CN116003324A - Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine - Google Patents
Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine Download PDFInfo
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- YRZNRFJEBAPCCO-UHFFFAOYSA-N Cn1cc2cc(N)c(Cl)cc2n1 Chemical compound Cn1cc2cc(N)c(Cl)cc2n1 YRZNRFJEBAPCCO-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 37
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 15
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 238000004537 pulping Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 150000001540 azides Chemical group 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- UESSEMPSSAXQJC-UHFFFAOYSA-N ethanol;methanamine Chemical compound NC.CCO UESSEMPSSAXQJC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 claims description 2
- 230000001546 nitrifying effect Effects 0.000 claims description 2
- 238000010979 pH adjustment Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- UVGYSEIWAOOIJR-UHFFFAOYSA-N 4-chloro-2-fluorobenzaldehyde Chemical compound FC1=CC(Cl)=CC=C1C=O UVGYSEIWAOOIJR-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 6
- 230000002152 alkylating effect Effects 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 238000006396 nitration reaction Methods 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- IMOCVQHHADWLQG-UHFFFAOYSA-N [O-][N+](=O)c1cc(C=O)c(F)cc1Cl Chemical compound [O-][N+](=O)c1cc(C=O)c(F)cc1Cl IMOCVQHHADWLQG-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- OMFJTPDSDCEUPI-UHFFFAOYSA-N N(=[N+]=[N-])C1=C(C=O)C=C(C(=C1)Cl)[N+](=O)[O-] Chemical compound N(=[N+]=[N-])C1=C(C=O)C=C(C(=C1)Cl)[N+](=O)[O-] OMFJTPDSDCEUPI-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- 230000011987 methylation Effects 0.000 description 9
- 238000007069 methylation reaction Methods 0.000 description 9
- CHLANRNBFOWJBG-UHFFFAOYSA-N 6-chloro-2-methyl-5-nitroindazole Chemical compound ClC=1C(=CC2=CN(N=C2C1)C)[N+](=O)[O-] CHLANRNBFOWJBG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 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 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- OKOSGBYZOWWAPH-UHFFFAOYSA-N 5-chloro-2-methyl-4-nitroaniline Chemical compound CC1=CC([N+]([O-])=O)=C(Cl)C=C1N OKOSGBYZOWWAPH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229940126701 oral medication Drugs 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 208000025721 COVID-19 Diseases 0.000 description 2
- 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 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- SXVCMKGCWGVSSX-UHFFFAOYSA-N 6-chloro-5-nitro-1h-indazole Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NN=C2 SXVCMKGCWGVSSX-UHFFFAOYSA-N 0.000 description 1
- IHZPAJAYYZNCOU-UHFFFAOYSA-N Candirone Natural products COC=1C(=O)C2=C(O)C(OC)=CC(OC)=C2OC=1C1=CC=C(O)C=C1 IHZPAJAYYZNCOU-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000013504 emergency use authorization Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229910000859 α-Fe Inorganic materials 0.000 description 1
Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine, which takes 4-chloro-2-fluorobenzaldehyde as a starting raw material, and directly synthesizes 6-chloro-2-methyl-2H-indazole-5-amine through the steps of nitration, azide substitution, cyclization, nitro reduction and the like. Compared with the prior art, the yield of the obtained product is greatly improved, the total yield of the route is 66.4 percent, which is about 7 times of the total yield of 9.9 percent in the prior art, and the yield is greatly improved; meanwhile, severe conditions such as the use of a highly toxic alkylating reagent methyl iodide, an expensive catalyst palladium-carbon, the need of autoclave hydrogenation reaction and the like are avoided, and complicated operations such as column chromatography and the like which are not beneficial to large-scale production are not needed.
Description
Technical Field
The invention belongs to the technical fields of organic synthetic chemistry and medicinal chemistry, relates to a synthesis method of an Ensitrelvir intermediate of a COVID19 therapeutic drug, and particularly relates to a synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine.
Background
The small molecule 3CL protease inhibitor Ensitrelvir (code: S-217622) developed by Japanese salt wild-type pharmaceutical is an oral drug for the treatment of COVID 19. Japanese salt field pharmaceutical announcements that the emergency use authorization of the company oral drug Ensitrelvir was approved by the Japanese drug and medical device agency (PMDA) and was applicable to new crown-infected persons over 12 years of age. Clinical research data of Ensitrelvir show that the drug effect of the Ensitrelvir is superior to that of several oral drugs which are obtained in batches at present, and the clinical cure rate of the new crown symptoms can reach 100%, so that great hope is brought to cure of the new crown symptoms.
