Preparation method of 5-bromo-2-methyl-3-isopropyl-indazole

Abstract

The invention discloses a preparation method of 5-bromo-methyl-3-isopropyl-indazole, which comprises the following steps: under the action of a dehydration reagent, carrying out dehydration reaction on a compound I to obtain a compound II; under the action of a catalyst, the compound II and a hydrogen source are subjected to a reduction reaction, and 5-bromine-2-methyl-3-isopropyl-indazole is prepared. The product selectivity is controlled through a dehydration reagent, the yield of the compound II at least reaches 85%, and the compound II and 5-bromo-2-methyl-3-isopropyl-indazole are not obtained at the same time; then carrying out a reduction reaction, so as to prepare 5-bromo-2-methyl-3-isopropyl-indazole; the total yield of the two-step reaction at least reaches 85% and even can reach 95% or above. The method is simple to operate, the dehydration reagent is low in price and easy to obtain, and the production risk is low. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing 5-bromo-2-methyl-3-isopropyl-indazole. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a class of serine / threonine kinases that can regulate cell division and proliferation and are key molecules in cell cycle regulation. Studies have found that CDKs bind to cyclins to form a dimeric complex, causing the substrate on the amino acid residue to phosphorylate, which in turn triggers cell cycle transcription. In view of the uncontrolled cell proliferation characteristics of cancer cells, CDK inhibitors can effectively inhibit intracellular effects and thereby achieve anti-tumor purposes. The CDK9 inhibitor LY2857785 can significantly reduce RNAP IICTD phosphorylation and has a special effect on the inhibition of leukemia cells (Molecular Cancer Therapeutics (2014), 13 (6): 1442-1456); Patent CN110117273A reports a group of 2-aminopyrimidine-substituted indazole derivatives for the treatment or prevention of medical symptoms mediated by certain CDKs (especially CDK4 and CDK6). The above compounds all require the use of the key intermediate 5-bromo-2-methyl-3-isopropyl-indazole (Formula III).

[0003] The existing synthetic route of 5-bromo-2-methyl-3-isopropyl-indazole is as follows:

[0004]

[0005] The biggest problem with this route is that compound I reduces the tertiary hydroxyl group under the action of trifluoroacetic acid / triethylsilane, but some of the hydroxyl groups are dehydrated to form double bonds, which requires further reduction by platinum dioxide. Moreover, triethylsilane is extremely flammable and explosive, sensitive to water, and releases hydrogen during production, which poses a huge safety hazard during production expansion.

[0006] Therefore, it is very important to design and implement a simple and efficient method for synthesizing this compound. Summary of the invention

[0007] In view of the above-mentioned shortcomings, the present invention provides a method for preparing 5-bromo-2-methyl-3-isopropyl-indazole, which eliminates the use of triethylsilyl hydrochloride, which not only makes the preparation method simpler, but also reduces safety risks and raw material costs, does not require special production equipment, and significantly improves production capacity.

[0008] The present invention adopts the following technical solution:

[0009] A method for preparing 5-bromo-2-methyl-3-isopropyl-indazole, the synthetic route is as follows:

[0010]

[0011] The method comprises: under the action of a dehydrating agent, compound I undergoes a dehydration reaction to obtain compound II; under the action of a catalyst, compound II undergoes a reduction reaction with a hydrogen source to obtain 5-bromo-2-methyl-3-isopropyl-indazole (formula III).

[0012] The reaction solvent of the dehydration reaction is toluene, ethyl acetate, butyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile or acetone.

[0013] The dehydrating agent is a combination of potassium hydrogen sulfate, trimethylsilyl chloride, trimethylsilyl bromide, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, concentrated sulfuric acid, or a base and one selected from methylsulfonic anhydride, methylsulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride, and trifluoromethanesulfonic anhydride; preferably a combination of potassium hydrogen sulfate, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, a base and one selected from methylsulfonic anhydride and p-toluenesulfonyl chloride; more preferably potassium hydrogen sulfate, p-toluenesulfonic acid, or p-toluenesulfonic acid monohydrate.

[0014] The base is at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and cesium carbonate, and more preferably triethylamine or potassium carbonate.

[0015] The molar ratio of the base to one selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride is 1:1 to 1.5:1.

[0016] The molar ratio of compound I to the dehydrating agent is 1:0.01 to 1:5, preferably 1:0.01 to 1:2.5, more preferably 1:0.01 to 1:1, and most preferably 1:0.05 to 1:1.

[0017] After the dehydration reaction is completed, those skilled in the art can purify the compound II by conventional post-treatment methods, and the post-treatment can be selected from extraction, beating, etc. For example, when the reaction solvent is toluene, ethyl acetate, butyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile or acetone, after the dehydration reaction is completed, one selected from ethyl acetate or dichloromethane and water are added for extraction, and the organic phase is taken, and the organic phase is washed with saturated brine, and then concentrated under reduced pressure to obtain compound II. When the reaction solvent is ethyl acetate or butyl acetate, after the dehydration reaction is completed, the reaction solution is cooled, water is added for extraction, the organic phase is taken, and the organic phase is concentrated to obtain a crude compound II. The crude compound II is beaten with a mixed solvent of ethyl acetate and n-heptane (ethyl acetate: n-heptane = 1:2 V / V) to obtain compound II.

