 2 Reacting the intermediate bromide of the formula 12 with urotropine in methylene dichloride at room temperature for 15h to form salt, dissolving the intermediate product of the formula 12 into 30% concentrated hydrochloric acid and absolute ethyl alcohol mixed solution, and continuously reacting at room temperature for 72h to obtain the intermediate amino hydrochloride of the formula 14. The remaining two steps are the same as in scheme one, and are first formylated to give formula 15And (3) cyclizing the intermediate compound shown in the formula 15 with DMFDMA to obtain the target product Iguratimod. The route is 6 steps of reactions, the reaction route is longer, the bromination side reaction is more and is not easy to purify, and the two steps of reactions in the route have too long reaction time and low yield, so that the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method suitable for industrialized production of Iguratimod, which can obtain Iguratimod with high yield and high purity, can be used as an industrialized method for large-scale production, and solves the problems in the prior art.
In order to solve the technical problems, the invention is realized by the following technical scheme:
the invention relates to a method suitable for industrial production of Iguratimod, which comprises the following steps:
step 1, phenol is dissolved in an organic solvent A, a copper catalyst is used for catalysis, an acid binding agent is added, and the reaction product is catalytically coupled with 4-chloro-3-nitroanisole to prepare an intermediate II:
step 2, preparing an intermediate III from the intermediate II in an organic solvent B through catalytic hydrogenation;
step 3, the intermediate III is subjected to methanesulfonyl chloride sulfonylation in an alkaline solvent to prepare an intermediate IV;
step 4, reacting the intermediate IV with 2-amino acetic acid in an organic solvent C under the catalysis of Lewis acid to obtain an intermediate V;
step 5, formylating the intermediate V in an organic solvent D with mixed anhydride to prepare an intermediate VI;
step 6, demethylating the intermediate VI in an organic solvent D to obtain an intermediate VII;
step 7, cyclizing the intermediate VII in an organic solvent E to obtain a crude Iguratimod product;
and 8, recrystallizing the Iguratimod crude product to obtain a refined Iguratimod product.
Further, in the step 1, the organic solvent a is one of N-methylpyrrolidone, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide; the copper catalyst is copper oxide and cuprous iodide, and the dosage of the catalyst is 5.0% of the weight of the compound 4-chloro-3-nitroanisole; the acid binding agent is potassium phosphate, potassium tert-butoxide, potassium carbonate and triethylamine; preferably potassium carbonate, and the dosage of the acid binding agent is 1.1 times of the molar quantity of the compound 4-chloro-3-nitroanisole; the dosage of the phenol is 1.0-1.5 times of the molar quantity of the compound 4-chloro-3-nitroanisole, the material is fed at room temperature, and the temperature is raised to 110 ℃ for reaction for 5 hours.
Further, in the step 2, the organic solvent B is methanol or absolute ethanol; and the volume dosage of the organic solvent B is 5 times of the weight of the intermediate II; the catalyst used in the catalytic hydrogenation is 10% Pd/C or Raney nickel, the dosage of the catalyst is 1.0% of the weight of the intermediate II, the hydrogen pressure in the catalytic hydrogenation is 0.1-0.5MPa, and the reaction temperature is controlled to be 20-40 ℃ for catalytic reaction for 3-5h; preferably, the hydrogen pressure is 0.3-0.5MPa, the materials are fed at room temperature, and the pressure is maintained, the temperature is raised to 35-40 ℃ for catalytic reaction for 4 hours.
Further, in the step 3, the basic solvent is pyridine, and the volume amount of the organic solvent C is 5 times of the weight of the intermediate III; the dosage of the methanesulfonyl chloride is 1.0-2.0 times of the molar quantity of the intermediate III, the methanesulfonyl chloride is fed below 20 ℃, and the methanesulfonyl chloride reacts for 3 hours at the temperature of 20-30 ℃; preferably, methanesulfonyl chloride is used in an amount 1.2 times the molar amount of intermediate III.
Further, in the step 4, the lewis acid is anhydrous aluminum trichloride, zinc chloride or phosphorus oxychloride, and the amount of the lewis acid is 2 times of the molar amount of the intermediate IV; the dosage of the 2-glycine is 1.0 to 1.5 times of the molar quantity of the intermediate IV; feeding below 20 ℃, heating to 30-50 ℃ and carrying out reflux reaction for 5-7h; the organic solvent C is dichloromethane.
