A preparation method for a key intermediate of Sotolacib

Abstract

The present invention relates to a method for preparing a key intermediate of sotolacib. The method uses ethyl acetoacetate as a raw material, first reacts with isobutyryl chloride to generate ethyl isobutyryl acetate, and then undergoes substitution, cyclization, aminolysis, and Hofmann rearrangement to obtain the target product, 2-isopropyl-3-amino-4-methylpyridine. The raw materials of the present invention are cheap and readily available, and there are no highly polluting or highly dangerous solvents or catalysts. The post-processing is relatively simple, the product has high purity, high yield, simple operation, low pollution, and low cost. All reactions of the present invention are common reactions, stable and safe, and all intermediate groups are stable, making it a route more suitable for the industrialization of the product.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and specifically provides a method for preparing 2-isopropyl-3-amino-4-methylpyridine, a key intermediate of the anticancer drug Sotolacib. Background Art

[0002] 2-Isopropyl-3-amino-4-methylpyridine is a key intermediate in the preparation of Lumakras (Sotorasib). Lumakras (Sotorasib), formerly known as AMG 510, is a small molecule designed to bind to KRAS G12C, locking the protein in an inactive state and preventing it from sending signals that drive uncontrolled cell growth. The drug's targeted approach does not affect unmutated KRAS proteins. On May 28, 2021, Amgen announced that the U.S. FDA has accelerated the approval of the KRAS G12C inhibitor Lumakras (Sotorasib) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying KRAS G12C mutations who have received at least one previous systemic treatment.

[0003] The preparation methods of 2-isopropyl-3-amino-4-methylpyridine reported in the literature mainly include:

[0004] 1) Patent WO2021097207 proposes using 2-chloro-3-amino-4-methylpyridine as the starting material, undergoing a Suzuki coupling reaction, and then undergoing a one-step reduction to obtain the target product. The reaction formula is as follows:

[0005]

[0006] The starting materials of this method are expensive, and noble metal catalysts are used. The boric acid reagent used is also relatively expensive, so this method is not the best option for the synthesis of this intermediate.

[0007] 2) Patent WO2021097207 also reports that ethyl isobutyrate is used as the starting material, and the target product is finally obtained through cyclization, hydrolysis, and Hofmann rearrangement reaction. The reaction formula is as follows:

[0008]

[0009] The raw materials for this method are relatively cheap and easy to obtain. However, since the cyano group is an easily hydrolyzed group and is relatively unstable, this limits the industrialization process of the project. Moreover, the patent does not mention the specific post-processing method and satisfactory yield, so its industrial feasibility is still somewhat unknown. Summary of the Invention

[0010] In order to overcome the shortcomings and deficiencies of the prior art, the present invention provides a method for preparing 2-isopropyl-3-amino-4-methylpyridine, a key intermediate of sotolacib, which has simple operation, cheap raw materials, stable intermediates, low reaction pollution and high product yield.

[0011] The technical solution adopted by the present invention is:

[0012] A method for preparing a key intermediate of sotolacib, comprising: using ethyl acetoacetate as a raw material, first reacting it with isobutyryl chloride to generate ethyl isobutyryl acetate, and then performing substitution, cyclization, aminolysis, and Hofmann rearrangement to obtain the target product, 2-isopropyl-3-amino-4-methylpyridine.

[0013] The specific reaction equation is as follows:

[0014]

[0015] Preferably, the method for preparing the key intermediate of Sotolacib comprises the following steps:

[0016] (1) Ethyl acetoacetate is added to a reaction flask, followed by toluene and magnesium ethoxide, and the reaction is carried out at elevated temperature for 1 hour. Finally, isobutyryl chloride is added dropwise, and the reaction is continued for 2 to 6 hours. After post-treatment, the product, ethyl isobutyryl acetate, is obtained;

[0017] (2) adding ethyl isobutyryl acetate, acetone, and L-proline to a reaction flask, heating the reaction, and keeping the temperature for 2 to 6 hours. After the reaction of the raw materials is complete, post-processing is performed to obtain ethyl 2-isobutyryl-3-methyl-2-butenoate;

