Preparation method of 5-bromo-4-fluoro-1-methylindazole

Abstract

The invention discloses a preparation method of 5-bromine-4-fluoro-1-methylindazole, which comprises the following steps: 1, reacting 4-bromine-3-fluoro-2-methylaniline with a methylation reagent in an alkaline solvent I, cooling after reacting for a certain time, adding a reducing reagent in batches, reacting for a certain time, and carrying out reductive amination reaction to obtain an intermediate A; 2, the intermediate A and isoamyl nitrite are subjected to a cyclization reaction in a second alkaline solvent under catalysis of a phase transfer catalyst, and 5-bromo-4-fluoro-1-methylindazole is obtained.The method effectively avoids the isomer problem when 5-bromo-4-fluoroindazole is adopted for direct methylation reaction in a traditional process, raw materials and auxiliary materials are easy to obtain, the process steps are short, the yield is high, and the method is suitable for industrial production. The method is mild in reaction condition, simple to operate and high in process yield, and a high-purity product can be obtained.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical intermediates, and specifically relates to a preparation method of 5-bromo-4-fluoro-1-methylindazole. Background Art

[0002] Orforglipron is a new chemically synthesized oral non-peptide drug developed by Eli Lilly and Company. It can exert an effective anti-diabetic effect by enhancing glucose-dependent insulin secretion and improving energy balance. In preclinical simulation studies, it showed good efficacy in reducing hyperglycemia in experimental animals and had pharmacokinetic characteristics conducive to oral administration. Orforglipron is currently in the phase III clinical trial stage. It shows good therapeutic effects in obesity and type 2 diabetes and has no obvious clinical adverse events. Its structural formula is as follows I:

[0003]

[0004] 5-Bromo-4-fluoro-1-methylindazole is a key fragment of the molecular structure of Orforglipron and one of the key intermediates for synthesizing Orforglipron. Its structural formula is as follows formula II:

[0005]

[0006] Currently, there are few reported synthetic routes for 5-bromo-4-fluoro-1-methylindazole. Among them, CN116390926, CN117069743, and WO2024137426 all report that 5-bromo-4-fluoro-1-methylindazole is prepared through three-step reactions using 4-bromo-3-fluoro-2-methylaniline as a raw material. However, in the third-step methylation reaction of this route, positional isomers will be produced, and the proportion of this isomer exceeds 30%, resulting in a low process yield. At the same time, the product needs to be purified by column chromatography, and it is difficult to scale up industrially, with poor feasibility. The specific route is as follows:

[0007]

[0008] Patent WO2024137426 also reports another route that uses 2,5-dibromofluorobenzene as a raw material to prepare 5-bromo-4-fluoro-1-methylindazole through three-step reactions. However, this route requires the use of a variety of controlled and dangerous reagents such as n-butyllithium and methylhydrazine, and the process safety is relatively poor. A variety of mixed solvents are used in the process, which is not conducive to solvent recovery and reuse and environmental protection. The route yield is low, the total yield of the four-step reaction is 20%, the route cost is relatively high, and the first-step n-butyllithium reaction requires the use of a low-temperature continuous flow device, resulting in a huge upfront equipment investment for industrial production and being not conducive to industrial scale-up. The specific route is as follows:

[0009]

[0010] To solve the deficiencies of the prior art, it is necessary to develop a synthetic method with higher process yield, simple and easy process operation, and suitable for industrial production to meet the large-scale demand for 5-bromo-4-fluoro-1-methylindazole in the future market. Summary of the Invention

[0012] The object of the present application is to provide a preparation method of 5-bromo-4-fluoro-1-methylindazole. Using 4-bromo-3-fluoro-2-methylaniline as a raw material, it undergoes a reductive amination reaction with a methylation reagent and a reducing reagent to obtain intermediate A; compound A is cyclized under the action of isoamyl nitrite and a base to obtain 5-bromo-4-fluoro-1-methylindazole. This method effectively avoids the isomer problem in the traditional process when directly methylating 5-bromo-4-fluoroindazole. The raw and auxiliary materials are easily available, the process steps are short, the reaction conditions are mild, the operation is simple, the process yield is high, and a high-purity product can be obtained.