Further, in the step 5, the mixed anhydride is acetic anhydride formate or tertiary valeric anhydride formate; the dosage of the mixed anhydride is 1.5 times of the molar quantity of the intermediate; in the step 5, the materials are fed below 20 ℃ and reacted for 3 hours at 20-30 ℃.
Further, in the step 6, the organic solvent D is acetonitrile, and the volume amount of the organic solvent D is 5-8 times of the weight of the intermediate VI; stirring and mixing intermediate VI and acetonitrile at room temperature, adding sodium iodide, cooling to 0-10deg.C, controlling the temperature of the reaction system to be lower than 20deg.C, adding aluminum trichloride in batches, naturally heating to 20-30deg.C after the addition, and stirring for reacting for 5 hr; after the reaction is completed, pouring the reaction solution into hydrochloric acid aqueous solution with temperature reduced in advance in batches, and stirring for 1h at room temperature after quenching is completed; suction filtration is carried out, and the filter cake is washed to be neutral by water, thus obtaining white solid intermediate VII.
Further, the molar amount of aluminum trichloride is 1-2 times that of the intermediate VI, and the amount of sodium iodide is 1-2 times that of the intermediate VI.
Further, in the step 7, the intermediate VII, the cyclization reagent and the catalyst B are stirred for 30min at 20 ℃, then the temperature is raised to 40-50 ℃ for reaction for 5 hours, after the reaction is completed, the reaction solution is poured into 5% sodium bicarbonate water, stirred for 1 hour, filtered, washed twice with 50% aqueous acetone, and dried under reduced pressure at 50 ℃ to obtain white solid which is a crude product of Iguratimod.
Further, the cyclization reagent is N, N-dimethylformamide dimethyl acetal (DMFDMA) or trimethyl orthoformate; preferably, the cyclic reagent is trimethyl orthoformate and is used together as a solvent, and the volume usage of the trimethyl orthoformate is 4 times of the weight of the intermediate VII; the catalyst B is sulfuric acid, hydrochloric acid or glacial acetic acid; and the catalyst B is preferably sulfuric acid, and the volume amount of the sulfuric acid is 0.6 times of the weight of the intermediate VII.
The invention has the following beneficial effects:
in the method, the heavy metal catalysis is adopted in the step 1, so that the reaction is almost quantitatively finished, the product purity is high, and the post-treatment is extremely simple; step 2, palladium-carbon hydrogenation is used for reducing nitro, so that the use of iron powder is reduced, the product purity is high, and the post-treatment is simple; step 4, catalyzing and acylating by using 2-glycine and zinc chloride, so that the step of synthesizing intermediates in the step is shortened; the method has the advantages of simple steps, green reaction, almost no pollution to the environment, extremely high product purity and almost no impurities; meanwhile, the cost of raw materials is low, and the production cost of Iguratimod is greatly reduced.
Of course, it is not necessary for any one product to practice the invention to achieve all of the advantages set forth above at the same time.
