CN118271292A - Synthesis method of drug for treating new crown drug Enxi Qu Wei raw material drug - Google Patents
Synthesis method of drug for treating new crown drug Enxi Qu Wei raw material drug Download PDFInfo
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- CN118271292A CN118271292A CN202211713331.0A CN202211713331A CN118271292A CN 118271292 A CN118271292 A CN 118271292A CN 202211713331 A CN202211713331 A CN 202211713331A CN 118271292 A CN118271292 A CN 118271292A
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- indazol
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- 239000003814 drug Substances 0.000 title claims abstract description 22
- 229940079593 drug Drugs 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title claims description 7
- 239000002994 raw material Substances 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 44
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 24
- -1 1- (6-chloro-2-methyl-2H-indazole-5-yl) -3- (2, 4, 5-trifluoro-benzyl) guanidine Chemical compound 0.000 claims description 22
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 15
- YRZNRFJEBAPCCO-UHFFFAOYSA-N Cn1cc2cc(N)c(Cl)cc2n1 Chemical compound Cn1cc2cc(N)c(Cl)cc2n1 YRZNRFJEBAPCCO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- BLJQJQNRXILVTA-UHFFFAOYSA-N (2,4,5-trifluorophenyl)methanamine Chemical compound NCC1=CC(F)=C(F)C=C1F BLJQJQNRXILVTA-UHFFFAOYSA-N 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 238000010189 synthetic method Methods 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 9
- YADGRHBCQYSHSZ-UHFFFAOYSA-N (5-methyl-1h-1,2,4-triazol-3-yl)methanamine Chemical compound CC1=NC(CN)=NN1 YADGRHBCQYSHSZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 230000010933 acylation Effects 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 210000001503 joint Anatomy 0.000 claims description 2
- 238000003032 molecular docking Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 241001678559 COVID-19 virus Species 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- KISIDCUHOLGEPR-UHFFFAOYSA-N 3-(chloromethyl)-1-methyl-1,2,4-triazole;hydrochloride Chemical compound Cl.CN1C=NC(CCl)=N1 KISIDCUHOLGEPR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 2
- GAUXEYCSWSMMFZ-UHFFFAOYSA-N 1-(bromomethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CBr)C=C1F GAUXEYCSWSMMFZ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OJQUPPYIFXZURP-UHFFFAOYSA-N 6-ethylsulfanyl-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CCSC(N(CC(C=C(C(F)=C1)F)=C1F)C(N1)=O)=NC1=O OJQUPPYIFXZURP-UHFFFAOYSA-N 0.000 description 2
- BFAFXODRFFVZRM-UHFFFAOYSA-N 6-ethylsulfanyl-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CCSC(N(CC(C=C(C(F)=C1)F)=C1F)C(N1CC2=NN(C)C=N2)=O)=NC1=O BFAFXODRFFVZRM-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 2
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 2
- MICCTXUOIKZJSQ-UHFFFAOYSA-N CN1N=C(C=C(C(N=C=S)=C2)Cl)C2=C1 Chemical compound CN1N=C(C=C(C(N=C=S)=C2)Cl)C2=C1 MICCTXUOIKZJSQ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CYDQNBVEIPQTBR-UHFFFAOYSA-N 3-(isocyanatomethyl)-1-methyl-1,2,4-triazole Chemical compound Cn1cnc(CN=C=O)n1 CYDQNBVEIPQTBR-UHFFFAOYSA-N 0.000 description 1
- UONAXWPHNRNXTB-UHFFFAOYSA-N 3-tert-butyl-6-ethylsulfanyl-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CCSC(N(CC(C=C(C(F)=C1)F)=C1F)C(N1C(C)(C)C)=O)=NC1=O UONAXWPHNRNXTB-UHFFFAOYSA-N 0.000 description 1
- BDGLMLJBANMNCP-UHFFFAOYSA-N 3-tert-butyl-6-ethylsulfanyl-1h-1,3,5-triazine-2,4-dione Chemical compound CCSC1=NC(=O)N(C(C)(C)C)C(=O)N1 BDGLMLJBANMNCP-UHFFFAOYSA-N 0.000 description 1
- QMPBBNUOBOFBFS-UHFFFAOYSA-N 6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CN1N=C(C=C(C(/N=C(\NC(N2CC3=NN(C)C=N3)=O)/N(CC(C=C(C(F)=C3)F)=C3F)C2=O)=C2)Cl)C2=C1 QMPBBNUOBOFBFS-UHFFFAOYSA-N 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 101710198474 Spike protein Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
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- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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Abstract
The invention relates to a method for synthesizing a bulk drug of an Enxi Qu Wei drug for treating a new crown, which has the advantages of short route, high yield and the like.