[0018] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester to the reaction flask, add ethanol and DMF-DMA, and heat the reaction for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate and ammonia water, heat and reflux for 2 to 8 hours. After the intermediate disappears, evaporate the ethanol, add water and dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain the product 2-isopropyl-4-methylnicotinate;

[0019] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester, ethanol, and ammonia water to a reaction flask, heat and react overnight, and obtain 2-isopropyl-4-methylnicotinamide after post-treatment;

[0020] (5) Add water and potassium hydroxide to the reaction flask, add 2-isopropyl-4-methylnicotinamide, and add bromine dropwise with stirring. Maintain the dropping temperature between T = 0-10°C. After the disappearance of the control raw material, increase the temperature to react for 2-4 hours. After the disappearance of the raw material and the intermediate state, the post-treatment yields 2-isopropyl-3-amino-4-methylpyridine.

[0021] Preferably, in step (1), the molar ratio of ethyl acetoacetate, isobutyryl chloride, and magnesium ethoxide is 1:1-1.5:1-2, and the reaction temperature is 60-80°C; the post-treatment operation in step (1) is: dropwise adding hydrochloric acid to quench the reaction, adding ammonia water to the organic phase, stirring at 1-10°C for 1 hour, separating the organic phase, adjusting the pH to 7 with acetic acid, stirring for 1 hour, separating the organic phase, distilling off toluene, and distilling.

[0022] Preferably, in step (2), the molar ratio of ethyl isobutyryl acetate to L-proline is 1:0.1-2, and the reaction temperature is 30°C to reflux; the post-treatment operation in step (2) is: cooling, adding hydrochloric acid to adjust the pH to 3-4, filtering, and rotary evaporating the organic phase to obtain the product, and directly proceeding to the next step.

[0023] Preferably, in step (3), the molar ratio of 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester, DMF-DMA, ammonium acetate and ammonia water is 1:1-3:0.1-2:1-3, and the reaction temperature is 30°C to reflux.

[0024] Preferably, in step (4), the molar ratio of 2-isopropyl-4-methylnicotinate to ammonia water is 1:1-15, and the reaction temperature is 20-50°C; and the post-treatment operation in step (4) is: precipitating the solid and filtering it.

[0025] Preferably, in step (5), the molar ratio of 2-isopropyl-4-methylnicotinamide, potassium hydroxide and bromine is 1:1-5:1-3, the dropping temperature is between 0 and 10°C, and the reaction temperature is 40 to 80°C.

[0026] Preferably, the post-treatment operation in step (5) is: cooling to room temperature, adding EA and stirring for 5 minutes, separating the layers, extracting the aqueous phase with EA again, combining the organic phases, adding activated carbon, heating to reflux for decolorization, filtering, and distilling under reduced pressure to obtain a crude product, which is slurried with cyclohexane while cooling, and filtered to obtain 2-isopropyl-3-amino-4-methylpyridine.

[0027] Preferably, the method for preparing the key intermediate of Sotolacib specifically comprises the following steps:

[0028] (1) Add 0.77 mol of ethyl acetoacetate to a 500 mL reaction flask, then add 600 g of toluene and 0.92 mol of magnesium ethoxide, heat to 60° C. and react for 1 hour, finally add 0.85 mol of isobutyryl chloride dropwise, heat to T=90° C. and react for 4 hours, add 100 g of hydrochloric acid dropwise to quench the reaction, add 150 g of ammonia water to the organic phase, stir at 1-10° C. for 1 hour, separate the organic phase, adjust the pH to 7 with acetic acid, stir for 1 hour, separate the organic phase, evaporate the toluene, and obtain the product ethyl isobutyryl acetate after rectification;

[0029] (2) Add 0.63 mol of ethyl isobutyryl acetate, 600 g of acetone, and 0.13 mol of L-proline to a reaction flask, raise the temperature to reflux for reaction, and keep the temperature for 5 hours. After the reaction of the raw materials is complete, cool the temperature, add hydrochloric acid to adjust the pH to 3-4, filter, and rotary evaporate the organic phase to obtain ethyl 2-isobutyryl-3-methyl-2-butenoate;