[0018] The reaction solvent of the reduction reaction is tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, acetone or dichloromethane.

[0019] The catalyst is selected from palladium carbon, platinum carbon and platinum dioxide.

[0020] The content of palladium in the palladium carbon is 1% to 20%, preferably 5% to 10%; the content of platinum in the platinum carbon is 1% to 20%, preferably 1% to 10%, more preferably 1% to 5%.

[0021] When the catalyst is selected from platinum carbon and platinum dioxide, it is not necessary to add a debromination inhibitor into the reaction system.

[0022] When the catalyst is selected from palladium carbon, a debromination inhibitor is added to the reaction system, and the volume ratio of the debromination inhibitor to the reaction solvent is 1:400 to 1:1000.

[0023] The debromination inhibitor is hydrobromic acid, and the mass fraction of the hydrobromic acid is 20%.

[0024] The mass ratio of compound II to the catalyst is 1:0.0005 to 1:0.1, preferably 1:0.001 to 1:0.05.

[0025] The hydrogen source is selected from hydrogen, ammonium formate, sodium formate, formic acid, hydrazine hydrate, ammonium acetate or sodium borohydride.

[0026] When the hydrogen source is selected from hydrogen, the hydrogen is in excess. When the hydrogen source is selected from ammonium formate, sodium formate, formic acid, hydrazine hydrate, ammonium acetate or sodium borohydride, the molar ratio of compound II to the hydrogen source is 1:1 to 1:10.

[0027] After the reduction reaction is completed, the reaction solution is filtered, and the filtrate is concentrated to remove the solvent to obtain 5-bromo-2-methyl-3-isopropyl-indazole.

[0028] The chemical name of compound I: 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol.

[0029] The chemical name of compound II: 5-bromo-2-methyl-3-(prop-1-en-2-yl)-2H-indazole.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The present invention controls the product selectivity by a dehydrating agent, and the yield of the compound II reaches at least 85%, instead of obtaining the compound II and 5-bromo-2-methyl-3-isopropyl-indazole at the same time; and then undergoes a reduction reaction to obtain 5-bromo-2-methyl-3-isopropyl-indazole; the total yield of the two-step reaction of the present invention reaches at least 85%, and can even reach more than 95%.

[0032] Compared with the existing process using triethylsilane dehydration reagent, the present invention greatly improves the disadvantages of the existing process of high cost, complex operation and high safety risk. The method of the present invention is simple to operate, the dehydration reagent is cheap and easy to obtain, the production risk is low, and it is suitable for industrial production. DETAILED DESCRIPTION

[0033] Example 1

[0034]

[0035] Compound I (10.0 g, 37.16 mmol) was dissolved in toluene (80 mL), p-toluenesulfonic acid monohydrate (0.35 g, 1.84 mmol) was added, and the mixture was heated to reflux for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness, and ethyl acetate (40 mL) and water (40 mL) were added for extraction to obtain the organic phase. The organic phase was washed with saturated brine and then concentrated under reduced pressure to obtain compound II, 9.15 g, with a yield of 98.1% and a HPLC purity of 97%. The product can be directly reacted in the next step without purification. 1 HNMR (400MHz, CDCL3) δ:7.71-7.68(m,1H),7.52(d,J=9.0Hz,1H),7.30(d,J=1.8Hz,1H),5.33-5.28(m,2H),4.18(s,3H),2.17(s,3H).

[0036] Example 2

[0037] Compound I (10.0 g, 37.16 mmol) and triethylamine (5.63 g, 55.7 mmol) were dissolved in ethyl acetate (50 mL), the reaction solution was cooled to 0-5 ° C, trifluoromethanesulfonic anhydride (10.48 g, 37.16 mmol) was added dropwise, and the reaction was heated to reflux for 3 hours after the addition was complete. After the reaction was completed, the reaction solution was cooled, water (50 mL) was added for extraction, and the organic phase was taken and concentrated to obtain a crude product. The crude product was slurried with a mixed solvent of ethyl acetate and n-heptane (ethyl acetate: n-heptane = 1: 2 V / V, 50 mL) to obtain compound II, 8.20 g, a yield of 88.0%, and HPLC purity: 97%.

[0038] Example 3

[0039] Compound I (10.0 g, 37.16 mmol) was dissolved in toluene (80 mL), p-toluenesulfonic acid (0.32 g, 1.86 mmol) was added, and the mixture was heated under reflux for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness, and ethyl acetate (40 mL) and water (40 mL) were added for extraction to obtain the organic phase. The organic phase was washed with saturated brine and then concentrated under reduced pressure to obtain compound II, 8.86 g, with a yield of 95.0% and HPLC purity of 97%.