Description
Technical Field
The invention belongs to the field of chemical medicines, and in particular relates to a synthesis method of an Enxi Qu Wei raw material medicine for treating a new crown medicine and an intermediate thereof.
Background
SARS-CoV-2 is an angiotensin converting enzyme 2 (ACE 2) expressed on the surface of the cell membrane of host cells and a spike protein targeted to the surface of its outer shell. ACE2 is expressed in nasal, alveolar and intestinal epithelial cells by specific binding into host cells.
Enxi Qu Wei (ENSITRELVIR FUMARIC ACID) fumarate is a drug developed by salt wild pharmaceutical Co., ltd. For treating infection caused by SARS-CoV-2. The medicine can play antiviral role of SARS-CoV-2 by inhibiting 3C-like (3 CL) protease, which is important for treating SARS-CoV-2 gene encoded polyprotein and viral replication.
Chinese cultural name of Enxi Qu Wei fumarate: (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione monofumaric acid, formula: c 22H17ClF3N9O2·C4H4O4, molecular weight: 647.95, CAS registry number 2757470-18-9, having the following chemical formula:
Prior art document patent CN202280000918 reports the synthetic route 1 of emcey Qu Wei as follows:
the method comprises the following steps:
Step 1:3- (tert-butyl) -6- (ethylthio) -1,3, 5-triazine-2, 4 (1H, 3H) -dione and 1- (bromomethyl) -2,4, 5-trifluorobenzene react to obtain 3- (tert-butyl) -6- (ethylthio) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione.
Step 2:3- (tert-butyl) -6- (ethylsulfanyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione tert-butyl gives the intermediate 6- (ethylsulfanyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione.
Step 3: reaction of 6- (ethylsulfanyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione with 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride gives 6- (ethylsulfanyl) -3- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4-dione.
Step 4: reaction of 6- (ethylsulfanyl) -3- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4-dione with 6-chloro-2-methyl-2H-indazol-5-amine gives encyclopedia Qu Wei.
The Enxi Qu Wei is obtained by 4 steps of reactions in the above route, but the problems of long route, low yield and the like exist.
Prior art document patent CN202210492413.0 reports the following synthetic route 2 for emcey Qu Wei:
the method comprises the following steps:
Step 1: the condensation reaction of 6-chloro-2-methyl-5-isothiocyanato-2H-indazole (II) and 2,4, 5-trifluoro phenyl methyl amine (III) is carried out to generate N- [ (6-chloro-2-methyl) -2H-indazole-5-yl ] -N' - [1- (2, 4, 5-trifluoro phenyl) methyl ] thiourea (IV);
step 2: ammonification of N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N '- [1- (2, 4, 5-trifluorophenyl) methyl ] thiourea (IV) with ammonia under the action of 2-iodoxybenzoic acid to obtain N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2, 4, 5-trifluorophenyl) methyl ] guanidine (V);
step 3: acylating N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2, 4, 5-trifluorophenyl) methyl ] guanidine (V) with 1-methyl-3-isocyanatomethyl-1H-1, 2, 4-triazole (VI) to produce 1- [ [1- (2, 4, 5-trifluorophenyl) methyl ] [ 6-chloro-2-methyl) -2H-indazol-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea (VII);
Step 4:1- [ [1- (2, 4, 5-trifluoro phenyl) methyl ] [ 6-chloro-2-methyl) -2H-indazole-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazole-3-yl) methyl ] urea (VII) and carbonyl chloride undergo a cyclization reaction under the action of an acid binding agent to prepare the Enxi Qu Wei.
