CN112321510A - Preparation method of 4-bromo-5-methyl-1H-indazole - Google Patents
Preparation method of 4-bromo-5-methyl-1H-indazole Download PDFInfo
- Publication number
- CN112321510A CN112321510A CN202011166424.7A CN202011166424A CN112321510A CN 112321510 A CN112321510 A CN 112321510A CN 202011166424 A CN202011166424 A CN 202011166424A CN 112321510 A CN112321510 A CN 112321510A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- bromo
- iii
- reacting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
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
Abstract
The invention discloses a preparation method of 4-bromo-5-methyl-1H-indazole, which comprises the following specific steps: (1) reacting the compound (II) with lithium diisopropylamide to generate a lithium reagent, and reacting the lithium reagent with dimethylformamide to generate a compound (III); (2) reacting the compound (III) with methoxylamine hydrochloride and potassium carbonate to obtain a compound (IV); (3) the compound (IV) is subjected to ring closure under the participation of hydrazine hydrate to generate the compound (I). The preparation method has higher yield.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of 4-bromo-5-methyl-1H-indazole.
Background
4-bromo-5-methyl-1H-indazole is a class of key intermediates, and WO2007/21937 discloses the following route for the synthesis of 4-bromo-5-methyl-1H-indazole compound I:
in the synthesis method, sulfuric acid and nitric acid are used for nitration when 2-bromo-1, 3-dimethyl-4-nitrobenzene is generated through the first-step reaction in the process of synthesizing the 4-bromo-5-methyl-1H-indazole compound I, so that the material is easy to flush during amplification, danger is caused, a large amount of waste acid is generated, and the synthesis method is not environment-friendly; meanwhile, the yield is low in the final step of diazotization ring closing, so that the production cost is very high, and the industrial amplification generation is not facilitated.
Disclosure of Invention
In view of the above problems in the prior art, the present applicant provides a method for preparing 4-bromo-5-methyl-1H-indazole. The preparation method has higher yield.
The technical scheme of the invention is as follows:
a process for the preparation of 4-bromo-5-methyl-1H-indazole, according to the following scheme:
the method comprises the following specific steps:
(1) reacting the compound (II) with lithium diisopropylamide to generate a lithium reagent, and reacting the lithium reagent with dimethylformamide to generate a compound (III);
(2) reacting the compound (III) with methoxylamine hydrochloride and potassium carbonate to obtain a compound (IV);
(3) the compound (IV) is subjected to ring closure under the participation of hydrazine hydrate to generate the compound (I).
In the step (1), the concentration of lithium diisopropylamide is 2.0M in tetrahydrofuran solution.
In the step (1), the solvent is tetrahydrofuran; the molar ratio of the compound (II) to lithium diisopropylamide and N, N-dimethylformamide is 1: 1.0-1.5.
In the step (1), the reaction conditions of the compound (II) and lithium diisopropylamide are as follows: the reaction temperature is-78 ℃, and the reaction time is 1-2 h; the reaction conditions of the lithium reagent and the N, N-dimethylformamide are as follows: the reaction temperature is-78 ℃, and the reaction time is 1-2 h.
In the step (2), the solvent is ethylene glycol dimethyl ether; the molar ratio of the compound (III) to the methoxylamine hydrochloride and the potassium carbonate is 1: 1.0-1.5; the reaction conditions are as follows: the heating temperature is 40-80 ℃, and the reaction time is 2-16 h.
In the step (3), the solvent is tetrahydrofuran, dioxane, methanol or ethanol; the mass ratio of the compound (IV) to hydrazine hydrate is 1: 1.0-10; the reaction conditions are as follows: the heating temperature is 40-100 ℃, and the reaction time is 2-16 h.
The beneficial technical effects of the invention are as follows:
the invention avoids a large amount of waste acid generated by nitration of sulfuric acid and nitric acid in the process of the total synthesis route which takes 2-bromo-4-fluorotoluene as the starting material, so that the whole synthesis process has small pollution and is easy to process, the lowest yield in each step also reaches 87.6%, and the total yield also reaches about 72.3%.
