CN117551038A - Synthesis method for promoting preparation of 4-bromo-7-methyl-1H-indazole ring by boric acid - Google Patents
Synthesis method for promoting preparation of 4-bromo-7-methyl-1H-indazole ring by boric acid Download PDFInfo
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 239000004327 boric acid Substances 0.000 title claims abstract description 27
- JTFKASPFJNQUBL-UHFFFAOYSA-N 4-bromo-7-methyl-1h-indazole Chemical group CC1=CC=C(Br)C2=C1NN=C2 JTFKASPFJNQUBL-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000001308 synthesis method Methods 0.000 title description 4
- 230000001737 promoting effect Effects 0.000 title description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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 abstract description 14
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000003960 organic solvent Substances 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 229940125782 compound 2 Drugs 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 14
- 238000000746 purification Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 230000000630 rising effect Effects 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- BXZCMNVTXPJOIG-UHFFFAOYSA-N 6-bromo-2-fluoro-3-methylbenzaldehyde Chemical compound CC1=CC=C(Br)C(C=O)=C1F BXZCMNVTXPJOIG-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- YZFVUQSAJMLFOZ-UHFFFAOYSA-N 4-bromo-2-fluoro-1-methylbenzene Chemical compound CC1=CC=C(Br)C=C1F YZFVUQSAJMLFOZ-UHFFFAOYSA-N 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 229940126214 compound 3 Drugs 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000006396 nitration reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YSFLQVNTBBUKEA-UHFFFAOYSA-N 1-bromo-2,4-dimethylbenzene Chemical compound CC1=CC=C(Br)C(C)=C1 YSFLQVNTBBUKEA-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 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 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
- B01J21/02—Boron or aluminium; Oxides or hydroxides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present application relates to an ideal novel method for synthesizing 4-bromo-7-methyl-1H-indazole. In the method, cheap and easily available 2-fluoro-4-bromotoluene is used as a raw material to react with N, N-dimethylformamide in the presence of a lithium reagent to prepare 6-bromo-2-fluoro-3-methylbenzaldehyde; and then the ring of the 6-bromo-2-fluoro-3-methylbenzaldehyde is closed under the action of hydrazine hydrate and boric acid to obtain the target compound 4-bromo-7-methyl-1H-indazole. The synthetic method has the advantages of simple route, simple and convenient operation, low potential safety hazard, high selectivity of each step, high yield, simple post-treatment and suitability for industrial production.
Description
Technical Field
The application belongs to the field of organic synthesis, and in particular relates to a synthesis method for promoting preparation of a 4-bromo-7-methyl-1H-indazole ring by using boric acid.
Background
4-bromo-7-methyl-1H-indazole is an important pharmaceutical intermediate, which is of great interest as an important molecular building block in a variety of drugs. In the prior art, the synthesis of 4-bromo-7-methyl-1H-indazole is mainly performed by a ring closure strategy, for example, the preparation is mainly performed by diazotization ring closure reaction, and the method is specifically as follows:
in the reaction, 2, 4-dimethyl bromobenzene is used as a raw material to carry out nitration reaction, then nitro is reduced to obtain a compound C, and finally amino of the compound C is converted into diazonium salt, and then the ring is closed under alkaline condition to obtain the 4-bromo-7-methyl-1H-indazole. In the method, the first step is to undergo a nitration reaction with large potential safety hazard and high equipment requirement; moreover, through practice, the reaction selectivity of the first step and the third step is poor, and the yield is not ideal; more importantly, in the synthesis process of the target product D, the properties of the product and the isomer are very similar, and the purification is difficult. Therefore, the prior art lacks a synthetic route of 4-bromo-7-methyl-1H-indazole, which has the advantages of simple route, simple and convenient operation, low potential safety hazard, high selectivity of each step, high yield, simple post-treatment and suitability for industrial production.
Disclosure of Invention
In view of the problems of low yield, high post-treatment purification difficulty, high implementation safety hidden trouble, high equipment requirement, difficult industrial production amplification and the like of the 4-bromo-7-methyl-1H-indazole synthesis method in the prior art, the inventor provides an ideal novel method for synthesizing the 4-bromo-7-methyl-1H-indazole.
The application provides a preparation method M1 of 4-bromo-7-methyl-1H-indazole, which comprises the following steps:
dissolving 6-bromo-2-fluoro-3-methylbenzaldehyde (hereinafter referred to as compound 2) in an organic solvent, adding hydrazine hydrate, carrying out reaction at a heating temperature, adding boric acid, continuing the heat-preserving reaction, and carrying out aftertreatment to obtain a target compound 4-bromo-7-methyl-1H-indazole (hereinafter referred to as compound 3).