The 6-chloro-2-alkyl-2H-indazol-5-amine structure is an important intermediate for synthesizing Ensitkelvir, and a synthetic method of 6-chloro-2-methyl-2H-indazol-5-amine is disclosed in WO2019153080, and the technical scheme disclosed in the patent is that a target compound is prepared from a starting raw material 2-methyl-4-nitro-5-chloroaniline through the steps of nitrosation, methylation, nitro reduction and the like. However, the starting material 2-methyl-4-nitro-5-chloroaniline has a complex structure and is relatively high in price, and is not a commercially available basic chemical. And the methylation step has serious selectivity problems, the main product is that methylation occurs at the nitrogen atom of benzylamine and is not at the target position, so that the single-step yield of the methylation step Int-2 is extremely low and is only 26.3%, and the total yield of the whole route is only 9.9%. And the process uses the highly toxic and expensive alkylating reagent methyl iodide. The above problems are not applicable to the industrial production of 6-chloro-2-methyl-2H-indazol-5-amine. Other different methods for the preparation of the compound 5-nitro-6-chloro-IH-indazole (WO 2015104662, EP3889150A 1) do not avoid the problem of poor N-alkylation selectivity of indazoles.
Disclosure of Invention
In order to solve the problems, the invention provides a synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine, which takes 4-chloro-2-fluorobenzaldehyde as a starting raw material, and the 6-chloro-2-methyl-2H-indazole-5-amine is directly synthesized through the steps of nitration, azide substitution, cyclization, nitro reduction and the like. The large-scale application of the method of the invention has very important significance for reducing the cost of the medicine and improving the accessibility of the medicine for the masses after Ensitrelvir is marketed.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine, which comprises the following steps:
a) Nitrifying a substance shown in the formula I to obtain a compound shown in the formula II;
b) The compound shown in the formula II is subjected to azide substitution to obtain a compound shown in the formula III;
c) The compound shown in the formula III is cyclized after methylamine is used for obtaining imine to obtain a compound shown in the formula IV;
d) The compound shown in the formula IV is subjected to nitro reduction to obtain a compound shown in the formula V;
wherein, the compound of formula I:
a compound of formula ii:
a compound of formula iii:
a compound of formula IV:
a compound of formula V:
WO2019153080 discloses a method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine, which comprises the following synthetic route:
however, the starting material 2-methyl-4-nitro-5-chloroaniline has a complex structure and is relatively high in price, and is not a commercially available basic chemical. And the methylation step has serious selectivity problems, the main product is that methylation occurs at the nitrogen atom of benzylamine and is not at the target position, so that the single-step yield of the methylation step Int-2 is extremely low and is only 26.3%, and the total yield of the whole route is only 9.9%. And the process uses the highly toxic and expensive alkylating reagent methyl iodide.
The method takes 4-chloro-2-fluorobenzaldehyde as a starting material, and directly synthesizes 6-chloro-2-methyl-2H-indazole-5-amine through the steps of nitration, azide substitution, cyclization, nitro reduction and the like. The large-scale application of the method of the invention has very important significance for reducing the cost of the medicine and improving the accessibility of the medicine for the masses after Ensitrelvir is marketed.
As a preferable scheme of the invention, the synthesis method comprises the following steps:
a) Dissolving a substance shown in a formula I in a solvent, adding nitric acid, reacting until the reaction is completed, washing the reaction liquid with water, filtering, and drying to obtain a compound shown in a formula II;
b) Adding a solvent into a substance shown in a formula II, adding sodium azide, stirring to react until the reaction is completed, and washing, extracting and concentrating a reaction solution to obtain a compound shown in a formula III;
c) Dissolving a substance shown in a formula III in a solvent, adding a methylamine solution, cyclizing, adding an organic base and cuprous iodide, reacting until the reaction is completed, filtering, concentrating and crystallizing the reaction solution to obtain a compound shown in a formula IV or a salt thereof;
d) Dissolving a substance shown in a formula IV in a solvent, adding a reducing agent, reacting until the reaction is completed, filtering, extracting, concentrating and pulping the reaction solution to obtain a compound shown in the formula V.
As a preferred embodiment of the present invention, in the step a), the reaction temperature is 0 to 50℃and the amount of nitric acid is 1.0 to 2.0 equivalents.