[0013] To achieve the above object, the present application provides the following technical solution: A preparation method of 5-bromo-4-fluoro-1-methylindazole, the steps are as follows:

[0014] Step 1: React 4-bromo-3-fluoro-2-methylaniline with a methylation reagent in an alkaline solvent I. After reacting for a certain time, cool down and add the reducing reagent in batches and then react for a certain time to obtain intermediate A through a reductive amination reaction;

[0015] Step 2: React intermediate A with isoamyl nitrite in an alkaline solvent II and carry out a cyclization reaction using a phase transfer catalyst to obtain 5-bromo-4-fluoro-1-methylindazole.

[0016] Preferably, the methylation reagent in Step 1 includes at least one of paraformaldehyde, DMF-DMA, dimethyl sulfate, or borane trimethylamine complex.

[0017] Preferably, the methylation reagent is paraformaldehyde, the reaction temperature with paraformaldehyde is 50 - 65°C, and the molar ratio of paraformaldehyde to 4-bromo-3-fluoro-2-methylaniline is 1.2 - 2.0:1.

[0018] Preferably, the molar ratio of paraformaldehyde to 4-bromo-3-fluoro-2-methylaniline is 1.2 - 1.5:1.

[0019] Preferably, the reaction temperature of 4-bromo-3-fluoro-2-methylaniline and the reducing reagent in Step 1 is 60 - 65°C. Preferably, the reducing reagent in Step 1 includes at least one of sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride.

[0020] Preferably, the reducing agent is sodium borohydride. The temperature of the system when adding sodium borohydride is -10 - 5°C, and the temperature of the system at the reaction temperature is 50 - 65°C. The molar ratio of sodium borohydride to 4-bromo-3-fluoro-2-methylaniline is 2.0 - 3.0:1.

[0021] Preferably, the temperature of the system when adding sodium borohydride is 0 - 5°C (-10 - 5°C), and the reaction temperature is 60 - 65°C. Preferably, the molar ratio of sodium borohydride to 4-bromo-3-fluoro-2-methylaniline is 2.0 - 2.5:1.

[0022] Preferably, the first solvent in Step 1 includes at least one of methanol, tetrahydrofuran, or DMF.

[0023] Preferably, the first solvent in Step 1 is methanol.

[0024] Preferably, the alkalinity in Step 1 is achieved by adding at least one of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, or cesium carbonate.

[0025] Preferably, the alkalinity in Step 1 is achieved by adding potassium hydroxide, and the molar ratio of potassium hydroxide to 4-bromo-3-fluoro-2-methylaniline is 2.0 - 3.0:1.

[0026] Preferably, the molar ratio of potassium hydroxide to 4-bromo-3-fluoro-2-methylaniline is 2.0 - 2.2:1.

[0027] Preferably, the molar ratio of isoamyl nitrite to Intermediate A is 2.0 - 3.5:1.

[0028] Preferably, the alkaline environment in Step 2 is achieved by adding at least one of potassium acetate, sodium acetate, potassium hydroxide, or sodium hydroxide.

[0029] Preferably, the alkaline environment in Step 2 is achieved by adding potassium acetate, and the molar ratio of potassium acetate to Intermediate A is 2.0 - 3.0:1.

[0030] Preferably, the molar ratio of potassium acetate to Intermediate A is 2.0 - 2.2:1.

[0031] Preferably, the phase transfer catalyst in Step 2 includes at least one of 18-crown-6, 15-crown-5, or cyclodextrin. Preferably, the phase transfer catalyst in Step 2 includes 18-crown-6.

[0032] Preferably, the second solvent in Step 2 includes at least one of chloroform, toluene, or 2-methyltetrahydrofuran. Preferably, the second solvent in Step 2 is chloroform.