The Enxi Qu Wei is obtained by 4 steps of reactions in the above route, but the problems of long route, low yield and the like still exist.
Therefore, the synthesis method with short route, safe and simple operation and low cost is provided, which is helpful for solving the accessibility problem of the raw material medicine for treating the new coronary drug Enxi Qu Wei.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a drug raw material, an intermediate and a synthesis method for treating a new coronary drug Enxi Qu Wei.
The invention aims to provide a synthetic method for obtaining an Enxi Qu Wei bulk drug by quick reaction. The method has the advantages of short route, safe and simple operation, low cost and the like.
The invention provides a method for synthesizing a new crown treatment drug Enxi Qu Weixin, which takes 1- (6-chloro-2-methyl-2H-indazole-5-amine, 2,4, 5-trifluoro-benzylamine and 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole as main starting raw materials and only carries out 2 steps of reactions to obtain Enxi Qu Wei.
The invention provides a synthetic method of Enxi Qu Weixin, which comprises the following steps:
Step 1, reacting 6-chloro-2-methyl-2H-indazole-5-amine with dicyandiamide sodium, and then reacting with 2,4, 5-trifluoro-benzylamine to obtain 1- (6-chloro-2-methyl-2H-indazole-5-yl) -3- (2, 4, 5-trifluoro-benzyl) guanidine;
step 2, 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluoro benzyl) guanidine, 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole and an acylating agent are subjected to acylation butt joint reaction, and then are subjected to acylation ring closure reaction with the acylating agent, so that the Enxi Qu Wei is obtained by a one-pot method.
In the reaction of step 1 in the present invention, the amino group in 6-chloro-2-methyl-2H-indazol-5-amine is more active than the amino group in2, 4, 5-trifluorobenzylamine, and is selected to react completely with dicyandiamide sodium to produce intermediate N- (6-chloro-2-methyl-2H-indazol-5-yl) carbamoyl cyanide, and then react with 2,4, 5-trifluorobenzylamine to produce 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine. In the reaction process, any excessive main material finally becomes impurities which are not easy to remove, excessive or less sodium dicyandiamide is added to cause by-product increase or incomplete reaction, and the mole feeding ratio of 6-chloro-2-methyl-2H-indazole-5-amine, 2,4, 5-trifluoro-benzylamine and sodium dicyandiamide is 1:0.9-1.1: 0.9 to 1.1, preferably 1:0.95 to 1.05:0.95 to 1.05, particularly preferably 1:1:1.
In the invention, the catalyst of the reaction in the step 1 is concentrated hydrochloric acid, and because two main materials and dicyandiamide sodium consume 4 equivalents of hydrochloric acid, in order to ensure that the reaction system is in an acidic condition, the molar charging ratio of 6-chloro-2-methyl-2H-indazole-5-amine to the concentrated hydrochloric acid is 1:4-5, preferably 1:4.5.
The reaction conditions of step1 in the present invention further include: the reaction is carried out in an ethanol-water mixed solvent, and the ethanol-water mixed solvent can ensure the dissolution of materials and products and is beneficial to the reaction. The reflux reaction of the 6-chloro-2-methyl-2H-indazole-5-amine and sodium dicyandiamide for 3 hours can ensure that the intermediate N- (6-chloro-2-methyl-2H-indazole-5-yl) carbamoyl cyanide is completely converted, and the reflux reaction of the 2,4, 5-trifluoro-benzylamine is added for 9 hours, so that the intermediate and the 2,4, 5-trifluoro-benzylamine can be completely reacted.
In the reaction of step 2, the acylate is introduced with carbonyl twice to directly influence the butt reaction of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine and 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole, and the subsequent ring closing reaction, the selection of which is important; the acylating agent is selected from triphosgene, carbonyl diimidazole and carbonyl chloride, wherein carbonyl diimidazole is preferable because of large steric hindrance, strong selectivity and less reaction byproducts.