In a preferred embodiment of the present invention, in the step b), the temperature of the stirring reaction is 0 to 80 ℃, the amount of the sodium azide is 1.0 to 2.0 equivalents, the solvent is dimethyl sulfoxide, and the amount of the dimethyl sulfoxide is 3.0 to 10.0V.
As a preferred embodiment of the present invention, in the step c), the reaction temperature is 10 to 60℃and the amount of methylamine is 1.0 to 6.0 equivalents.
As a preferred embodiment of the present invention, in the step c), the methylamine solution is 30% methylamine methanol solution or 30% methylamine ethanol solution.
In a preferred embodiment of the present invention, in the step c), the organic base is triethylamine or tetramethyl ethylenediamine.
As a preferred embodiment of the present invention, the step d) specifically includes: adding a substance shown in formula IV into a three-port reaction bottle, stirring acetic acid and ethanol, heating to 50-60 ℃, adding iron powder into the three-port bottle in batches, controlling the temperature to 60-70 ℃, and preserving heat; after the reaction is completed, the reaction liquid is subjected to multiple pH adjustment, filtration, extraction, concentration and pulping to obtain the compound shown in the formula V.
As a preferred embodiment of the present invention, the iron powder is used in an amount of 1.0 to 9.0 equivalents.
As a preferred embodiment of the present invention, the step d) specifically includes: adding a substance shown in a formula IV in a three-port reaction bottle, ferric trichloride hexahydrate, acetonitrile, water and active carbon, stirring and heating to 70-80 ℃, adding hydrazine hydrate in the three-port bottle, and preserving heat; after the reaction is completed, the pH of the reaction solution is adjusted for a plurality of times, and the reaction solution is filtered, extracted, concentrated and pulped to obtain a compound shown in a formula V; wherein the dosage of the hydrazine hydrate is 3.0 to 12.0 equivalents.
In the invention, the introduction of methyl on the nitrogen atom in the 6-chloro-2-methyl-2H-indazol-5-amine structure is directly constructed by methylamine and aromatic aldehyde without a selective methylation step. Directly avoiding the generation of a large number of isomers caused by poor methylation selectivity, greatly reducing separation and purification, and being a key step for improving the overall yield of a synthetic route.
The invention avoids the use of highly toxic alkylating agents such as methyl iodide and common noble metal catalysts for nitroreduction, for example palladium on carbon; the nitro is reduced to the corresponding amino through reduction of ferrite and hydrazine hydrate, so that the high-pressure kettle hydrogenation reaction is not needed, and special equipment such as the high-pressure kettle and the like is avoided.
Compared with the prior art, the invention has the following beneficial effects:
1) The synthesis method of the invention has the advantages of simple structure of the initial raw materials and easy commercial batch availability.
2) The synthesis method provided by the invention avoids the problems of difficult separation and purification caused by poor selectivity of methylation steps in the current route and the presence of a large number of isomers, and improves the total yield and purity.
3) Compared with the prior art, the synthesis method has the advantages that the yield of the obtained product is greatly improved, the total yield of the route is 66.4 percent, which is about 7 times of the total yield of 9.9 percent in the prior art, and the yield is greatly improved; meanwhile, severe conditions such as the use of a highly toxic alkylating reagent methyl iodide, an expensive catalyst palladium-carbon, the need of autoclave hydrogenation reaction and the like are avoided, and complicated operations such as column chromatography and the like which are not beneficial to large-scale production are not needed.
4) The synthesis method provided by the invention has good repeatability through hundred-gram and kilogram-level amplification verification, and is a technical route which is economical, environment-friendly, simple in post-treatment and convenient for amplified production.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
FIG. 2 is a spectrum of a compound represented by formula V obtained in example 14 of the present invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the present invention, the raw materials and reagents or equipment used are commercially available.
Referring to fig. 1, the invention takes 4-chloro-2-fluorobenzaldehyde as a starting material, and directly synthesizes 6-chloro-2-methyl-2H-indazole-5-amine through the steps of nitration, azide substitution, cyclization, nitro reduction and the like.