[0033] Compared with the prior art, the beneficial effects of the present application are as follows: The present application effectively avoids the isomer problem in the direct methylation reaction of 5-bromo-4-fluoroindazole in the traditional process. The raw materials and auxiliary materials are easily available, the process steps are short, the reaction conditions are mild, the operation is simple, the process yield is high, and a product with high purity can be obtained. The process steps are short. Intermediate A does not need to be purified and separated and can directly undergo the second-step reaction. The reaction conditions are mild and the operation is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is the HPLC spectrum of 5-bromo-4-fluoro-1-methylindazole obtained in Example 1 of the present invention;

[0035] Figure 2 It is the LC-MS spectrum of 5-bromo-4-fluoro-1-methylindazole obtained in Example 1 of the present invention;

[0036] Figure 3 It is the HPLC spectrum of 5-bromo-4-fluoro-1-methylindazole obtained in Example 2 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0037] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without making creative efforts belong to the scope of protection of the present application.

[0038] Example 1

[0039] A preparation method of 5-bromo-4-fluoro-1-methylindazole, and the reaction route is as follows:

[0040]

[0041] The specific steps include:

[0042] Step 1: Add 4-bromo-3-fluoro-2-methylaniline (10 mmol), paraformaldehyde (15 mmol, 1.5 eq), potassium hydroxide (20 mmol, 2.0 eq) and 100 mL of anhydrous methanol to a reaction flask. Replace with nitrogen three times, reflux for 3 hours, then cool to 0 °C, and add sodium borohydride (20 mmol, 2.0 eq) in batches. After addition, heat to reflux for 12 hours. After monitoring the reaction to completion by TLC, add 30 mL of water dropwise to quench the reaction under an ice-water bath, concentrate under reduced pressure to remove methanol, then add 30 mL of ethyl acetate for extraction, separate the layers, and concentrate the organic phase under reduced pressure to obtain 2.09 g of crude intermediate A, with a crude yield of 95.9%.

[0043] Step 2: Add intermediate A (8 mmol), potassium acetate (16 mmol), 18-crown-6 (5%), and 80 mL of chloroform into the reaction flask. Dropwise add isoamyl nitrite (20 mmol) at 0 - 10 °C. After the addition, heat to reflux and react for 15 hours. After monitoring the reaction to completion by TLC, add 10 mL of water, extract, separate the layers. Wash the organic phase with water once and then concentrate to obtain the crude product. Add 8 mL of ethyl acetate to the crude product and stir to dissolve at 40 - 50 °C. After complete dissolution, dropwise add 32 mL of n-heptane to the feed solution to cool and crystallize. Filter, and dry the filter cake to obtain 1.7 g of a yellow solid, which is 5-bromo-4-fluoro-1-methylindazole, as Figure 1 and 2 shown, with a purity of 99.85% and a yield of 92.9%.

[0044] Example 2

[0045] Step 1: Add 4-bromo-3-fluoro-2-methylaniline (10 mmol), paraformaldehyde (12 mmol, 1.2 eq), potassium hydroxide (20 mmol, 2.0 eq), and 100 mL of anhydrous methanol into the reaction flask. Replace the air with nitrogen three times, reflux and react for 3 hours. Then cool to 0 °C and add sodium borohydride (20 mmol, 2.0 eq) in batches. After the addition, heat to reflux and react for 12 hours. After monitoring the reaction to completion by TLC, dropwise add 30 mL of water to quench the reaction under an ice-water bath, then concentrate under reduced pressure to remove methanol. Then add 30 mL of ethyl acetate for extraction, separate the layers. Take the organic phase and concentrate under reduced pressure to obtain 2.0 g of a yellow solid crude product of intermediate A, with a crude product yield of 89.9%.