Drawings
FIG. 1 shows 4-bromo-5-methyl-1H-indazole prepared in example 11H-NMR spectrum
FIG. 2 is a GC spectrum of 4-bromo-5-methyl-1H-indazole prepared in example 1
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A method of making 4-bromo-5-methyl-1H-indazole, comprising the steps of:
(1) synthesis of Compound III
189g (1mol) of 2-bromo-4-fluorotoluene and 1000ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to-78 ℃, 500ml (1mol) of 2.0M LDA solution is dropwise added, the temperature is kept for reacting for 2 hours after the dropwise addition, 73g (1mol) of N, N-dimethylformamide is dropwise added, the mixture is slowly returned to the room temperature after the dropwise addition, the mixture is stirred for 2 hours, and the HPLC tracking reaction is carried out until the 2-bromo-4-fluorotoluene is completely reacted; quenching into saturated ammonium chloride aqueous solution, extracting with 2000ml ethyl acetate for layering, drying and concentrating the organic phase to obtain 190g of compound III, and obtaining the following molar yield: 87.6 percent.
(2) Synthesis of Compound IV
Adding 108.5g (500mmol) of compound III, 41.8g (500mmol) of methoxyamine hydrochloride, 69g (500mmol) of potassium carbonate and 500ml of ethylene glycol dimethyl ether into a reaction bottle, heating to 80 ℃, stirring for 16 hours, and carrying out HPLC tracking reaction until the compound III is completely reacted; cooling, filtering, concentrating the filtrate, pulping isopropyl ether to obtain 103g of a compound IV, wherein the molar yield is as follows: 78.4 percent.
(3) Synthesis of Compound I
Adding 98.4g (400mmol) of compound IV, 500ml of dioxane and 25g of 80% hydrazine hydrate (400mmol) into a reaction bottle, heating to 100 ℃, stirring for 16 hours, and carrying out HPLC tracking reaction until the compound IV is completely reacted; adding 500ml of water to quench and react, adding 600ml of ethyl acetate to separate layers, washing with saturated sodium chloride, drying and concentrating an organic layer, and recrystallizing with toluene to obtain 70g of a compound I, wherein the molar yield is as follows: 82.9 percent.
FIG. 1 shows the hydrogen spectrum, 1H-NMR (400MHz, CDCl) of 4-bromo-5-methyl-1H-indazole compound I3)δ:8.07(s,1H，H-3),7.36～7.34(d,J＝8Hz，1H，H-7),7.26～7.24(d,J＝8Hz，1H，H-6)，2.50(s,3H，CH3)。
Fig. 2 is a gas chromatogram of 4-bromo-5-methyl-1H-indazole compound I, showing that the purity of 4-bromo-5-methyl-1H-indazole compound I is greater than 97%.
Example 2
A method of making 4-bromo-5-methyl-1H-indazole, comprising the steps of:
(1) synthesis of Compound III
189g (1mol) of 2-bromo-4-fluorotoluene and 1000ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to-78 ℃, 600ml (1.2mol) of 2.0M LDA solution is dropwise added, the temperature is kept for reaction for 1.5 hours after the dropwise addition, 87.6g (1.2mol) of N, N-dimethylformamide is dropwise added, the mixture is slowly returned to the room temperature after the dropwise addition, the mixture is stirred for 1.5 hours, and the HPLC tracking reaction is carried out until the 2-bromo-4-fluorotoluene is completely reacted; quenching into saturated ammonium chloride aqueous solution, extracting with 2000ml ethyl acetate for layering, drying and concentrating the organic phase to obtain 195g of compound III, molar yield: 89.9 percent.
(2) Synthesis of Compound IV
108.5g (500mmol) of the compound III, 50.1g (600mmol) of methoxylamine hydrochloride, 82.8g (600mmol) of potassium carbonate and 500ml of ethylene glycol dimethyl ether are added into a reaction bottle, the mixture is heated to 60 ℃ and stirred for 10 hours, and the reaction is followed by HPLC until the compound III is completely reacted; cooling, filtering, concentrating the filtrate, pulping isopropyl ether to obtain 108g of a compound IV, wherein the molar yield is as follows: 87.8 percent.