In one embodiment of the present invention, the organic solvent is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether, preferably dimethyl sulfoxide.
In one embodiment of the invention, the volume to mass ratio of organic solvent to compound 2 is 2-10mL/g, preferably 3-5mL/g.
In one embodiment of the invention, the molar ratio of compound 2 to hydrazine hydrate to boric acid is 1:1.0-6.0:1.0-3.0, preferably 1:5.5:1.5.
In one embodiment of the invention, the reaction temperature is 70-120 ℃, preferably 90-110 ℃, more preferably 100 ℃.
In one embodiment of the invention, the reaction is carried out at elevated temperature for a reaction period of from 0.5 to 2 hours.
In one embodiment of the invention, the reaction time period for continuing the incubation reaction after adding boric acid is 1 to 10 hours, preferably 2 to 8 hours, more preferably 3 to 5 hours.
In one embodiment of the invention, the removal of water and a portion of the solvent is performed prior to the addition of boric acid, preferably by separation using a water separator.
In one embodiment of the invention, the post-treatment step comprises: the reaction solution is added into water for quenching, and the compound 3 is prepared by reduced pressure distillation and purification after the extraction of an organic solvent. In one embodiment of the invention, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane and toluene, preferably ethyl acetate.
In one embodiment of the invention, the purification step is selected from one or more of recrystallization and column chromatography. In one embodiment of the invention, the purification step is carried out by means of recrystallization, preferably with a mixture of ethyl acetate and petroleum ether. Further, the volume ratio of the ethyl acetate to the petroleum ether is 1:1.2-2.
The application also provides a preparation method M2 of the 4-bromo-7-methyl-1H-indazole, which comprises the following steps:
step 1, 2-fluoro-4-bromotoluene (hereinafter referred to as compound 1) is dissolved in an organic solvent 1, reacts with N, N-dimethylformamide in the presence of a lithium reagent, and is subjected to post-treatment to obtain a compound 2;
and 2, dissolving the compound 2 in an organic solvent 2, adding hydrazine hydrate, carrying out reaction at a temperature rising, adding boric acid, continuing the heat-preserving reaction, and carrying out aftertreatment to obtain the target compound 3.
In one embodiment of the present invention, step 1 is performed under inert gas. In one embodiment of the invention, the inert gas is argon or nitrogen.
In one embodiment of the present invention, the organic solvent 1 is selected from one or more of acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran and diethyl ether, preferably tetrahydrofuran or diethyl ether.
In one embodiment of the invention, the lithium reagent is selected from one or more of lithium diisopropylamide and n-butyllithium, preferably lithium diisopropylamide.
In one embodiment of the invention, the volume to mass ratio of organic solvent 1 to compound 1 is 5-15mL/g.
In one embodiment of the invention, the molar ratio of compound 1 to lithium reagent is 1:1 to 1.5.
In one embodiment of the invention, the mass to volume ratio of compound 1 to N, N-dimethylformamide is 1g/0.5-1mL.
In one embodiment of the invention, the reaction temperature of step 1 is room temperature.
In one embodiment of the invention, the reaction time of step 1 is from 0.5 to 3 hours.
In one embodiment of the invention, the post-treatment step of step 1 comprises: quenching reaction, extracting with organic solvent, vacuum distilling, and purifying to obtain compound 2.
In one embodiment of the present invention, the organic solvent 2 is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether, preferably dimethyl sulfoxide.
In one embodiment of the invention, the volume to mass ratio of organic solvent 2 to compound 2 is 2-10mL/g, preferably 3-5mL/g.
In one embodiment of the invention, the molar ratio of compound 2 to hydrazine hydrate, boric acid is 1:1.0-6.0:1.0-3.0, preferably 1:5.5:1.5.
In one embodiment of the invention, the reaction temperature of step 2 is 70-120 ℃, preferably 90-110 ℃, more preferably 100 ℃.
In one embodiment of the present invention, the reaction is carried out at elevated temperature in step 2 for a reaction period of 0.5 to 2 hours.
In one embodiment of the present invention, the reaction time period for continuing the incubation reaction after adding boric acid in step 2 is 1 to 10 hours, preferably 2 to 8 hours, more preferably 3 to 5 hours.
In one embodiment of the present invention, in step 2, the removal of water and a part of the solvent is performed before adding boric acid, preferably by separating it using a water separator.