[0046] Step 2: Add intermediate A (8 mmol), potassium acetate (24 mmol), 18-crown-6 (5%), and 80 mL of chloroform into the reaction flask. Dropwise add isoamyl nitrite (28 mmol) at 0 - 10 °C. After the addition, heat to reflux and react for 15 hours. After monitoring the reaction to completion by TLC, add 10 mL of water, extract, separate the layers. Wash the organic phase with water once and then concentrate to obtain the crude product. Add 8 mL of ethyl acetate to the crude product and stir to dissolve at 40 - 50 °C. After complete dissolution, dropwise add 32 mL of n-heptane to the feed solution to cool and crystallize. Filter, and dry the filter cake to obtain 1.6 g of a yellow solid, which is 5-bromo-4-fluoro-1-methylindazole, as Figure 3 shown, with a purity of 99.64% and a yield of 89.0%.

[0047] Example 3

[0048] Step 1: Add 4-bromo-3-fluoro-2-methylaniline (10 mmol), paraformaldehyde (12 mmol, 1.2 eq), potassium tert-butoxide (20 mmol, 2.0 eq) and 100 mL of anhydrous methanol into a reaction flask. Replace the air with nitrogen three times, reflux for 3 hours, then cool to 0 °C, and add sodium borohydride (20 mmol, 2.0 eq) in batches. After addition, heat to reflux for 12 hours. After monitoring the reaction to completion by TLC, add 30 mL of water dropwise under an ice-water bath to quench the reaction, concentrate under reduced pressure to remove methanol, then add 30 mL of ethyl acetate for extraction, separate the layers, and concentrate the organic phase under reduced pressure to obtain 1.6 g of crude intermediate A as a yellow solid, with a crude yield of 75%.

[0049] Step 2: Add intermediate A (8 mmol), potassium hydroxide (24 mmol), 18-crown-6 (5%) and 80 mL of chloroform into a reaction flask. Dropwise add isoamyl nitrite (28 mmol) at 0 - 10 °C. After addition, heat to reflux for 15 hours. After monitoring the reaction to completion by TLC, add 10 mL of water, extract, separate the layers, wash the organic phase with water once and then concentrate to obtain the crude product. Add 8 mL of ethyl acetate to the crude product and stir to dissolve at 40 - 50 °C. After complete dissolution, add 32 mL of n-heptane dropwise to the feed solution to cool and crystallize, filter, and dry the filter cake to obtain 1.3 g of yellow solid, with a purity of 99.44% and a yield of 70%.

[0050] Example 4

[0051] Step 1: Add 4-bromo-3-fluoro-2-methylaniline (10 mmol), DMF-DMA (15 mmol, 1.5 eq), potassium hydroxide (20 mmol, 2.0 eq) and 100 mL of DMF into a reaction flask. Replace the air with nitrogen three times, reflux for 3 hours, then cool to 0 °C, and add sodium borohydride (20 mmol, 2.0 eq) in batches. After addition, heat to reflux for 12 hours. After monitoring the reaction to completion by TLC, add 30 mL of water dropwise under an ice-water bath to quench the reaction, concentrate under reduced pressure to remove methanol, then add 30 mL of ethyl acetate for extraction, separate the layers, and concentrate the organic phase under reduced pressure to obtain 1.5 g of crude intermediate A as a yellow solid, with a crude yield of 67%.

[0052] Step 2: Add intermediate A (8 mmol), potassium acetate (16 mmol), 15-crown-5 (5%) and 80 mL of chloroform into a reaction flask. Dropwise add isoamyl nitrite (20 mmol) at 0 - 10 °C. After addition, heat to reflux for 15 hours. After monitoring the reaction to completion by TLC, add 10 mL of water, extract, separate the layers, wash the organic phase with water once and then concentrate to obtain the crude product. Add 8 mL of ethyl acetate to the crude product and stir to dissolve at 40 - 50 °C. After complete dissolution, add 32 mL of n-heptane dropwise to the feed solution to cool and crystallize, filter, and dry the filter cake to obtain 1.3 g of yellow solid, with a purity of 99.27% and a yield of 72%.