(3) Synthesis of Compound I
Adding 98.4g (400mmol) of compound IV, 500ml of ethanol and 125g of 80% hydrazine hydrate (2000mmol) into a reaction bottle, heating to 70 ℃, stirring for 9 hours, and carrying out HPLC tracking reaction until the compound IV is completely reacted; adding 500ml of water to quench and react, adding 600ml of ethyl acetate to separate layers, washing with saturated sodium chloride, drying and concentrating an organic layer, and recrystallizing with toluene to obtain 73g of a compound I, wherein the molar yield is as follows: 86.5 percent.
Example 3
A method of making 4-bromo-5-methyl-1H-indazole, comprising the steps of:
(1) synthesis of Compound III
189g (1mol) of 2-bromo-4-fluorotoluene and 1000ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to-78 ℃, 750ml (1.5mol) of 2.0M LDA solution is dropwise added, the temperature is kept for reacting for 1 hour after the dropwise addition, 109.5g (1.5mol) of N, N-dimethylformamide is dropwise added, the mixture is slowly returned to the room temperature after the dropwise addition, the mixture is stirred for 1 hour, and the HPLC tracking reaction is carried out until the 2-bromo-4-fluorotoluene is completely reacted; quenching into saturated ammonium chloride aqueous solution, extracting with 2000ml ethyl acetate for layering, drying and concentrating the organic phase to obtain 198g of compound III, with molar yield: 91.3 percent.
(2) Synthesis of Compound IV
108.5g (500mmol) of the compound III, 62.7g (750mmol) of methoxyamine hydrochloride, 103.5g (750mmol) of potassium carbonate and 500ml of ethylene glycol dimethyl ether are added into a reaction bottle, the mixture is heated to 40 ℃ and stirred for 2 hours, and the reaction is followed by HPLC until the compound III is completely reacted; cooling, filtering, concentrating the filtrate, pulping isopropyl ether to obtain 110g of a compound IV, wherein the molar yield is as follows: 89.4 percent.
(3) Synthesis of Compound I
Adding 98.4g (400mmol) of compound IV, 500ml of tetrahydrofuran and 250g of 80% hydrazine hydrate (4000mmol) into a reaction bottle, heating to 40 ℃, stirring for 2 hours, and carrying out HPLC tracking reaction until the compound IV is completely reacted; adding 500ml of water to quench and react, adding 600ml of ethyl acetate to separate layers, washing with saturated sodium chloride, drying and concentrating an organic layer, and recrystallizing with toluene to obtain 78g of a compound I with a molar yield: 92.4 percent.
Claims (6)
1. A process for the preparation of 4-bromo-5-methyl-1H-indazole, characterized in that it is carried out according to the following route:
the method comprises the following specific steps:
(1) reacting the compound (II) with lithium diisopropylamide to generate a lithium reagent, and reacting the lithium reagent with dimethylformamide to generate a compound (III);
(2) reacting the compound (III) with methoxylamine hydrochloride and potassium carbonate to obtain a compound (IV);
(3) the compound (IV) is subjected to ring closure under the participation of hydrazine hydrate to generate the compound (I).
2. The method according to claim 1, wherein in the step (1), the concentration of lithium diisopropylamide is 2.0M in tetrahydrofuran.
3. The process according to claim 1, wherein in the step (1), the solvent is tetrahydrofuran; the molar ratio of the compound (II) to lithium diisopropylamide and N, N-dimethylformamide is 1: 1.0-1.5.
4. The process according to claim 1, wherein in step (1), the compound (II) is reacted with lithium diisopropylamide under the following conditions: the reaction temperature is-78 ℃, and the reaction time is 1-2 h; the reaction conditions of the lithium reagent and the N, N-dimethylformamide are as follows: the reaction temperature is-78 ℃, and the reaction time is 1-2 h.
5. The method according to claim 1, wherein in the step (2), the solvent is ethylene glycol dimethyl ether; the molar ratio of the compound (III) to the methoxylamine hydrochloride and the potassium carbonate is 1: 1.0-1.5; the reaction conditions are as follows: the heating temperature is 40-80 ℃, and the reaction time is 2-16 h.