In the present invention, the reaction solvent in step2 is selected from tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, preferably dimethylacetamide, while the solubility of the materials and the products at room temperature is compatible with the catalyst.
In the reaction of the step 2, organic base is required to be added as a catalyst, wherein the organic base is selected from triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and N, N-diisopropylethylamine, and the 1, 8-diazabicyclo [5.4.0] undec-7-ene has strong alkalinity, is favorable for the separation and adsorption combination of imidazolyl in carbonyl diimidazole, promotes the reaction process, has few byproducts and is preferred.
In the present invention, the molar ratio of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine to 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole was found to be 1:0.9 to 1.1, preferably 1:0.95 to 1.05, and particularly preferably 1:1, as determined by experimental investigation, as an impurity which is not easily removed from any excess of the main materials in the reaction in step 2.
In the step 2 of the invention, carbonyl diimidazole is taken as an acylate in the stage of the acylation docking reaction of the main material, and excessive or less feeding of the carbonyl diimidazole can lead to increase of byproducts or incomplete reaction; and 1, 8-diazabicyclo [5.4.0] undec-7-ene is used as a catalyst, and the same equivalent feeding as carbonyl diimidazole needs to be ensured, so that the molar feeding ratio of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluoro-benzyl) guanidine, carbonyl diimidazole and 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1:0.9-1.1: 0.9 to 1.1, preferably 1:0.95 to 1.05:0.95 to 1.05, particularly preferably 1:1:1. In the step 2 of the ring closure reaction, excessive additional materials of carbonyldiimidazole and 1, 8-diazabicyclo [5.4.0] undec-7-ene can promote the reaction progress, the incomplete ring closure reaction is avoided, and through experimental investigation, the molar feed ratio of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine to the additional materials of carbonyldiimidazole and 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1:1.2-1.8: 1.2 to 1.8, preferably 1:1.4 to 1.6:1.4 to 1.6, particularly preferably 1:1.5:1.5.
The method for preparing the En Qu Xiwei by the one-pot method in the step 2 also comprises the control of the feeding sequence, the reaction temperature, the reaction time, the post-treatment, the final recrystallization operation and other conditions, and the high yield and the high purity of the En Qu Xiwei can be ensured based on the control.
The invention provides a synthetic method of Enxi Qu Weixin with 2 steps of reactions, short route, high yield and industrialization potential, which is different from the synthetic route of Enxi Qu Wei in the prior art document CN20228000091, and the steps are obviously shortened and the yield is higher. Compared with the Enxi Qu Wei step synthesis route in the prior art document CN202210492413, the route is shorter, and the synthesis efficiency and the yield are higher by using the one-pot method.
Drawings
Fig. 1: synthetic route of crude drug of Enxi Qu Wei
The specific implementation method comprises the following steps:
The technical solutions in the embodiments of the present invention will be described in detail in the following embodiments of the present invention, but the following embodiments are only for understanding the present invention, and are not limited to the present invention, which can be implemented in various ways defined and covered by the claims.
The synthetic method of Enxi Qu Weixin and the advantages of this method are further described below in conjunction with examples 1 and 2 of the present invention and comparative examples.
EXAMPLE 1 Synthesis of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine
6-Chloro-2-methyl-2H-indazol-5-amine (90.8 g,0.5 mol), dicyandiamide sodium (44.5 g,0.5 mol), concentrated hydrochloric acid (187 ml), absolute ethanol (200 ml), water (0.8L) were added to a three-necked flask, reflux reacted for 3H, 2,4, 5-trifluorobenzyl amine (80.6 g,0.5 mol) was added, reflux reacted for 9H continued, cooled to room temperature, dichloromethane 1.2L and 0.5L water were added, ph was adjusted to 7-8 with 30% sodium hydroxide solution, the separated liquid was washed with water 2 times (1L/time), the organic phase was dried with 60g of anhydrous sodium sulfate for 2H, concentrated under reduced pressure to dryness, the residue was added with 400ml of n-hexane, filtered, and after drying the filter cake, recrystallized with absolute ethanol (500 ml) -water (920 ml) to give the objective product 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) -3- (6.152 g, yield 83％).Ms m/z 368.1(M+1).1H NMR(300MHz d6-DMSO)：δ3.93(s,3H),4.61(s,2H),6.68(d,1H),6.94(s,1H),7.18(s,1H),7.46(s,1H),8.02(s,1H).