[0053] Example 5

[0054] Step 1: Add 4-bromo-3-fluoro-2-methylaniline (10 mmol), paraformaldehyde (15 mmol, 1.5 eq), potassium hydroxide (20 mmol, 2.0 eq) and 100 mL of anhydrous methanol into a reaction flask. Replace the air with nitrogen three times, reflux for 3 hours, then cool to 0 °C, and add sodium cyanoborohydride (20 mmol, 2.0 eq) portionwise. After addition, heat to reflux for 12 hours. After monitoring the reaction to completion by TLC, add 30 mL of water dropwise under an ice-water bath to quench the reaction, concentrate under reduced pressure to remove methanol, then add 30 mL of ethyl acetate for extraction, separate the layers, and concentrate the organic phase under reduced pressure to obtain 1.8 g of crude yellow solid intermediate A, with a crude yield of 79%.

[0055] Step 2: Add intermediate A (8 mmol), potassium acetate (16 mmol), cyclodextrin (5%) and 80 mL of chloroform into a reaction flask. Dropwise add isoamyl nitrite (20 mmol) at 0 - 10 °C. After addition, heat to reflux for 15 hours. After monitoring the reaction to completion by TLC, add 10 mL of water for extraction, separate the layers, wash the organic phase with water once and then concentrate to obtain the crude product. Add 8 mL of ethyl acetate to the crude product and stir to dissolve at 40 - 50 °C. After complete dissolution, add 32 mL of n-heptane dropwise to the feed solution to cool and crystallize. Filter, and dry the filter cake to obtain 1.2 g of yellow solid, with a purity of 99.59% and a yield of 65%.

[0056] Unless otherwise specified, the methods used in the present invention are all conventional methods in the art.

[0057] The above are only the preferred embodiments of the present invention, and do not impose any limitations on the present invention. Any simple modifications, changes and equivalent transformations made to the above embodiments according to the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing 5-bromo-4-fluoro-1-methylindazole, characterized in that, The steps are as follows: Step 1: React 4-bromo-3-fluoro-2-methylaniline with a methylation reagent in a basic solvent I. After reacting for a certain time, cool down and add the reducing reagent in batches and react for a certain time to obtain intermediate A through reductive amination reaction; Step 2: React intermediate A with isoamyl nitrite in a basic solvent II and carry out a cyclization reaction catalyzed by a phase transfer catalyst to obtain 5-bromo-4-fluoro-1-methylindazole.

2. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, characterized in that, In Step 1, the methylation reagent includes at least one of paraformaldehyde, DMF-DMA, dimethyl sulfate or borane trimethylamine complex.

3. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1 or 2, characterized in that, In Step 1, the reducing reagent includes at least one of sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

4. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, characterized in that, In Step 1, the solvent I includes at least one of methanol, tetrahydrofuran or DMF.

5. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, characterized in that, In Step 1, the basic system is achieved by adding at least one of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide or cesium carbonate.

6. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, characterized in that, In Step 2, the basic system is achieved by adding at least one of potassium acetate, sodium acetate, potassium hydroxide or sodium hydroxide.

7. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, wherein, In Step 2, the phase transfer catalyst includes at least one of 18-crown-6, 15-crown-5 or cyclodextrin.

8. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 1, characterized in that In Step 2, the solvent II includes at least one of chloroform, toluene or 2-methyltetrahydrofuran.

9. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 3, characterized in that In Step 1, the reducing reagent is sodium borohydride. The system temperature when adding sodium borohydride is -10 - 5°C, and the reaction system temperature after adding the reducing reagent is 50 - 65°C.

10. The preparation method of 5-bromo-4-fluoro-1-methylindazole according to claim 9, characterized in that The molar ratio of sodium borohydride to 4-bromo-3-fluoro-2-methylaniline is 2.0 - 3.0:1.

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