6. The process according to claim 1, wherein in the step (3), the solvent is tetrahydrofuran, dioxane, methanol or ethanol; the mass ratio of the compound (IV) to hydrazine hydrate is 1: 1.0-10; the reaction conditions are as follows: the heating temperature is 40-100 ℃, and the reaction time is 2-16 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011166424.7A CN112321510A (en) | 2020-10-27 | 2020-10-27 | Preparation method of 4-bromo-5-methyl-1H-indazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011166424.7A CN112321510A (en) | 2020-10-27 | 2020-10-27 | Preparation method of 4-bromo-5-methyl-1H-indazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112321510A true CN112321510A (en) | 2021-02-05 |
Family
ID=74297737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011166424.7A Pending CN112321510A (en) | 2020-10-27 | 2020-10-27 | Preparation method of 4-bromo-5-methyl-1H-indazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112321510A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113912544A (en) * | 2021-11-29 | 2022-01-11 | 沧州普瑞东方科技有限公司 | Preparation method of 5-bromo-1-methylindazole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105051048A (en) * | 2013-03-15 | 2015-11-11 | 伊莱利利公司 | 1 -hydroxy-benzooxaboroles as antiparasitic agents |
| WO2020210828A1 (en) * | 2019-04-12 | 2020-10-15 | Hibercell, Inc. | (aza)indazolyl-aryl sulfonamide and related compounds and their use in treating medical conditions |
-
2020
- 2020-10-27 CN CN202011166424.7A patent/CN112321510A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105051048A (en) * | 2013-03-15 | 2015-11-11 | 伊莱利利公司 | 1 -hydroxy-benzooxaboroles as antiparasitic agents |
| WO2020210828A1 (en) * | 2019-04-12 | 2020-10-15 | Hibercell, Inc. | (aza)indazolyl-aryl sulfonamide and related compounds and their use in treating medical conditions |
Non-Patent Citations (1)
| Title |
|---|
| YIHAN WANG ET AL.: "Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113912544A (en) * | 2021-11-29 | 2022-01-11 | 沧州普瑞东方科技有限公司 | Preparation method of 5-bromo-1-methylindazole |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112321510A (en) | Preparation method of 4-bromo-5-methyl-1H-indazole | |
| CN110078633B (en) | Preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride | |
| CN113354521B (en) | Preparation method of 2-methoxy-5-fluorobromoacetophenone | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| CN112299967B (en) | Preparation method of 3-methoxy-4-fluorobenzaldehyde | |
| CN109879806A (en) | A kind of isoquinolin indenes ether derivant and preparation method thereof | |
| CN114105984B (en) | Method for preparing indolizine type corrosion inhibitor | |
| CN114890879A (en) | Monobromo method of beta-dicarbonyl compound | |
| CN110862421B (en) | Synthetic method of nitrogenous heterocyclic ferrocene derivative | |
| CN114163364A (en) | 2-methoxy allyl sulfonic ester and its synthesis method | |
| CN108822008B (en) | Method for chemically synthesizing diaryl sulfone with asymmetric structure | |
| CN108727323B (en) | Method for catalytically synthesizing trifluoromethyl substituted homoisoflavone compound by using N-heterocyclic carbene | |
| CN113354558B (en) | Preparation method of 2-amino-5-fluorobenzonitrile | |
| CN115650851A (en) | Preparation method of 2-fluoro-4-bromo-6-methyl benzoate | |
| CN113480437B (en) | Preparation method of 2-bromo-3-fluoronitrobenzene | |
| CN113461538A (en) | Preparation method of 2-chloro-3-bromoaniline | |
| CN112321480B (en) | Methylation synthesis method of N-heterocyclic compound | |
| CN105017268A (en) | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method | |
| CN113912556B (en) | Synthesis method of alpha, beta-dicarbonyl-1, 2, 3-triazole compound | |
| CN113354542B (en) | Preparation method of 2-fluoro-6-nitroaniline | |
| CN115385781B (en) | Method for preparing 1, 4-tetraalkoxy-2-butene compound | |
| CN117682974B (en) | Preparation method of 2-propionyl-1-pyrroline | |
| CN114751814B (en) | Preparation method of sesquiterpenoids | |
| CN112778199B (en) | Compound containing nitrate functional group and synthetic method thereof | |
| CN113372200B (en) | Preparation method of 2-bromo-6-fluoroanisole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210205 |