[0030] (3) Add 0.45 mol of 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester, 450 g of ethanol, and 0.68 mol of DMF-DMA to the reaction flask, and heat and reflux for 2 hours. After the reaction of the raw materials is completed, 0.09 mol of ammonium acetate and 1.13 mol of ammonia water are added, and the temperature is refluxed for 8 hours. After the intermediate disappears, the ethanol is evaporated, 300 g of water and 300 g of dichloromethane are added, and the dichloromethane is washed with saturated sodium chloride, dried, and spin-dried to obtain the product 2-isopropyl-4-methylnicotinate;

[0031] (4) Add 0.41 mol of ethyl 2-isopropyl-4-methylnicotinate, 300 g of ethanol, and 3.3 mol of aqueous ammonia to a reaction flask, heat to 40°C, react overnight, cool to room temperature, precipitate a solid, and filter to obtain 2-isopropyl-4-methylnicotinamide;

[0032] (5) 600 g of water, 0.79 mol of potassium hydroxide, and 0.31 mol of 2-isopropyl-4-methylnicotinamide were added to the reaction flask, and 0.38 mol of bromine was added dropwise under stirring. The dropping temperature was maintained between T = 0 and 10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept warm for 2 hours. The disappearance of the raw material and the intermediate state was detected, and the temperature was cooled to room temperature. 300 g of ethyl acetate was added and stirred for 5 minutes. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, the temperature was raised to reflux for decolorization, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain the fine product 2-isopropyl-3-amino-4-methylpyridine.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] (1) The raw materials for the preparation of 2-isopropyl-3-amino-4-methylpyridine of the present invention are cheap and readily available, and there are no highly polluting and highly dangerous solvents or catalysts. The post-processing is relatively simple, the product purity is high, the yield is high, the operation is simple, the pollution is low, and the cost is low.

[0035] (2) All reactions of the present invention are common reactions, which are stable and safe, and all intermediate groups have good stability, which is a route that is more suitable for the industrialization of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1This is the H NMR spectrum of 2-isopropyl-3-amino-4-methylpyridine. DETAILED DESCRIPTION

[0037] The technical solutions of the present invention are further specifically described below through examples. These examples are provided for the purpose of illustrating the present invention and are not intended to limit the present invention. All other examples obtained by persons of ordinary skill in the art based on the examples in this application without creative work are intended to fall within the scope of protection of this application.

[0038] Example 1

[0039] (1) Ethyl acetoacetate (100 g, 0.77 mol) was added to a 500 mL reaction flask, followed by 600 g of toluene and magnesium ethoxide (133 g, 0.92 mol). The temperature was raised to 60° C. and the reaction was continued for 1 hour. Finally, isobutyryl chloride (90 g, 0.85 mol) was added dropwise, and the temperature was raised to T=90° C. and the reaction was continued for 4 hours. 100 g of hydrochloric acid was added dropwise to quench the reaction. 150 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10° C. for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour. The organic phase was separated, the toluene was evaporated, and the product, ethyl isobutyryl acetate (115.2 g) was obtained after rectification. The yield was 94.5%, and the HPLC purity was 99.2%; EI-MS m / z: 159.3 [M+H] + .

[0040] (2) Ethyl isobutyryl acetate (100 g, 0.63 mol), 600 g acetone, and L-proline (14.5 g, 0.13 mol) were added to the reaction flask, and the temperature was raised to reflux for reaction. The temperature was kept for 5 hours. After the reaction of the raw materials was detected to be complete, the temperature was lowered, hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 112.1 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 89.4% and a HPLC purity of 99%; EI-MS m / z: 199.5 [M+H] + .

[0041] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (90 g, 0.45 mol) from the previous step to the reaction flask, add 450 g of ethanol and DMF-DMA (81 g, 0.68 mol), and heat and reflux for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (7 g, 0.09 mol) and ammonia water (78 g, 1.13 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 75 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 79.7% and a HPLC purity of 95%; EI-MS m / z: 208.1 [M+H] + .

[0042] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester (85 g, 0.41 mol), 300 g ethanol, and aqueous ammonia (223 g, 3.3 mol) to the reaction flask, heat to 40°C and react overnight, cool to room temperature to precipitate solid, filter, and post-process to obtain 67.9 g of 2-isopropyl-4-methylnicotinamide, with a yield of 92.9% and an HPLC purity of 97.6%; EI-MS m / z: 179.3 [M+H] + .