Example 2 Synthesis of Enxi Qu Wei
5-Methyl-3-aminomethyl-1H-1, 2, 4-triazole (11.2 g,0.1 mol) and N, N-dimethylacetamide (200 mL) were added to a three-necked flask, stirred for dissolution, stirred and cooled to-5℃to 5 ℃. Carbonyl diimidazole (16.2 g,0.1 mmol) was added in portions at a temperature of 20℃or less, stirred at room temperature for 1H, 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine (36.8 g,0.1 mol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (15.2 g,0.1 mol) were added in portions at a temperature of 20℃or less, stirring was continued for 1H at a temperature of 20-30℃under control, carbonyl diimidazole (24.3 g,0.15 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (22.8 g,0.15 mol) were added in portions at a temperature of 20℃or less, stirring was performed for 24H at room temperature, methylene chloride (400 ml) and water (200 ml) were added, the aqueous fraction was stirred, the organic phase was washed with water 2 times (200 ml/time), anhydrous sodium sulfate (15 g) was dried for 2H, the filtrate was filtered, and the crystalline product was concentrated to give a dry filtrate (100 ml) which was dried to give a dry product of the desired crystalline product (100 ml, ethanol, and ethanol was concentrated to give a dry filtrate (43 g, ethanol-free) and ethanol product was added 82％),Ms m/z 532.1(M+1).1H NMR(300MHz d6-DMSO)：δ3.88(s,3H),4.18(s,3H),5.15(s,2H),5.33(s,2H),6.94-6.85(m,1H),7.06(s,1H),7.43-7.35(m,1H),7.46(s,1H),7.80(d,1H),8.01(s,1H).
Comparative example:
the synthetic process of enci Qu Wei referred to in chinese patent CN202280000918 [ example 7 ], is as follows:
Process 1 Synthesis of Compound 18
Compound 4 (926 mg, 4.04 mmol), acetonitrile (7.41 mL), potassium carbonate (726 mg, 5.25 mmol) and 2,4, 5-trifluorobenzyl bromide (1000 mg, 4.44 mmol) were mixed. The reaction solution was stirred at 80 ℃ for 40 minutes, cooled, and then diluted with ethyl acetate. After insoluble matter was filtered off, the filtrate was concentrated to give a crude product (1.51 g, 4.04mmol, yield: quantitative) of compound 18.
Process 2 Synthesis of Compound 19
Compound 18 (1.51 g, 4.04 mmol) and TFA (3.02 mL) were mixed. The reaction solution was stirred at room temperature for 4 hours and allowed to stand overnight. TFA was removed by distillation under the reduced pressure, and toluene was added to the residue to azeotrope. Isopropyl ether was added to the residue to suspend it, and then filtered to give compound 19 (1.22 g, 3.84mmol, yield 95%).
Process 3 Synthesis of Compound 20
Compound 19 (200 mg, 0.63 mmol), DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol) and 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60℃for 2 hours, and a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform and filtered. The residue was mixed with DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol) and 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (159 mg, 0.946 mmol). The reaction solution was stirred at 60℃for 6 hours, and a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform and collected by filtration to give compound 20 (116 mg, 0.281mmol, yield 45%).