In one embodiment of the invention, the post-treatment step of step 2 comprises: the reaction solution is added into water for quenching, and the compound 3 is prepared by reduced pressure distillation and purification after the extraction of an organic solvent.
In one embodiment of the present invention, in step 1 and step 2, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane and toluene, preferably ethyl acetate;
in one embodiment of the present invention, in step 1 and step 2, the purification process may be one or more of column chromatography purification, recrystallization purification.
In one embodiment of the invention, step 1 is: under the protection of inert gas, adding the compound 1 into the organic solvent 1, controlling the temperature to minus 78 ℃, dropwise adding a lithium reagent, keeping the temperature and stirring for 1-3 hours, adding N, N-dimethylformamide, heating to room temperature, carrying out reaction, quenching the reaction after the reaction is finished, extracting the obtained solution with the organic solvent, combining the organic phases, distilling the solvent under reduced pressure, and purifying the residue to obtain the compound 2.
In one embodiment of the invention, step 2 is: compound 2 was added to organic solvent 2 and hydrazine hydrate was added with stirring. After the addition, heating to react for 0.5-2h, separating to remove water and part of solvent, adding boric acid, continuing to react for 1-5h at a constant temperature, pouring the reaction liquid into water after the reaction is completed, extracting by using an organic solvent, distilling the obtained organic phase under reduced pressure to remove the solvent, obtaining a residue, and purifying to obtain the target compound 3.
The application has the following beneficial effects:
1. the invention provides a simple and effective synthetic route, creatively promotes the forward direction of the ring closing reaction by adding boric acid as an auxiliary reagent in the ring closing step, ensures that oxime intermediates can be completely converted into products, greatly improves the yield, avoids the generation of isomers in the prior art, improves the reaction yield, reduces the product purification difficulty, and provides a reliable route for the industrial generation of compounds.
2. In the synthesis process, no nitration reaction is adopted, so that the high potential safety hazard caused by nitration and the high requirement on reaction equipment in the prior art are avoided;
3. the raw materials and the reagents used in the invention are available in market, the post-treatment and purification operations are simple and convenient, the method is suitable for large-scale production, and reliable reference is provided for the preparation of similar compounds.
Detailed Description
In order to better understand the solution of the present application, the following description will be made in detail and fully with reference to the technical solutions in the examples. It will be apparent that the described embodiments are merely some, but not all, of the embodiments of the present application. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments herein without making any inventive effort, shall fall within the scope of the present application. In the examples below, unless otherwise indicated, the specific conditions of the test methods described are generally carried out in accordance with conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents are obtained commercially or prepared using public information.
Example 1
Step one: synthesis of Compound 2
Compound 1 (10 g,5.18mmol,1 eq) was added to 100mL tetrahydrofuran, the temperature was controlled to-78 ℃ under argon protection, lithium Diisopropylamide (LDA) (31.2 mL,62.21mmol,1.2eq,2m in THF) was added dropwise, the temperature was kept for 2h, 8mL DMF was added, the reaction was allowed to proceed at room temperature for 0.5h, saturated ammonium chloride solution (100 mL) was flushed, ethyl acetate (80 ml×3) was extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product obtained was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixture (25 mL) of=5:10), after heating and stirring until the solid was completely dissolved, the temperature was slowly lowered to room temperature, and the mixture was filtered and dried to obtain 9.4g of compound 2, purity 98.3%, yield 83.52%.
Step two: synthesis of Compound 3
Compound 2 (9.0 g,40.76mmol,1 eq) was dissolved in dimethyl sulfoxide (30 mL) and a 50% aqueous solution of hydrazine hydrate (22.45 g,224.19mmol,5.5 eq) was added with stirring. The reaction was heated to 100℃for 0.5 hours, water and a part of the solvent were removed by using a water separator, and boric acid (3.8 g,61.14mmol,1.5 eq) was then added to the reaction, and the reaction was continued at 100℃for 5 hours. After completion of the reaction, the reaction solution was poured into 150mL of water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product obtained was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixed solution (30 mL) of=8:10), the mixture was stirred at a temperature higher than the temperature until the solid was completely dissolved, and then slowly cooled to the chamberWarm, filtered and dried to give 7.17g of the target compound 3, 97.6% pure and 83.38% yield.