[0043] (5) 600 g of water, 44 g of potassium hydroxide (0.79 mol), and 56 g of 2-isopropyl-4-methylnicotinamide (0.31 mol) were added to the reaction flask, and 60.3 g of bromine (0.38 mol) was added dropwise under stirring. The temperature of the addition was kept between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 300 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, and the temperature was raised to reflux for decolorization. The mixture was filtered and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 38.3 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 81.1% and a purity of 99.9% by HPLC; EI-MS m / z: 151.3 [M+H] + , the H NMR spectrum is as follows Figure 1 shown.

[0044] Example 2

[0045] (1) Ethyl acetoacetate (100 g, 0.77 mol) was added to a 500 mL reaction flask, followed by 600 g of toluene and magnesium ethoxide (111.3 g, 0.77 mol). The temperature was raised to 60°C for reaction for 1 hour. Finally, isobutyryl chloride (90 g, 0.85 mol) was added dropwise, and the temperature was raised to T = 90°C for reaction for 4 hours. 100 g of hydrochloric acid was added dropwise to quench the reaction. 100 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10°C for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour. The organic phase was separated, the toluene was evaporated, and the product was obtained after distillation. 103.6 g of ethyl isobutyryl acetate was obtained with a yield of 85.2%; EI-MS m / z: 159.3 [M+H] + .

[0046] (2) Ethyl isobutyryl acetate (100 g, 0.63 mol), 600 g acetone, and L-proline (7.25 g, 0.063 mol) were added to the reaction flask, and the temperature was raised to reflux for reaction. The temperature was kept for 5 hours, and the temperature was lowered. Hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 93.8 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 74.8%; EI-MS m / z: 199.5 [M+H] + .

[0047] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (90 g, 0.45 mol) from the previous step to the reaction flask, add 450 g of ethanol and DMF-DMA (65 g, 0.55 mol), and heat and reflux for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (7 g, 0.09 mol) and ammonia water (78 g, 1.13 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 68 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 72.3%; EI-MS m / z: 208.1 [M+H] + .

[0048] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester (85 g, 0.41 mol), 300 g of ethanol, and aqueous ammonia (169 g, 2.5 mol) to the reaction flask, heat to 40°C and react overnight, cool to room temperature to precipitate solid, filter, and post-process to obtain 65 g of 2-isopropyl-4-methylnicotinamide, with a yield of 88.9%; EI-MS m / z: 179.3 [M+H] + .

[0049] (5) 600 g of water, potassium hydroxide (34.5 g, 0.62 mol) and 2-isopropyl-4-methylnicotinamide (56 g, 0.31 mol) were added to the reaction flask, and bromine (60.3 g, 0.38 mol) was added dropwise under stirring. The temperature of the addition was kept between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 300 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, the temperature was raised to reflux for decolorization, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 35 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 74.1%; EI-MS m / z: 151.3 [M+H] + .

[0050] Example 3

[0051] (1) Ethyl acetoacetate (100 g, 0.77 mol) was added to a 500 mL reaction flask, followed by 600 g of toluene and magnesium ethoxide (133 g, 0.92 mol). The temperature was raised to 60° C. and the reaction was continued for 1 hour. Finally, isobutyryl chloride (123 g, 1.16 mol) was added dropwise, and the temperature was raised to T=90° C. and the reaction was continued for 4 hours. 100 g of hydrochloric acid was added dropwise to quench the reaction. 150 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10° C. for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour. The organic phase was separated, the toluene was evaporated, and the product was obtained after rectification, 114.5 g of ethyl isobutyryl acetate, with a yield of 94%; EI-MS m / z: 159.3 [M+H] + .

[0052] (2) Ethyl isobutyryl acetate (100 g, 0.63 mol), acetone 600 g, and L-proline (72.5 g, 0.65 mol) were added to the reaction flask, and the temperature was raised to reflux for reaction. The temperature was kept for 5 hours. After the reaction of the raw materials was detected to be complete, the temperature was lowered, hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 112.6 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 89.8%; EI-MS m / z: 199.5 [M+H] + .