Example 1
See FIG. 1, synthesis of 4-chloro-2-fluoro-5-nitrobenzaldehyde (II)
4-chloro-2-fluorobenzaldehyde (85 g,0.53mol,1.0 eq) was put into a 250mL three-necked flask, concentrated sulfuric acid (255 g,3 wt) was added, the temperature was raised to 30 ℃ and stirred for dissolution, the temperature was initially lowered to 5-15 ℃, 98% nitric acid (41.4 g,0.64mol,1.2 eq) was slowly added dropwise, the reaction temperature was controlled to 5-15 ℃, the dropwise addition was completed, and then the temperature was raised to 20-30 ℃ and stirred for 5 hours. After the reaction of the central control 4-chloro-2-fluorobenzaldehyde (I) is finished, pouring the reaction solution into 510g of water, controlling the temperature to be not more than 20 ℃, pulping for 1h at 20-25 ℃, and carrying out suction filtration. The filter cake was slurried with 340g (4 wt) of water at room temperature for 1h and again suction filtered. The filter cake was again rinsed with 340g (4 wt%) of water and dried to give 103.5g of compound II in 94.8% yield and 99.0% purity.
Example 2
See FIG. 1, synthesis of 4-chloro-2-fluoro-5-nitrobenzaldehyde (II)
4-chloro-2-fluorobenzaldehyde (170 g,1.07mol,1.0 eq) is put into a 5000mL three-necked flask, concentrated sulfuric acid (510 g,3 wt) is added, the temperature is raised to 30 ℃ and stirred for dissolution, the temperature is reduced to 5-15 ℃, 98% nitric acid (102.2 g,1.6mol,1.5 eq) is slowly added dropwise, the reaction temperature is controlled to 5-15 ℃ after the dropwise addition, and the temperature is controlled to 5-15 ℃ and stirred for 3 hours. After the reaction of the central control 4-chloro-2-fluorobenzaldehyde (I) is finished, pouring the reaction solution into 1020g of water, controlling the temperature to be not more than 20 ℃, pulping for 1h at 20-25 ℃, and carrying out suction filtration. The filter cake was slurried with 680g (4 wt) of water at room temperature for 1h and again suction filtered. The filter cake was again rinsed with 680g (4 wt%) of water and dried to give 200.0g of compound II in 91.7% yield and 99.0% purity.
Example 3
See FIG. 1, synthesis of 4-chloro-2-fluoro-5-nitrobenzaldehyde (II)
4-chloro-2-fluorobenzaldehyde (170 g,1.07mol,1.0 eq) is put into a 5000mL three-necked flask, concentrated sulfuric acid (510 g,3 wt) is added, the temperature is raised to 30 ℃ and stirred for dissolution, the temperature is reduced to 5-15 ℃, 98% nitric acid (82.5 g,1.28mol,1.2 eq) is slowly added dropwise, the reaction temperature is controlled to 5-15 ℃, the dropwise addition is completed, and the temperature is raised to 35-45 ℃ and stirred for reaction for 1h. After the reaction of the central control 4-chloro-2-fluorobenzaldehyde (I) is finished, pouring the reaction solution into 1020g of water, controlling the temperature to be not more than 20 ℃, pulping for 1h at 20-25 ℃, and carrying out suction filtration. The filter cake was slurried with 680g (4 wt) of water at room temperature for 1h and again suction filtered. The filter cake was again rinsed with 680g (4 wt%) of water and dried to give 205.0g of compound II in 94.0% yield and 99.2% purity.
Example 4:
see FIG. 1, synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde (III)
4-chloro-2-fluoro-5-nitrobenzaldehyde (II, 50g,0.25mol,1.0 eq) and dimethyl sulfoxide (440 g, 8V) were stirred and mixed, sodium azide (31.9 g,0.49mol,2.0 eq) was added in portions, the internal temperature was controlled at 10-20℃and the reaction temperature was controlled at 10-20℃after the addition, and the reaction was carried out for 4 hours. The 4-chloro-2-fluoro-5-nitrobenzaldehyde serving as a raw material for the middle control (HPLC) is less than or equal to 2.0 percent and can be subjected to post-treatment, under stirring, the reaction solution is slowly added into 1200g of ice water for quenching, then 500g of ethyl acetate is added for extraction, the organic phase is separated, the organic phase is respectively washed with half-saturated salt water for 3 times, 300g of the organic phase is washed with 300g of saturated salt water for one time. Finally, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 50.9g of solid III as a product in 91.5% yield and 98.0% purity.