Detailed Description
Embodiment one:
a. preparation of intermediate II (4-phenoxy-3-nitroanisole):
1kg of 4-chloro-3-nitroanisole, 0.56kg of phenol, 50g of cuprous iodide and 6L of DMF are added into a 20L glass reaction kettle at room temperature, and 0.81kg of potassium carbonate is added below 30 ℃; heating to 110 ℃ for reaction for 5 hours, and cooling to room temperature; pouring the reaction solution into 15L ice water, extracting 3 times with 5L toluene, washing an organic layer with 5L water for 3 times, finally adding anhydrous sodium sulfate for drying, filtering, and concentrating to obtain 1.25kg of black brown oily 4-phenoxy-3-nitroanisole, wherein the yield is 95.6% and the purity is 97.230%;
b. preparation of intermediate III (4-phenoxy-3-aminoanisole):
1.25kg of 4-phenoxy-3-nitroanisole oily matter is dissolved in 6.25L of methanol, 12.5g of 10% Pd/C is added, the mixture is stirred and dispersed, then the mixture is added into a 20L hydrogenation reaction kettle, the mixture is sealed, nitrogen is replaced for 3 times, hydrogen is replaced for 3 times, finally hydrogenation is carried out to the hydrogen pressure of 0.3-0.5MPa, the mixture is maintained, the temperature is raised to 35-40 ℃ for reaction for 4 hours, the pressure is relieved, the mixture is cooled to the room temperature, the mixture is filtered and concentrated in vacuum, so as to obtain light yellow oily matter, 2.5L of mixed solution of ethyl acetate and 5L of n-hexane is added into the 20L glass reaction kettle, the mixture is stirred, the mixture is heated to reflux and dissolved, the mixture is cooled to the room temperature for recrystallization, so as to obtain 0.89kg of white solid 4-phenoxy-3-aminoanisole, the yield is 81.0%, and the purity is 99.800%;
c. preparation of intermediate IV (4-phenoxy-3-methanesulfonyl anisole):
at room temperature, adding 0.89kg of 4-phenoxy-3-aminoanisole and 4.45L of pyridine into a 20L glass reaction kettle, stirring and cooling to 0-10 ℃, slowly dropwise adding 0.57kg of methanesulfonyl chloride below 20 ℃, adding Bi Jiaoban, and heating to 20-30 ℃ for reaction for 3 hours; pouring the reaction solution into 10L of 6% dilute hydrochloric acid, extracting for 3 times with 5L of dichloromethane, combining organic layers, washing with water to neutrality, drying with anhydrous sodium sulfate, and filtering to obtain a dry light purple dichloromethane solution of 4-phenoxy-3-methanesulfonamido anisole;
d. preparation of intermediate v (N- [4 (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride:
adding a dichloromethane solution of the dried 4-phenoxy-3-methanesulfonyl anisole into a 50L glass reaction kettle, stirring and cooling to 0-10 ℃, adding 1.13kg of anhydrous zinc chloride below 20 ℃, stirring and cooling to 0-10 ℃, adding 0.34kg of 2-glycine, stirring and heating to reflux reaction for 6 hours after the addition, cooling to room temperature, pouring the reaction solution into 10L of 6% diluted hydrochloric acid for quenching until the pH value is=1-3, precipitating a large amount of solid, filtering, washing to neutrality, and obtaining 1.50kg of light yellow solid N- [4- (2-aminoacyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride with the yield of 94.0% and the purity of 95.3%;