[0053] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (90 g, 0.45 mol) from the previous step to the reaction flask, add 450 g of ethanol and DMF-DMA (162 g, 0.9 mol), and heat and reflux for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (7 g, 0.09 mol) and ammonia water (78 g, 1.13 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 62 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 65.9%; EI-MS m / z: 208.1 [M+H] + .

[0054] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester (85 g, 0.41 mol), 300 g ethanol, and aqueous ammonia (415.6 g, 6.15 mol) to the reaction flask, heat to 40°C and react overnight, cool to room temperature to precipitate solid, filter, and post-process to obtain 66.7 g of 2-isopropyl-4-methylnicotinamide, with a yield of 91.3%; EI-MS m / z: 179.3 [M+H] + .

[0055] (5) 600 g of water, 44 g of potassium hydroxide (0.79 mol), and 56 g of 2-isopropyl-4-methylnicotinamide (0.31 mol) were added to the reaction flask, and 74.6 g of bromine (0.47 mol) was added dropwise under stirring. The temperature of the addition was kept between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 300 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, and the temperature was raised to reflux for decolorization. The mixture was filtered and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 35.9 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 76%; EI-MS m / z: 151.3 [M+H] + .

[0056] Example 4

[0057] (1) Ethyl acetoacetate (100 g, 0.77 mol) was added to a 500 mL reaction flask, followed by 600 g of toluene and magnesium ethoxide (133 g, 0.92 mol). The temperature was raised to 80°C for reaction for 1 hour. Finally, isobutyryl chloride (90 g, 0.85 mol) was added dropwise, and the temperature was raised to T = 90°C for reaction for 4 hours. 100 g of hydrochloric acid was added dropwise to quench the reaction. 150 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10°C for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour. The organic phase was separated, the toluene was evaporated, and the product was obtained after distillation. 100.3 g of ethyl isobutyryl acetate was obtained with a yield of 82.3%; EI-MS m / z: 159.3 [M+H] + .

[0058] (2) Ethyl isobutyryl acetate (100 g, 0.63 mol), acetone 600 g, and L-proline (14.5 g, 0.13 mol) were added to the reaction flask, and the temperature was raised to 30°C for reaction. The temperature was kept for 5 hours. After the reaction of the raw materials was detected to be complete, the temperature was lowered, hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 40.4 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 32.2%; EI-MS m / z: 199.5 [M+H] + .

[0059] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (90 g, 0.45 mol) from the previous step to the reaction flask, add 450 g of ethanol and DMF-DMA (81 g, 0.68 mol), heat to 40 ° C and react for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (7 g, 0.09 mol) and ammonia water (78 g, 1.13 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 65 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 69.1%; EI-MS m / z: 208.1 [M+H] + .

[0060] (4) Ethyl 2-isopropyl-4-methylnicotinate (85 g, 0.41 mol), 300 g of ethanol, and aqueous ammonia (223 g, 3.3 mol) were added to the reaction flask and reacted overnight at 20°C. The mixture was cooled to room temperature to precipitate a solid, which was filtered and post-treated to obtain 55.6 g of 2-isopropyl-4-methylnicotinamide (yield 76.1%); EI-MS m / z: 179.3 [M+H] + .

[0061] (5) 600 g of water, 44 g of potassium hydroxide (0.79 mol), and 56 g of 2-isopropyl-4-methylnicotinamide (0.31 mol) were added to the reaction flask, and 60.3 g of bromine (0.38 mol) was added dropwise under stirring. The temperature of the addition was kept between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 40 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 300 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, the temperature was raised to reflux for decolorization, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 25.6 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 54.2%; EI-MS m / z: 151.3 [M+H] + .

[0062] Example 5

[0063] (1) Ethyl acetoacetate (100 g, 0.77 mol) was added to a 500 mL reaction flask, followed by 600 g of toluene and magnesium ethoxide (222.6 g, 1.54 mol). The temperature was raised to 60°C for reaction for 1 hour, and finally isobutyryl chloride (122.8 g, 1.16 mol) was added dropwise. The temperature was raised to T = 90°C for reaction for 4 hours. 100 g of hydrochloric acid was added dropwise to quench the reaction. 150 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10°C for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour, and the organic phase was separated. The toluene was evaporated and distilled to obtain 112.5 g of ethyl isobutyryl acetate (yield 92.1%). EI-MS m / z: 159.3 [M+H] + .