Example 5
See FIG. 1, synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde (III)
4-chloro-2-fluoro-5-nitrobenzaldehyde (II, 300g,1.47mol,1.0 eq) and dimethyl sulfoxide (180 g, 6V) were stirred and mixed, sodium azide (153.3 g,2.36mol,1.6 eq) was added in portions, the internal temperature was controlled at 10-20℃and the reaction temperature was controlled at 30-40℃after the addition, and the reaction was carried out for 2 hours. The 4-chloro-2-fluoro-5-nitrobenzaldehyde serving as a raw material for the middle control (HPLC) is less than or equal to 2.0 percent and can be subjected to post-treatment, the reaction solution is slowly added into 5400g of ice water for quenching under stirring, 1500g of ethyl acetate is added for extraction, the organic phase is separated, the organic phase is respectively washed with half-saturated salt water for 3 times, 500g of the organic phase is washed with 500g of saturated salt water for one time. Finally, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 310.5g of solid III as a product in 93.0% yield with a purity of 98.1%.
Example 6
See FIG. 1, synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde (III)
4-chloro-2-fluoro-5-nitrobenzaldehyde (II, 100g,0.49mol,1.0 eq) and dimethyl sulfoxide (800 g, 8V) were stirred and mixed, sodium azide (41.5 g,0.64mol,1.3 eq) was added in portions, the internal temperature was controlled at 10-20 ℃, the reaction temperature was controlled at 55-65 ℃ after the addition, and the reaction was carried out for 3 hours. The 4-chloro-2-fluoro-5-nitrobenzaldehyde serving as a raw material for the middle control (HPLC) is less than or equal to 2.0 percent and can be subjected to post-treatment, under stirring, the reaction solution is slowly added into 4000g of ice water for quenching, 700g of ethyl acetate is added for extraction, the organic phase is separated, the organic phase is respectively washed with half-saturated salt water for 3 times, 500g of the organic phase is washed with 500g of saturated salt water for one time. Finally, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 101.0g of solid III as a product in 90.7% yield and 98.5% purity.
Example 7
See FIG. 1, synthesis of 6-chloro-2-methyl-5-nitro-2H-indazole (IV, one pot method)
2-azido-4-chloro-5-nitrobenzaldehyde (III, 20g,0.088mol,1.0 eq) and methylene chloride (158.4 g, 6V) were put into a 250mL three-necked flask and stirred, the temperature was controlled at 10-20 ℃, 30% methylamine/methanol solution (32 g,0.31mol,3.5 eq) was added dropwise at this temperature, stirring was continued after the dropwise addition, the temperature was returned to 20-30 ℃, the reaction was completed by a medium control (TLC), and 25g of solid or oily substance was obtained by concentrating the reaction solution. Tetrahydrofuran (100 g,5 wt) was added thereto, the solution was stirred, triethylamine (8.9 g,1.0 eq) and cuprous iodide (1.7 g,0.1 eq) were added thereto, and the mixture was stirred at 10-20℃for about 8 hours. The reaction solution was filtered through a sand core funnel lined with (4 g,0.2 w) silica gel at 10-20℃and rinsed with tetrahydrofuran (60 g,3 wt) and the filtrate was concentrated to give solid product IV15.83g, yield 85% purity 98.0%.
Example 8
See FIG. 1, synthesis of 6-chloro-2-methyl-5-nitro-2H-indazole (IV, one pot method)
2-azido-4-chloro-5-nitrobenzaldehyde (III, 50g,0.22mol,1.0 eq) and tetrahydrofuran (267.0 g, 6V) are put into a 500mL three-port bottle for stirring, the temperature is controlled to be 20-30 ℃, 30% methylamine/methanol solution (56.9 g,0.55mol,2.5 eq) is dropwise added at the temperature, the mixture is heated to 30-40 ℃ for continuous stirring, the medium control (TLC) reaction is complete, triethylamine (8.9 g,1.0 eq) and cuprous iodide (4.2 g,0.1 eq) are added, and the mixture is stirred for reaction for about 6 hours at 20-30 ℃. The reaction solution was filtered through a sand core funnel lined with (10 g,0.2 w) silica gel, rinsed with tetrahydrofuran (150 g,3 wt) and the filtrate was concentrated to give solid product IV41.1g, yield 88% purity 98.3%.