e. preparation of intermediate vi (N- [4- (2-carboxamidoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide):
adding 3.6L of anhydrous formic acid and 3.6L of acetic anhydride into a 20L glass reaction kettle, and then heating the reaction liquid to 40-45 ℃ for reaction for 0.5 hour; cooling to 0-10 ℃, adding 1.50kg of N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride into the reaction liquid below 20 ℃, stirring and heating to 40-45 ℃ for reaction for 3 hours, pouring the reaction liquid into 10L of water after the reaction is finished, and stirring for 1 hour. Suction filtering and washing with water to neutrality to obtain white solid N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide 1.17kg with yield of 80.0% and purity of 97.280%;
f. preparation of intermediate vii (N- [4- (2-carboxamidoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide:
sequentially adding 5.8L of acetonitrile and 1.17kg of N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide into a 20L glass reaction kettle, stirring at room temperature for a plurality of minutes, adding 1.17kg of sodium iodide, cooling to 0-10 ℃, controlling the internal temperature to be lower than 20 ℃, adding 0.45kg of aluminum trichloride in batches, naturally heating to 20-30 ℃ after the addition, and carrying out heat preservation stirring reaction for 5 hours; after the reaction is finished, pouring the reaction solution into 1N hydrochloric acid aqueous solution which is cooled in advance in batches (the internal temperature is controlled to be lower than 25 ℃), and stirring for 1h at room temperature after quenching is finished; suction filtration, washing the filter cake with water to neutrality, gives 1.0kg of white solid N- [4- (2-formylaminoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide (yield: 88.8%, HPLC purity: 98.320%);
g. preparing a crude product of Iguratimod:
1kg of N- [4- (2-formamidoacetyl) -5-phenolic hydroxyl-2-phenoxyphenyl ] methanesulfonamide, 4L of trimethyl orthoformate and 17ml of concentrated sulfuric acid are added into a 20L glass reaction kettle, the mixture is stirred for 30min at 20 ℃ with heat preservation (the conversion rate is 64.3%), the mixture is heated to the internal temperature of 40-50 ℃ for reaction for 5 hours (the conversion rate is 99.9%), after the reaction is completed, the reaction solution is poured into 10L of 5% sodium bicarbonate water and stirred for 1 hour; suction filtration, washing twice with 1L of 50% aqueous acetone, drying under reduced pressure at 50 ℃ to obtain 0.84kg (yield 82.0%, HPLC purity 99.76%) of white solid which is Iguratimod crude product;
h. refining Iguratimod:
adding 0.75kg of the Iguratimod crude product obtained in the last step and 2.25L of N, N-dimethylformamide into a 20L glass reaction kettle, heating to 70-75 ℃ to dissolve, stirring for 15-20min at a temperature of 0-5 ℃ to keep the temperature, stirring and crystallizing overnight, then carrying out vacuum suction filtration on the mixture, washing a filter cake with a proper amount of water, and drying the obtained solid under reduced pressure for 10 hours at 55-60 ℃ to obtain 0.71kg of Iguratimod refined product (the yield is 94.7%, the HPLC purity is 99.95%, and the maximum single impurity is 0.04%).