[0064] (2) Ethyl isobutyryl acetate (100 g, 0.63 mol), 600 g acetone, and L-proline (140.5 g, 1.26 mol) were added to the reaction flask, and the temperature was raised to reflux for reaction. The temperature was kept for 5 hours. After the reaction of the raw materials was detected to be complete, the temperature was lowered, hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 110.9 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 88.5%; EI-MS m / z: 199.5 [M+H] + .

[0065] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (90 g, 0.45 mol) from the previous step to the reaction flask, add 450 g of ethanol and DMF-DMA (160.8 g, 1.35 mol), and heat and reflux for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (70 g, 0.9 mol) and ammonia water (93.1 g, 1.35 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 34.1 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 36.3%; EI-MS m / z: 208.1 [M+H] +.

[0066] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester (85 g, 0.41 mol), 300 g of ethanol, and aqueous ammonia (415.6 g, 6.15 mol) to the reaction flask, heat to reflux and react overnight, cool to room temperature to precipitate solid, filter, and post-process to obtain 49.3 g of 2-isopropyl-4-methylnicotinamide, with a yield of 67.5%; EI-MS m / z: 179.3 [M+H] + .

[0067] (5) 600 g of water, 86.3 g of potassium hydroxide (1.55 mol), and 56 g of 2-isopropyl-4-methylnicotinamide (0.31 mol) were added to the reaction flask. Bromine (147.6 g, 0.93 mol) was added dropwise under stirring. The temperature of addition was maintained between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 300 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 100 g of ethyl acetate. The organic phases were combined, 2 g of activated carbon was added, the temperature was raised to reflux for decolorization, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 21.6 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 45.7%; EI-MS m / z: 151.3 [M+H] + .

[0068] Example 6

[0069] (1) Ethyl acetoacetate (500 g, 3.85 mol) was added to a 500 mL reaction flask, followed by 3000 g of toluene and magnesium ethoxide (665 g, 4.6 mol). The temperature was raised to 60° C. and the mixture was reacted for 1 hour. Finally, isobutyryl chloride (450 g, 4.25 mol) was added dropwise, and the temperature was raised to T=90° C. and the mixture was reacted for 4 hours. 500 g of hydrochloric acid was added dropwise to quench the reaction. 750 g of ammonia water was added to the organic phase, and the mixture was stirred at 1-10° C. for 1 hour. The organic phase was separated, and the pH was adjusted to 7 with acetic acid. The mixture was stirred for 1 hour, the organic phase was separated, the toluene was evaporated, and the product, ethyl isobutyryl acetate (573.5 g) was obtained after rectification. The yield was 94.1%, and the HPLC purity was 99.3%; EI-MS m / z: 159.3 [M+H] + .

[0070] (2) Ethyl isobutyryl acetate (300 g, 1.89 mol), 1800 g acetone, and L-proline (43.5 g, 0.39 mol) were added to the reaction flask, and the temperature was raised to reflux for reaction. The temperature was kept for 5 hours. After the reaction of the raw materials was detected to be complete, the temperature was lowered, hydrochloric acid was added to adjust the pH to 3-4, and the mixture was filtered. The organic phase was rotary evaporated to obtain 338.2 g of ethyl 2-isobutyryl-3-methyl-2-butenoate, with a yield of 89.9% and a HPLC purity of 98.9%; EI-MS m / z: 199.5 [M+H] + .

[0071] (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester (180 g, 0.9 mol) from the previous step to the reaction flask, add 900 g of ethanol and DMF-DMA (162 g, 1.36 mol), and heat and reflux for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate (14 g, 0.18 mol) and ammonia water (156 g, 2.26 mol). Heat and reflux for 8 hours. After the intermediate disappears, evaporate the ethanol, add 600 g of water and 600 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain 149.2 g of the product 2-isopropyl-4-methylnicotinate, with a yield of 79.3% and a HPLC purity of 95.6%; EI-MS m / z: 208.1 [M+H] + .