Example 9
See FIG. 1, synthesis of 6-chloro-2-methyl-5-nitro-2H-indazole (IV, one pot method)
2-azido-4-chloro-5-nitrobenzaldehyde (III, 50g,0.22mol,1.0 eq) and tetrahydrofuran (267.0 g, 6V) are put into a 500mL three-port bottle for stirring, the temperature is controlled to be 20-30 ℃, 30% methylamine/ethanol solution (56.9 g,0.55mol,2.5 eq) is dropwise added at the temperature, the mixture is heated to 30-40 ℃ after the dripping, stirring is continued, the medium-control (TLC) reaction is completed, tetramethyl ethylenediamine (25.6 g,1.0 eq) and cuprous iodide (4.2 g,0.1 eq) are added, and the mixture is stirred for reaction for about 4 hours at 20-30 ℃. The reaction solution was filtered through a sand core funnel lined with (10 g,0.2 w) silica gel, rinsed with tetrahydrofuran (150 g,3 wt) and the filtrate was concentrated to give solid product iv40.2g, 86% yield, 98.8% purity.
Example 10
See FIG. 1, synthesis of 6-chloro-2-methyl-5-nitro-2H-indazole (IV, one pot method)
2-azido-4-chloro-5-nitrobenzaldehyde (III, 50g,0.22mol,1.0 eq) and dioxane (250.0 g, 5V) are put into a 500mL three-port bottle for stirring, the temperature is controlled to be 20-30 ℃, 30% methylamine/ethanol solution (45.6 g,0.44mol,2.0 eq) is dropwise added at the temperature, stirring is continued until the temperature reaches 40-50 ℃, the medium control (TLC) reaction is complete, tetramethyl ethylenediamine (25.6 g,1.0 eq) and cuprous iodide (4.2 g,0.1 eq) are added, and stirring is performed for about 4 hours at the temperature of 40-50 ℃. After cooling to 20-30℃the reaction solution was filtered through a sand core funnel lined with (10 g,0.2 w) silica gel, rinsed with dioxane (150 g,3 wt) and the filtrate was concentrated to give solid product IV43.0g, 92% yield, 97.5% purity.
Example 11
See FIG. 1, synthesis of 6-chloro-2-methyl-2H-indazol-5-amine (V)
6-chloro-2-methyl-5-nitro-2H-indazole (IV, 11.8g,0.056mol,1.0 eq), acetic acid (40.1 g,0.67mol,12.0 eq), ethanol (86.4 g, 9V) are added into a 250mL three-necked flask, stirred and heated to 50-60 ℃, iron powder is added into the system in batches at a controlled temperature of 60-70 ℃, iron powder (18.7 g,0.33mol,6.0 eq) is added together, the addition is continued for 3 hours at 60-70 ℃, the reaction is completely controlled in the middle, the temperature is reduced to 40-50 ℃ for hot filtration, hot ethanol (37.2 g, 4V) is used for rinsing, the filtrate is concentrated, sodium bicarbonate is added for adjusting the pH to 7-8, 2-methyltetrahydrofuran (40.36 g, 4V) is added for extraction, the aqueous phase is extracted once by 2-methyltetrahydrofuran (40.36 g, 4V), mixing organic phases, adding 215g of 1N hydrochloric acid solution to adjust pH=1, separating liquid, adding 2-methyltetrahydrofuran (10V, 100 g) into an aqueous phase for extraction once, adding 150g of 20% sodium carbonate solution to adjust pH=8-9 into the aqueous phase, respectively adding 100g of 2-methyltetrahydrofuran for extraction 2 times, mixing the organic phases, washing the organic phases with water (5 wt,60 g), washing with brine (5 wt,60 g), adding anhydrous sodium sulfate (11.8 g,1 wt) into the organic phases for drying, decolorizing with active carbon (1.2 g,0.1 wt), filtering, concentrating, adding N-heptane (23.6 g,2 wt) and pulping to obtain a target product of 9.12g of solid V, wherein the yield is 90%, and the purity is 99.0%.