Embodiment two:
a. preparation of intermediate II (4-phenoxy-3-nitroanisole):
1kg of 4-chloro-3-nitroanisole, 0.56kg of phenol, 50g of cuprous iodide and 4.5L of 1, 4-dioxane are added into a 20L glass reaction kettle at room temperature, and 0.5kg of potassium tert-butoxide is added below 30 ℃; heating to 110 ℃ for reaction for 5 hours, and cooling to room temperature; the reaction solution was poured into 15L of ice water, extracted 3 times with 5L of toluene, the organic layer was washed 3 times with 5L of water, finally dried over anhydrous sodium sulfate, filtered and concentrated to give 1.31kg of 4-phenoxy-3-nitroanisole as a dark brown oil, yield 96.1% and purity 98.20%.
b. Preparation of intermediate III (4-phenoxy-3-aminoanisole):
1.25kg of 4-phenoxy-3-nitroanisole oily matter is dissolved in 7.0L of absolute ethyl alcohol, 12.5g of 10% Pd/C is added, the mixture is stirred and dispersed, then the mixture is added into a 20L hydrogenation reaction kettle, the mixture is sealed, nitrogen is replaced for 3 times, hydrogen is replaced for 3 times, finally hydrogenation is carried out until the hydrogen pressure is 0.3-0.5MPa, the mixture is maintained, the temperature is raised to 35-40 ℃ for reaction for 4 hours, the mixture is decompressed and cooled to room temperature, the mixture is filtered and concentrated in vacuum, so as to obtain light yellow oily matter, 2.5L of mixed solution of ethyl acetate and 5L of n-hexane is added into the 20L glass reaction kettle, the mixture is stirred and heated to reflux for dissolving, the mixture is cooled to room temperature for recrystallization, so as to obtain 0.90kg of white solid 4-phenoxy-3-aminoanisole, and the yield is 82.3%, and the purity is 99.9%;
c. preparation of intermediate IV (4-phenoxy-3-methanesulfonyl anisole):
at room temperature, adding 0.9kg of 4-phenoxy-3-aminoanisole and 4.5L of pyridine into a 20L glass reaction kettle, stirring and cooling to 0-10 ℃, slowly dropwise adding 0.6kg of methanesulfonyl chloride below 20 ℃, adding Bi Jiaoban, and heating to 20-30 ℃ for reaction for 3 hours; pouring the reaction solution into 10L of 6% dilute hydrochloric acid, extracting for 3 times with 5L of dichloromethane, combining organic layers, washing with water to neutrality, drying with anhydrous sodium sulfate, and filtering to obtain a dry light purple dichloromethane solution of 4-phenoxy-3-methanesulfonamido anisole;
d. preparation of intermediate v (N- [4 (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride:
adding a dichloromethane solution of the dried 4-phenoxy-3-methanesulfonyl anisole into a 50L glass reaction kettle, stirring and cooling to 0-10 ℃, adding 1.8kg of anhydrous aluminum trichloride below 20 ℃, stirring and cooling to 0-10 ℃, adding 0.3kg of 2-glycine, stirring and heating to reflux reaction for 6 hours after adding, cooling to room temperature, pouring the reaction solution into 10L of 6% diluted hydrochloric acid for quenching until pH=1-3, precipitating a large amount of solid, filtering, washing to neutrality, and obtaining 1.59kg of light yellow solid N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride with the yield of 94.8% and the purity of 95.9%;
e. preparation of intermediate vi (N- [4- (2-carboxamidoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide):
adding 3.6L of anhydrous formic acid and 3L of tertiary valeric anhydride into a 20L glass reaction kettle, heating the reaction liquid to 40-45 ℃ for reaction for 0.5 hour, cooling to 0-10 ℃, adding 1.50kg of N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride into the reaction liquid below 20 ℃, stirring and heating to 40-45 ℃ for reaction for 3 hours, and pouring the reaction liquid into 10L of water and stirring for 1 hour after the reaction is finished; suction filtering and washing with water to neutrality to obtain white solid N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide 1.2kg with a yield of 81.2% and a purity of 97.50%;
f. preparation of intermediate vii (N- [4- (2-carboxamidoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide:
sequentially adding 5.8L of acetonitrile and 1.17kg of N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide into a 20L glass reaction kettle, stirring at room temperature for a plurality of minutes, adding 1.2kg of sodium iodide, cooling to 0-10 ℃, controlling the internal temperature to be lower than 20 ℃, adding 0.5kg of aluminum trichloride in batches, naturally heating to 20-30 ℃ after the addition, and carrying out heat preservation stirring reaction for 5 hours; after the reaction is finished, pouring the reaction solution into 1N hydrochloric acid aqueous solution which is cooled in advance in batches (the internal temperature is controlled to be lower than 25 ℃), and stirring for 1h at room temperature after quenching is finished; suction filtration, washing the filter cake with water to neutrality, gives 1.08kg of white solid N- [4- (2-formylaminoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide (yield: 89.1%, HPLC purity: 98.6%);
g. preparing a crude product of Iguratimod:
1kg of N- [4- (2-formylaminoacetyl) -5-phenolic hydroxyl-2-phenoxyphenyl ] methanesulfonamide, 5.3L of N, N-dimethylformamide dimethyl acetal and 17ml (30 g) of concentrated sulfuric acid are added into a 20L glass reaction kettle, the mixture is stirred for 30min at 20 ℃ under heat preservation (the conversion rate is 64.9%), the temperature is raised to 40-50 ℃ for reaction for 5 hours (the conversion rate is 99.9%), and after the reaction is completed, the reaction solution is poured into 10L of 5% sodium bicarbonate water and stirred for 1 hour; suction filtration, washing twice with 1L of 50% aqueous acetone, drying under reduced pressure at 50 ℃ to obtain 0.86kg (yield 82.8%, HPLC purity 99.8%) of white solid which is Iguratimod crude product;
h. refining Iguratimod:
adding 0.8kg of the Iguratimod crude product obtained in the last step and 2.4L of N, N-dimethylformamide into a 20L glass reaction kettle, heating to 70-75 ℃ for dissolving, stirring for 15-20min at a temperature of 0-5 ℃ for crystallizing overnight at a temperature of 0-5 ℃, then carrying out vacuum suction filtration on the mixture, washing a filter cake with a proper amount of water, and drying the obtained solid under reduced pressure for 10 hours at 55-60 ℃ to obtain 0.76kg of Iguratimod refined product (the yield is 95.3%, the HPLC purity is 99.96%, and the maximum single impurity is 0.03%).