Process 4 Synthesis of Compound (I-0115, enxi Qu Wei)
Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL) and 6-chloro-2-methyl-2H-indazole-5-ammonia (60.8 mg, 0.335 mmol) were mixed. LHMDS (558. Mu.L, 0.558 mmol) was added dropwise to the reaction solution at 0 ℃. The reaction solution was stirred at 0 ℃ for 2.5 hours and at room temperature for 40 minutes, and a saturated aqueous ammonium chloride solution was added. The organic layer was extracted with chloroform and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol) to give compound (I-0115) (61.8 mg, 0.116mmol, yield 42%).
Compared with the synthetic method of the Enxi Qu Wei provided by the comparative example, the synthetic method of the invention of the examples 1 and 2 has the advantages of short route, high yield, reduced health damage to production operators and more environment-friendly property.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A method for synthesizing a new crown medicine Enxi Qu Wei bulk drug is characterized in that:
Step 1, reacting 6-chloro-2-methyl-2H-indazole-5-amine with dicyandiamide sodium, and then reacting with 2,4, 5-trifluoro-benzylamine to obtain 1- (6-chloro-2-methyl-2H-indazole-5-yl) -3- (2, 4, 5-trifluoro-benzyl) guanidine;
step 2, 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluoro benzyl) guanidine, 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole and an acylating agent are subjected to acylation butt joint reaction, and then are subjected to acylation ring closure reaction with the acylating agent, so that the Enxi Qu Wei is obtained by a one-pot method.
2. The synthesis method according to claim 1, wherein in the reaction in the step 1, the molar feed ratio of 6-chloro-2-methyl-2H-indazol-5-amine, 2,4, 5-trifluorobenzylamine and dicyandiamide sodium is 1:0.9-1.1: 0.9 to 1.1, preferably 1:0.95 to 1.05:0.95 to 1.05, particularly preferably 1:1:1.
3. The synthesis method according to claim 1, wherein the reaction catalyst in step 1 is concentrated hydrochloric acid, and the molar feed ratio of 6-chloro-2-methyl-2H-indazol-5-amine to concentrated hydrochloric acid is 1:4-5, preferably 1:4.5.
4. The synthetic method of claim 1 wherein the step 1 reaction conditions comprise: and (3) carrying out a reaction in an ethanol-water mixed solvent, wherein 1, 6-chloro-2-methyl-2H-indazole-5-amine and sodium dicyandiamide are subjected to a reflux reaction for 3 hours, and then 2,4, 5-trifluoro-benzylamine is added for a reflux reaction for 9 hours.
5. The synthesis according to claim 1, wherein the acylating agent of step 2 reaction is selected from triphosgene, carbonyldiimidazole, carbonyl chloride, preferably carbonyldiimidazole.
6. The synthetic method according to claims 1 and 5, characterized in that the step 2 reaction solvent is selected from tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, preferably dimethylacetamide.
7. The synthetic method according to claim 1 and 5, wherein an organic base is added as a catalyst in the reaction of step 2, wherein the organic base is selected from the group consisting of triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-diisopropylethylamine, and preferably 1, 8-diazabicyclo [5.4.0] undec-7-ene.
8. The synthesis according to claim 1, characterized in that the molar feed ratio of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine to 5-methyl-3-aminomethyl-1H-1, 2, 4-triazole in the reaction of step 2 is 1:0.9 to 1.1, preferably 1:0.95 to 1.05, particularly preferably 1:1.
9. The synthetic method according to claims 1, 5 and 7, characterized in that the molar feed ratio of step 2 acylation docking reaction stage 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) guanidine, carbonyldiimidazole and 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1:0.9-1.1: 0.9 to 1.1, preferably 1:0.95 to 1.05:0.95 to 1.05, particularly preferably 1:1:1; the molar charging ratio of 1- (6-chloro-2-methyl-2H-indazol-5-yl) -3- (2, 4, 5-trifluoro-benzyl) guanidine to the carbonyl diimidazole and 1, 8-diazabicyclo [5.4.0] undec-7-ene as the additional materials in the ring closing reaction stage is 1:1.2-1.8: 1.2 to 1.8, preferably 1:1.4 to 1.6:1.4 to 1.6, particularly preferably 1:1.5:1.5.
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