Example 12
See FIG. 1, synthesis of 6-chloro-2-methyl-2H-indazol-5-amine (V)
6-chloro-2-methyl-5-nitro-2H-indazole (IV, 30g,0.14mol,1.0 eq), acetic acid (100.8 g,1.68mol,12.0 eq), ethanol (86.4 g, 7.2V), water (54 g, 1.8V) were added into a 500mL three-necked flask and stirred and warmed to 50-60℃the iron powder was added to the system in portions with a controlled temperature of 60-70℃and iron powder (39.2 g,0.7mol,5.0 eq) added together, the addition was continued for 6H at 60-70℃with a controlled temperature, the reaction was completed with a medium control, the temperature was reduced to 40-50℃for hot filtration, the filtrate was rinsed with hot ethanol (96.0 g, 4V), the pH was adjusted to 8-9 with sodium carbonate, EA (108.0 g, 4V) was added for extraction, and the aqueous phase was further extracted with EA (108.0 g, 4V), combining organic phases, adding 538g of 1N hydrochloric acid solution to adjust pH to 1, separating liquid, adding EA (108.0 g, 4V) to the aqueous phase for extraction once, adding 375g of 20% sodium carbonate solution to the aqueous phase to adjust pH to 8-9, respectively adding ethyl acetate (108 g, 2V) for extraction 2 times, combining the organic phases, washing the organic phases with water (150 g,5 wt), washing with brine (150 g,5 wt), adding anhydrous sodium sulfate (30.0 g,1 wt) to the organic phases for drying, decolorizing with active carbon (3.0 g,0.1 wt), filtering, concentrating, adding N-heptane (60.0 g,2 wt) and pulping to obtain a target product of 22.7g of solid V with the yield of 88% and the purity of 99.3%.
Example 13
See FIG. 1, synthesis of 6-chloro-2-methyl-2H-indazol-5-amine (V)
6-chloro-2-methyl-5-nitro-2H-indazole (IV, 70g,0.33mol,1.0 eq), ferric trichloride hexahydrate (4.5 g,0.017mol,5% eq), methanol (280.0 g,4 wt), water (280 g,4 wt), activated carbon (7 g,0.1 wt) were added to a 1000mL three-port flask and stirred and warmed to 70-80 ℃ to begin dropwise adding 80% hydrazine hydrate (186.8 g,3.0mol,9.0 eq), the temperature was controlled to 70-80 ℃, refluxing and heat preservation were continued at 70-80 ℃ for 2 hours after the addition, the reaction was completely controlled, filtration was carried out at 20-30 ℃, rinsing with methanol (70.0 g,1 wt), concentrated filtrate was added with toluene (350.0 g,5 wt) to extract, aqueous phase was further extracted with toluene (210.0 g,3 wt), organic phase was combined, washed (210 g,3 wt), brine (140 g, 140 wt), sodium (70 g,2 wt) was added to the aqueous phase was dried and dried to obtain a dry product (2.0 g,2 wt) of dry product, 3.0% pure, 3.0 wt, 2% dry, 3% of the target sodium (dry product was obtained by beating, and drying and pulping.
Example 14
See FIG. 1, synthesis of 6-chloro-2-methyl-2H-indazol-5-amine (V)
6-chloro-2-methyl-5-nitro-2H-indazole (IV, 50g,0.24mol,1.0 eq), ferric trichloride hexahydrate (3.2 g,0.012mol,5% eq), acetonitrile (200.0 g,4 wt), water (200 g,4 wt), activated carbon (5 g,0.1 wt) were added into a 1000mL three-port flask and stirred and warmed to 70-80 ℃ to begin dropwise adding 80% hydrazine hydrate (105.1 g,1.68mol,7.0 eq), controlling the temperature to 70-80 ℃, refluxing and heat-preserving after adding 70-80 ℃ for 6H, the medium-controlled reaction was completed, cooling to 20-30 ℃ and filtering, rinsing with acetonitrile alcohol (50.0 g,1 wt), concentrating the filtrate, adding ethyl acetate (250.0 g,5 wt) for extraction, continuously extracting with ethyl acetate (150.0 g,3 wt), combining organic phases, washing (150 g,3 wt), brine (100 g, 100 wt), adding sodium sulfate (100 g, 100 wt) into a dry sulfuric acid solution (2 g, 0g,1 wt) to obtain a dry-phase, a dry product of which is shown in the formula (1V, 2.0V), and a dry-phase, a dry-solid product of which is obtained by a dry method shown in the specification of which has a dry filtration chart of (1.0 g, 2V, 0g, 0% of pure standard (1V) is shown in).
Compared with the prior art, the synthesis method provided by the invention has the advantages that the yield of the obtained product is greatly improved, and the total yield of the synthesis route is 66.4%, which is about 7 times of the total yield of 9.9% in the prior art, and is greatly improved; meanwhile, severe conditions such as the use of a highly toxic alkylating reagent methyl iodide, an expensive catalyst palladium-carbon, the need of autoclave hydrogenation reaction and the like are avoided, and complicated operations such as column chromatography and the like which are not beneficial to large-scale production are not needed.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various modifications and additions may be made without departing from the scope of the invention. Equivalent embodiments of the present invention will be apparent to those skilled in the art having the benefit of the teachings disclosed herein, when considered in the light of the foregoing disclosure, and without departing from the spirit and scope of the invention; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present invention still fall within the scope of the technical solution of the present invention.