1 H NMR(400MHz,DMSO)δ8.02(s,1H),7.22(d,J＝7.4Hz,1H),7.06(dd,J＝7.4,0.8Hz,1H),2.49(s,3H).
[M+H] + ＝210.8
Example 2:
step one: synthesis of Compound 2
Compound 1 (10 g,5.18mmol,1 eq) was added to 100mL tetrahydrofuran, the temperature was controlled to-78 ℃ under argon protection, lithium Diisopropylamide (LDA) (26 mL,51.84mmol,1eq,2m in THF) was added dropwise, the temperature was kept for 2h, 8mL DMF was added, the reaction was allowed to proceed at room temperature for 0.5h, saturated ammonium chloride solution (100 mL) was added, ethyl acetate (80 ml×3) was extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product obtained was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixture (25 mL) of=5:10), after heating and stirring until the solid was completely dissolved, the temperature was slowly lowered to room temperature, and the mixture was filtered and dried to obtain 8.3g of compound 2 with a purity of 97.85% and a yield of 72.18%.
Step two: synthesis of Compound 3
Compound 2 (8.0 g,36.07mmol,1 eq) was dissolved in dimethyl sulfoxide (27 mL) and a 50% aqueous solution of hydrazine hydrate (19.86 g,198.37mmol,5.5 eq) was added with stirring. The reaction was heated to 100℃for 0.5 hours, water and part of the solvent were removed by separation, and then boric acid (2.24 g,36.07mmol,1 eq) was added to the reaction, and the reaction was continued at 100℃for 5 hours. After the reaction was completed, the reaction solution was poured into 130mL of water, extracted with ethyl acetate (45 mL x 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product obtained was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixed solution (25 mL) of=8:10), the temperature was raised and stirredAfter stirring until the solid had been completely dissolved, the mixture was slowly cooled to room temperature, filtered and dried to give 5.15g of the target compound 3, 96.8% pure and 67.65% yield.
1 H NMR(400MHz,DMSO)δ8.02(s,1H),7.22(d,J＝7.4Hz,1H),7.06(dd,J＝7.4,0.8Hz,1H),2.49(s,3H).
[M+H] + ＝210.8
Example 3:
step one: synthesis of Compound 2
Compound 1 (10 g,5.18mmol,1 eq) was added to 100mL tetrahydrofuran, the temperature was controlled to-78℃under argon protection, n-butyllithium (38.88 mL,77.77mmol,1.5eq,2M in THF) was added dropwise, the temperature was kept for 2h, 8mL DMF was added, the reaction was allowed to proceed to room temperature for 0.5h, saturated ammonium chloride solution (100 mL) was added, ethyl acetate (80 mL. Times.3) was extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product obtained was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixture (30 mL) of=5:10), after heating and stirring until the solid was completely dissolved, the temperature was slowly lowered to room temperature, and the mixture was filtered and dried to obtain 5.93g of compound 2, 96.37% pure and 50.79% yield.
Step two: synthesis of Compound 3
Compound 2 (5.0 g,22.65mmol,1 eq) was dissolved in dimethyl sulfoxide (17 mL) and a 50% aqueous solution of hydrazine hydrate (12.47 g,124.55mmol,5.5 eq) was added with stirring. The reaction was heated to 100℃for 0.5 hours, water and part of the solvent were removed by separation, and then boric acid (3.56 g,57.29mmol,2.53 eq) was added to the reaction, and the reaction was continued at 100℃for 5 hours. After the reaction was completed, the reaction solution was poured into 80mL of water, extracted with ethyl acetate (25 mL x 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixture (15 mL) of=8:10), after heating and stirring until the solid was completely dissolved, the mixture was slowly cooled to room temperature, filtered and dried to obtain 3.3g of the target compound 3, purity 97.34%, yield 67.21%.
1 H NMR(400MHz,DMSO)δ8.02(s,1H),7.22(d,J＝7.4Hz,1H),7.06(dd,J＝7.4,0.8Hz,1H),2.49(s,3H).
[M+H] + ＝210.8
Comparative examples
Step two: synthesis of Compound 3
Compound 2 (10.0 g,40.76mmol,1 eq) was dissolved in dimethyl sulfoxide (35 mL) and a 50% aqueous solution of hydrazine hydrate (24.86 g,248.34mmol,6.1 eq) was added with stirring. Heating to 100 ℃ for reaction for 0.5 hour, separating and removing water and partial solvent, and continuing the reaction for 5 hours at 100 ℃. After completion of the reaction, the reaction solution was poured into 160mL of water, extracted with ethyl acetate (55 mL. Times.3), the organic phases were combined, the solvent was distilled off under reduced pressure, and the crude product was dissolved in ethyl acetate and petroleum ether (V) EA :V PE In the mixed solution (40 mL) of=8:10), after heating and stirring until the solid was completely dissolved, the temperature was slowly lowered to room temperature, filtration and drying gave 3.53g of the target compound 3, purity 90.32%, yield 33.45%.