[0040] Example 4

[0041] Compound I (10.0 g, 37.16 mmol) was dissolved in anhydrous 1,4-dioxane (80 mL), potassium hydrogen sulfate (5.06 g, 37.16 mmol) was added, and the mixture was heated to reflux for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness, and ethyl acetate (40 mL) and water (40 mL) were added for extraction to obtain the organic phase. The organic phase was washed with saturated brine and then concentrated under reduced pressure to obtain compound II, 8.58 g, with a yield of 92.0% and HPLC purity of 98%.

[0042] Example 5

[0043]

[0044] Compound II (8.0 g, 31.9 mmol) was dissolved in THF (20 mL), and platinum dioxide (0.08 g) was added. The mixture was placed in a hydrogen stream under normal pressure and reacted at room temperature for 8 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to remove the solvent to obtain compound III, 8.0 g, with a yield of 99.2%. 1HNMR (400MHz, CDCL3) δ7.91-7.88(m,1H),7.49(d,J=9.0Hz,1H),7.28(d,J=1.8Hz,1H),4.12(s,3H),3.40-3.37(m,1H),1.49(d,J=7.0Hz,6H).

[0045] Example 6

[0046] Compound II (8.0 g, 31.9 mmol) was dissolved in ethyl acetate (20 mL), 5% platinum carbon (0.08 g) was added, and the mixture was placed in a hydrogen stream under normal pressure and reacted at room temperature for 10 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to remove the solvent to obtain compound III, 7.9 g, with a yield of 98.0%.

[0047] Example 7

[0048] Compound II (8 g, 31.9 mmol) was dissolved in ethyl acetate (20 mL), 5% palladium carbon (0.08 g) was added, and then one drop (about 20 μL) of hydrobromic acid (mass fraction: 20%) was added, and placed in a hydrogen flow under normal pressure and reacted at room temperature for 10 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to remove the solvent to obtain compound III, 7.7 g, with a yield of 95.5%.

[0049] Comparative Example 1

[0050] Referring to WO2019207463A1, compound I was used as a raw material to prepare compound III, and the method was as follows:

[0051] At 0°C, compound I (202.7 mg, 0.753 mmol) was dissolved in DCM (10 mL), and TFA (847 mg, 7.43 mmol) and Et3SiH (846 mg, 7.43 mmol) were added to the stirred solution of compound II, and the mixture was stirred at 25°C for 36 h, at which time TLC showed that the starting material disappeared, and LCMS monitored that the reaction was complete, and the ratio of compound II to compound III was 1:2 (HPLC normalization method); water (10 mL) was added to the reaction solution for extraction, and the organic phase was taken, the organic phase was washed with saturated brine, and then concentrated under reduced pressure to obtain a crude product, and the crude product was purified by normal phase silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:2 V / V gradient elution) to obtain a mixed product of compound II and compound III 145 mg, with a yield of 77%.

Claims

1. A method for preparing 5-bromo-2-methyl-3-isopropyl-indazole, characterized in that: The synthetic route is as follows: The method comprises: under the action of a dehydrating agent, compound I undergoes a dehydration reaction to obtain compound II; under the action of a catalyst, compound II undergoes a reduction reaction with a hydrogen source to obtain 5-bromo-2-methyl-3-isopropyl-indazole.

2. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The reaction solvent of the dehydration reaction is toluene, ethyl acetate, butyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile or acetone.

3. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The dehydration reagent is potassium hydrogen sulfate, trimethylsilyl chloride, trimethylsilyl bromide, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, concentrated sulfuric acid, or a combination of a base and one selected from methylsulfonic anhydride, methylsulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride, and trifluoromethanesulfonic anhydride; the base is at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

4. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1 or 3, characterized in that: The dehydrating agent is a combination of potassium hydrogen sulfate, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, a base and one selected from methylsulfonic anhydride and p-toluenesulfonyl chloride, preferably potassium hydrogen sulfate, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate.

5. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 3, characterized in that: The base is at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate and cesium carbonate, preferably triethylamine or potassium carbonate.

6. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The molar ratio of compound I to the dehydrating agent is 1:0.01 to 1:5, preferably 1:0.01 to 1:2.5, more preferably 1:0.01 to 1:1, and most preferably 1:0.05 to 1:

1.

7. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The reaction solvent of the reduction reaction is tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, acetone or dichloromethane.

8. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The catalyst is selected from palladium carbon, platinum carbon, and platinum dioxide; when the catalyst is selected from platinum carbon and platinum dioxide, no debromination inhibitor needs to be added to the reaction system; when the catalyst is selected from palladium carbon, a debromination inhibitor is added to the reaction system.

9. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The mass ratio of compound II to the catalyst is 1:0.0005 to 1:0.1, preferably 1:0.001 to 1:0.

05.

10. The method for preparing 5-bromo-2-methyl-3-isopropyl-indazole according to claim 1, characterized in that: The hydrogen source is selected from hydrogen, ammonium formate, sodium formate, formic acid, hydrazine hydrate, ammonium acetate or sodium borohydride.

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