Embodiment III:
a. preparation of intermediate II (4-phenoxy-3-nitroanisole):
1kg of 4-chloro-3-nitroanisole, 0.56kg of phenol, 26g of copper oxide and 5L of dimethyl sulfoxide are added into a 20L glass reaction kettle at room temperature, and 0.5kg of potassium tert-butoxide is added below 30 ℃; heating to 110 ℃ for reaction for 5 hours, and cooling to room temperature; pouring the reaction solution into 15L ice water, extracting 3 times with 5L toluene, washing an organic layer with 5L water for 3 times, finally adding anhydrous sodium sulfate for drying, filtering, and concentrating to obtain 1.28kg of black brown oily 4-phenoxy-3-nitroanisole, wherein the yield is 95.9%, and the purity is 98.0%;
b. preparation of intermediate III (4-phenoxy-3-aminoanisole):
1.25kg of 4-phenoxy-3-nitroanisole oily matter is dissolved in 7.0L of methanol, 12.5g of 10% Pd/C is added, the mixture is stirred and dispersed, then the mixture is added into a 20L hydrogenation reaction kettle, the mixture is sealed, nitrogen is replaced for 3 times, hydrogen is replaced for 3 times, finally hydrogenation is carried out to the hydrogen pressure of 0.4-0.5MPa, the mixture is maintained, the temperature is raised to 40-45 ℃ for reaction for 4 hours, the pressure is relieved, the mixture is cooled to the room temperature, the mixture is filtered and concentrated in vacuum, so as to obtain light yellow oily matter, 23L of mixed solution of ethyl acetate and 5L of n-hexane is added into the 20L glass reaction kettle, the mixture is stirred and heated to reflux and clear, the mixture is cooled to the room temperature for recrystallization, so as to obtain 1.01kg of white solid 4-phenoxy-3-amino anisole, and the yield is 83.7%, and the purity is 99.9%;
c. preparation of intermediate IV (4-phenoxy-3-methanesulfonyl anisole):
at room temperature, 1.0kg of 4-phenoxy-3-aminoanisole and 4.8L of pyridine are put into a 20L glass reaction kettle, stirred and cooled to 0-10 ℃, 0.7kg of methanesulfonyl chloride is slowly added dropwise below 20 ℃, and Bi Jiaoban is added, and the temperature is raised to 20-30 ℃ for reaction for 3 hours; pouring the reaction solution into 10L of 6% dilute hydrochloric acid, extracting for 3 times with 5L of dichloromethane, combining organic layers, washing with water to neutrality, drying with anhydrous sodium sulfate, and filtering to obtain a dry light purple dichloromethane solution of 4-phenoxy-3-methanesulfonamido anisole;
d. preparation of intermediate v (N- [4 (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride:
adding a dried methylene dichloride solution of 4-phenoxy-3-methanesulfonyl anisole into a 50L glass reaction kettle, stirring and cooling to 0-10 ℃, adding 1.23kg of anhydrous zinc chloride below 20 ℃, stirring and cooling to 0-10 ℃, adding 0.32kg of 2-glycine, stirring and heating to reflux reaction for 6 hours after adding, cooling to room temperature, pouring the reaction solution into 10L of 6% diluted hydrochloric acid for quenching until pH=1-3, precipitating a large amount of solid, filtering, washing to neutrality, and obtaining 1.86kg of light yellow solid N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride with the yield of 95.4% and the purity of 96.3%;
e. preparation of intermediate vi (N- [4- (2-carboxamidoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide):
adding 3.6L of anhydrous formic acid and 4L of acetic anhydride into a 20L glass reaction kettle, and then heating the reaction liquid to 40-45 ℃ for reaction for 0.5 hour; cooling to 0-10 ℃, adding 1.80kg of N- [4- (2-aminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide hydrochloride into the reaction liquid below 20 ℃, stirring and heating to 40-45 ℃ for reaction for 3 hours, pouring the reaction liquid into 10L of water after the reaction is finished, and stirring for 1 hour; suction filtering and washing with water to neutrality to obtain white solid N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide 1.35kg with a yield of 82.6% and a purity of 97.8%;
f. preparation of intermediate vii (N- [4- (2-carboxamidoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide:
acetonitrile 6L and N- [4- (2-formylaminoacetyl) -5-methoxy-2-phenoxyphenyl ] methanesulfonamide 1.30kg are sequentially added into a 20L glass reaction kettle, and after stirring for a plurality of minutes at room temperature, sodium iodide 1.4kg is added; cooling to 0-10 ℃, controlling the internal temperature to be lower than 20 ℃, adding 0.58kg of aluminum trichloride in batches, naturally heating to 20-30 ℃ after the addition, preserving heat, stirring and reacting for 5 hours; after the reaction is finished, pouring the reaction solution into 1N hydrochloric acid aqueous solution which is cooled in advance in batches (the internal temperature is controlled to be lower than 25 ℃), and stirring for 1h at room temperature after quenching is finished; suction filtration, washing the filter cake with water to neutrality, gives 1.13kg of white solid N- [4- (2-formylaminoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide (yield: 90.3%, HPLC purity: 98.9%);