In the above comparative example, when the intermediate oxime was not promoted with boric acid to close the ring, the yield of the obtained target product was only 33.45% and the purity was only 90.32%. Thus, the reaction results are sufficient to demonstrate that in step two, boric acid plays a positive role in the preparation of the target compound.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.
Claims (10)
1. A method for preparing 4-bromo-7-methyl-1H-indazole, comprising the steps of:
and (3) dissolving the compound 2 in an organic solvent, adding hydrazine hydrate, carrying out reaction at a heating temperature, adding boric acid, continuing the heat-preserving reaction, and carrying out aftertreatment to obtain the target compound 4-bromo-7-methyl-1H-indazole.
2. The method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether; and/or
The volume-mass ratio of the organic solvent to the compound 2 is 2-10mL/g; and/or
The molar ratio of the compound 2 to the hydrazine hydrate to the boric acid is 1:1.0-6.0:1.0-3.0.
3. The preparation method according to claim 1 or 2, wherein the reaction temperature is 70-120 ℃; and/or
The reaction time of the reaction is 0.5-2h under the condition of heating; and/or
The reaction time of the continuous heat preservation reaction after adding boric acid is 1-10h.
4. A method according to any one of claims 1 to 3, further comprising the step of removing water and part of the solvent prior to adding boric acid.
5. The production method according to any one of claims 1 to 4, wherein the post-treatment step comprises: the reaction solution is added into water for quenching, and the organic solvent is extracted, distilled under reduced pressure and purified.
6. The process according to claim 5, wherein the organic solvent used for extraction is one or more selected from the group consisting of ethyl acetate, methylene chloride, ethylene dichloride and toluene; and/or
The purification step is selected from one or more of recrystallization and column chromatography.
7. A method for preparing 4-bromo-7-methyl-1H-indazole, comprising the steps of:
step 1, dissolving a compound 1 in an organic solvent 1, reacting with N, N-dimethylformamide in the presence of a lithium reagent, and performing post-treatment to obtain a compound 2;
and 2, dissolving the compound 2 in an organic solvent 2, adding hydrazine hydrate, carrying out reaction at a temperature rising, adding boric acid, continuing the heat-preserving reaction, and carrying out aftertreatment to obtain the target compound 4-bromo-7-methyl-1H-indazole.
8. The method according to claim 7, wherein step 1 is performed under inert gas atmosphere; and/or
The organic solvent 1 is selected from one or more of acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran and diethyl ether; and/or
The lithium reagent is selected from one or more of lithium diisopropylamide and n-butyllithium; and/or
The volume-mass ratio of the organic solvent 1 to the compound 1 is 5-15mL/g; and/or
The molar ratio of the compound 1 to the lithium reagent is 1:1-1.5; and/or
The mass volume ratio of the compound 1 to the N, N-dimethylformamide is 1g/0.5-1mL; and/or;
the reaction temperature of the step 1 is room temperature; and/or
The reaction time of the step 1 is 0.5-3h; and/or
The post-treatment step of the step 1 comprises the following steps: quenching reaction, extracting with organic solvent, and vacuum distilling and purifying.
9. The preparation method according to claim 7 or 8, wherein the organic solvent 2 is one or more selected from the group consisting of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether; and/or
The volume-mass ratio of the organic solvent 2 to the compound 2 is 2-10mL/g; and/or
The molar ratio of the compound 2 to the hydrazine hydrate to the boric acid is 1:1.0-6.0:1.0-3.0; and/or
The reaction temperature in the step 2 is 70-120 ℃; and/or
The reaction time for the reaction at the temperature in the step 2 is 0.5-2h; and/or
In the step 2, the reaction duration of the continuous heat preservation reaction after adding boric acid is 1-10h; and/or
Step 2 further comprises the operation of removing water and part of the solvent before adding boric acid; and/or
The post-treatment step of the step 2 comprises the following steps: the reaction solution is added into water for quenching, and the organic solvent is extracted, distilled and purified under reduced pressure.
10. The preparation method according to claim 9, wherein in step 1 and step 2, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane and toluene; and/or
In step 1 and step 2, the purification step is selected from one or more of column chromatography purification and recrystallization purification.
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