Claims (10)
1. A method for synthesizing 6-chloro-2-methyl-2 h-indazol-5-amine, the method comprising the steps of:
a) Nitrifying a substance shown in the formula I to obtain a compound shown in the formula II;
b) The compound shown in the formula II is subjected to azide substitution to obtain a compound shown in the formula III;
c) The compound shown in the formula III is cyclized after methylamine is used for obtaining imine to obtain a compound shown in the formula IV;
d) The compound shown in the formula IV is subjected to nitro reduction to obtain a compound shown in the formula V;
wherein, the compound of formula I:
a compound of formula ii:
a compound of formula iii:
a compound of formula IV:
a compound of formula V:
2. the method for synthesizing 6-chloro-2-methyl-2 h-indazol-5-amine according to claim 1, wherein said method comprises the steps of:
a) Dissolving a substance shown in a formula I in a solvent, adding nitric acid, reacting until the reaction is completed, washing the reaction liquid with water, filtering, and drying to obtain a compound shown in a formula II;
b) Adding a solvent into a substance shown in a formula II, adding sodium azide, stirring to react until the reaction is completed, and washing, extracting and concentrating a reaction solution to obtain a compound shown in a formula III;
c) Dissolving a substance shown in a formula III in a solvent, adding a methylamine solution, cyclizing, adding an organic base and cuprous iodide, reacting until the reaction is completed, filtering, concentrating and crystallizing the reaction solution to obtain a compound shown in a formula IV or a salt thereof;
d) Dissolving a substance shown in a formula IV in a solvent, adding a reducing agent, reacting until the reaction is completed, filtering, extracting, concentrating and pulping the reaction solution to obtain a compound shown in the formula V.
3. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 2, wherein in said step a), the reaction temperature is 0 to 50 ℃, and the amount of nitric acid is 1.0 to 2.0 equivalents.
4. The method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine according to claim 2, wherein in said step b), the temperature of the stirring reaction is 0-80 ℃, the amount of sodium azide is 1.0-2.0 equivalent, the solvent is dimethyl sulfoxide, and the amount of dimethyl sulfoxide is 3.0-10.0V.
5. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 2, wherein in said step c), the reaction temperature is 10 to 60 ℃ and the amount of methylamine is 1.0 to 6.0 equivalents.
6. The method for synthesizing 6-chloro-2-methyl-2 h-indazol-5-amine according to claim 2, wherein in said step c), the methylamine solution is 30% methylamine methanol solution or 30% methylamine ethanol solution.
7. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 2, wherein in said step c), the organic base is triethylamine or tetramethyl ethylenediamine.
8. The method for synthesizing 6-chloro-2-methyl-2 h-indazol-5-amine according to claim 1 or 2, wherein said step d) is specifically: adding a substance shown in formula IV into a three-port reaction bottle, stirring acetic acid and ethanol, heating to 50-60 ℃, adding iron powder into the three-port bottle in batches, controlling the temperature to 60-70 ℃, and preserving heat; after the reaction is completed, the reaction liquid is subjected to multiple pH adjustment, filtration, extraction, concentration and pulping to obtain the compound shown in the formula V.
9. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 8, wherein the amount of iron powder is 1.0 to 9.0 equivalents.
10. The method for synthesizing 6-chloro-2-methyl-2 h-indazol-5-amine according to claim 1 or 2, wherein said step d) is specifically: adding a substance shown in a formula IV in a three-port reaction bottle, ferric trichloride hexahydrate, acetonitrile, water and active carbon, stirring and heating to 70-80 ℃, adding hydrazine hydrate in the three-port bottle, and preserving heat; after the reaction is completed, the pH of the reaction solution is adjusted for a plurality of times, and the reaction solution is filtered, extracted, concentrated and pulped to obtain a compound shown in a formula V; wherein the dosage of the hydrazine hydrate is 3.0 to 12.0 equivalents.
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| JIANTAO HU ET AL.: "A General and Efficient Approach to 2H-Indazoles and 1H-Pyrazoles Through Copper-catalyzed Intramolecular N-N Bond Formation under Mild Conditions", 《CHEM. COMMUN.》, vol. 47, 31 December 2011 (2011-12-31), pages 10133 - 10135, XP055885488, DOI: 10.1039/c1cc13908h * |
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