g. preparing a crude product of Iguratimod:
1.1kg of N- [4- (2-formylaminoacetyl) -5-phenolic hydroxy-2-phenoxyphenyl ] methanesulfonamide, 5.5L of N, N-dimethylformamide dimethyl acetal and 18ml (32 g) of concentrated sulfuric acid were put into a 20L glass reactor, stirred at 20℃for 30 minutes (conversion: 65.6%), heated to an internal temperature of 40 to 50℃and reacted for 5 hours (conversion: 99.9%), and after completion of the reaction, the reaction mixture was poured into 10L of 5% sodium hydrogencarbonate water and stirred for 1 hour. Suction filtration, washing twice with 1L of 50% aqueous acetone, drying under reduced pressure at 50 ℃ to obtain 0.91kg (yield 84.6%, HPLC purity 99.90%) of white solid which is Iguratimod crude product;
h. refining Iguratimod:
adding 0.9kg of the Iguratimod crude product obtained in the last step and 25L of N, N-dimethylformamide into a 20L glass reaction kettle, heating to 70-75 ℃ to dissolve, stirring for 15-20min at a temperature of 0-5 ℃, stirring for crystallization overnight at a temperature of 0-5 ℃, then carrying out vacuum suction filtration on the mixture, washing a filter cake with a proper amount of water, and drying the obtained solid under reduced pressure for 10 hours at 55-60 ℃ to obtain 0.86kg of Iguratimod refined product (yield 95.4%, HPLC purity 99.98%, maximum single impurity: 0.02%).
Table one: in the industrial production of Iguratimod, the related impurities are as follows:
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because of the production process difference, a plurality of key impurities exist in the product and are difficult to completely remove, the quality of the product is seriously affected, and the following standards which are prepared according to the second edition of the latest Chinese pharmacopoeia 2020 and accord with clinical medicines are adopted:
and (II) table: clinical pharmaceutical standard
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The Iguratimod refined products obtained in the first, second and third examples were tested, and the obtained results are shown in the following table three:
table three: iguratimod refined product detection result
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In the above, the correspondence between the impurities in table two and the impurities in table one is:
impurity A-corresponding impurity 1, impurity B-corresponding impurity 9, impurity C-corresponding impurity 10, impurity D-corresponding impurity 13, impurity E-corresponding impurity 17, impurity G-corresponding impurity 20, impurity I-corresponding impurity 11, impurity J-corresponding impurity 21.
According to the above table three, in the three examples of the present invention, by optimizing the reaction parameters in each step, the impurity a, impurity B, impurity C, impurity D, impurity E, impurity F, impurity H, impurity I and impurity J in the obtained Iguratimod fine product were all in accordance with the ICH guidelines, and only a small amount of impurity E (0.02%) and impurity D (0.04%) were detected. In the whole reaction process, the invention eliminates the use of flammable and explosive reagents and toxic reagents, reduces waste discharge, is beneficial to labor protection, reduces production cost and improves economic benefit.
In the description of the present specification, the descriptions of the terms "one embodiment," "example," "specific example," and the like, mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
Claims (10)
1. A method suitable for industrial production of Iguratimod, comprising:
step 1, phenol is dissolved in an organic solvent A, a copper catalyst is used for catalysis, an acid binding agent is added, and the reaction product is catalytically coupled with 4-chloro-3-nitroanisole to prepare an intermediate II:
step 2, preparing an intermediate III from the intermediate II in an organic solvent B through catalytic hydrogenation;
step 3, the intermediate III is subjected to methanesulfonyl chloride sulfonylation in an alkaline solvent to prepare an intermediate IV;
step 4, reacting the intermediate IV with 2-amino acetic acid in an organic solvent C under the catalysis of Lewis acid to obtain an intermediate V;
step 5, formylating the intermediate V with mixed anhydride to obtain an intermediate VI;
step 6, demethylating the intermediate VI in an organic solvent D to obtain an intermediate VII;
step 7, cyclizing the intermediate VII in an organic solvent E to obtain a crude Iguratimod product;
and 8, recrystallizing the Iguratimod crude product to obtain a refined Iguratimod I.
2. The method according to claim 1, wherein in the step 1, the organic solvent a is one of N-methylpyrrolidone, 1, 4-dioxane, N-dimethylformamide or dimethylsulfoxide;
the copper catalyst is copper oxide and cuprous iodide, and the dosage of the catalyst is 5.0% of the weight of the compound 4-chloro-3-nitroanisole;
the acid binding agent is potassium phosphate, potassium tert-butoxide, potassium carbonate and triethylamine, and the dosage of the acid binding agent is 1.1 times of the molar quantity of the compound 4-chloro-3-nitroanisole;
the dosage of the phenol is 1.0-1.5 times of the molar quantity of the compound 4-chloro-3-nitroanisole, the material is fed at room temperature, and the temperature is raised to 110 ℃ for reaction for 5 hours.
3. The method according to claim 1, wherein in the step 2, the organic solvent B is methanol or absolute ethanol; and the volume dosage of the organic solvent B is 5 times of the weight of the intermediate II;
the catalyst used in the catalytic hydrogenation is 10% Pd/C or Raney nickel, the dosage of the catalyst is 1.0% of the weight of the intermediate II, the hydrogen pressure in the catalytic hydrogenation is 0.1-0.5MPa, and the reaction temperature is controlled to be 20-40 ℃ for catalytic reaction for 3-5h.
4. A process suitable for the industrial production of Iguratimod according to claim 1, characterized in that in said step 3, said basic solvent is pyridine and said organic solvent C is used in a volume quantity 5 times the weight of intermediate III;
the dosage of the methanesulfonyl chloride is 1.0-2.0 times of the molar quantity of the intermediate III, the methanesulfonyl chloride is fed below 20 ℃, and the methanesulfonyl chloride reacts for 3 hours at the temperature of 20-30 ℃.
5. A process suitable for the industrial production of Iguratimod according to claim 1, characterized in that in said step 4, the lewis acid is anhydrous aluminium trichloride, zinc chloride or phosphorus oxychloride and the lewis acid is used in an amount 2 times the molar amount of intermediate IV;
the organic solvent C is dichloromethane;
the dosage of the 2-glycine is 1.0 to 1.5 times of the molar quantity of the intermediate IV;
and feeding below 20 ℃, heating to 30-50 ℃ and carrying out reflux reaction for 5-7hh.
6. A method according to claim 1, wherein in step 5, the mixed anhydride is acetic anhydride formate or tertiary valeric anhydride formate; the dosage of the mixed anhydride is 1.5 times of the molar quantity of the intermediate;
in the step 5, the materials are fed below 20 ℃ and reacted for 3 hours at 20-30 ℃.
7. The method for industrially producing Iguratimod according to claim 1, wherein in the step 6, the organic solvent D is acetonitrile, and the volume amount of the organic solvent D is 5 to 8 times by weight of the intermediate VI;
stirring and mixing intermediate VI and acetonitrile at room temperature, adding sodium iodide, cooling to 0-10deg.C, controlling the temperature of the reaction system to be lower than 20deg.C, adding aluminum trichloride in batches, naturally heating to 20-30deg.C after the addition, and stirring for reacting for 5 hr; after the reaction is completed, pouring the reaction solution into hydrochloric acid aqueous solution with temperature reduced in advance in batches, and stirring for 1h at room temperature after quenching is completed; suction filtration is carried out, and the filter cake is washed to be neutral by water, thus obtaining white solid intermediate VII.
8. A process according to claim 7, wherein the molar amount of aluminum trichloride is 1-2 times the molar amount of intermediate VI and the amount of sodium iodide is 1-2 times the weight of intermediate VI.
9. The method for industrially producing Iguratimod according to claim 1, wherein in the step 7, intermediate VII, the cyclization agent and catalyst B are stirred at 20 ℃ for 30min under heat preservation, then the temperature is raised to 40-50 ℃ for reaction for 5 hours, after completion, the reaction solution is poured into 5% sodium bicarbonate water, stirred for 1 hour, suction filtered, washed twice with 50% aqueous acetone, and dried under reduced pressure at 50 ℃ to obtain a white solid as a crude Iguratimod product.
10. A method according to claim 9, wherein the cyclizing reagent is N, N-dimethylformamide dimethyl acetal (DMFDMA) or trimethyl orthoformate and the volume amount of the cyclizing reagent is 4 times the weight of intermediate VII;
the catalyst B is sulfuric acid, hydrochloric acid or glacial acetic acid, and the volume dosage of the catalyst B is 0.6 time of the weight of the intermediate VII.
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