[0072] (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester (510 g, 2.46 mol), 1800 g of ethanol, and aqueous ammonia (1338 g, 19.8 mol) to the reaction flask, heat to 40°C and react overnight, cool to room temperature to precipitate solid, filter, and post-process to obtain 401.7 g of 2-isopropyl-4-methylnicotinamide, with a yield of 91.6% and an HPLC purity of 98.1%; EI-MS m / z: 179.3 [M+H] + .

[0073] (5) 900 g of water, 66 g of potassium hydroxide (1.19 mol), and 84 g of 2-isopropyl-4-methylnicotinamide (0.47 mol) were added to the reaction flask. Bromine (90.5 g, 0.57 mol) was added dropwise under stirring. The temperature of the addition was kept between T = 0-10 ° C. After the disappearance of the control raw material, the temperature was quickly raised to 60 ° C and kept for 2 hours. The raw material and the intermediate state disappeared, and the temperature was lowered to room temperature. 450 g of ethyl acetate was added and stirred for 5 min. The layers were separated, and the aqueous phase was extracted once with 150 g of ethyl acetate. The organic phases were combined, 3 g of activated carbon was added, and the temperature was raised to reflux for decolorization. The mixture was filtered and distilled under reduced pressure to obtain a crude product. The crude product was cooled and slurried with cyclohexane, and filtered to obtain 57.9 g of fine 2-isopropyl-3-amino-4-methylpyridine, with a yield of 81.8% and a purity of 99.9% by HPLC; EI-MS m / z: 151.3 [M+H] + .

[0074] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing a key intermediate of Sotolacib, characterized in that: The steps include: (1) Add ethyl acetoacetate to a reaction flask, then add toluene and magnesium ethoxide, heat and react for 1 hour, finally dropwise add isobutyryl chloride, and react for another 2 to 6 hours. After post-treatment, the product ethyl isobutyryl acetate is obtained; (2) Add ethyl isobutyryl acetate, acetone, and L-proline to the reaction flask, raise the temperature for reaction, and keep the temperature for 2 to 6 hours. After the reaction of the raw materials is complete, post-process and obtain ethyl 2-isobutyryl-3-methyl-2-butenoate; (3) Add 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester to the reaction flask, add ethanol and DMF-DMA, and heat to react for 2 hours. After the reaction of the raw materials is completed, add ammonium acetate and ammonia water, heat and reflux for 2 to 8 hours. After the intermediate disappears, evaporate the ethanol, add water and dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain the product 2-isopropyl-4-methylnicotinate; (4) Add 2-isopropyl-4-methylnicotinic acid ethyl ester, ethanol, and ammonia water to the reaction flask, heat and react overnight, and obtain 2-isopropyl-4-methylnicotinamide after post-treatment; (5) Add water and potassium hydroxide to the reaction flask, add 2-isopropyl-4-methylnicotinamide, and add bromine dropwise under stirring. After the disappearance of the intermediate control raw material, heat the reaction for 2 to 4 hours, and detect the disappearance of the raw material and the intermediate state. After post-treatment, 2-isopropyl-3-amino-4-methylpyridine is obtained; In step (1), the molar ratio of ethyl acetoacetate, isobutyryl chloride, and magnesium ethoxide is 1:1-1.5:1-2, and the reaction temperature is 60-80°C; the post-treatment operation in step (1) is: adding hydrochloric acid dropwise to quench the reaction, adding ammonia water to the organic phase, stirring at 1-10°C for 1 hour, separating the organic phase, adjusting the pH to 7 with acetic acid, stirring for 1 hour, separating the organic phase, distilling off toluene, and distilling; In step (2), the molar ratio of ethyl isobutyryl acetate to L-proline is 1:0.1-2, and the reaction temperature is 30°C to reflux; the post-treatment operation in step (2) is: cooling, adding hydrochloric acid to adjust the pH to 3-4, filtering, and rotary evaporating the organic phase to obtain the product, and directly proceeding to the next step; In step (3), the molar ratio of 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester, DMF-DMA, ammonium acetate, and ammonia water is 1:1-3:0.1-2:1-3, and the reaction temperature is 30°C to reflux; In step (4), the ratio of 2-isopropyl-4-methylnicotinate to ammonia water is 1:1-15, and the reaction temperature is 20-50°C; the post-treatment operation in step (4) is: precipitating the solid and filtering; In step (5), the molar ratio of 2-isopropyl-4-methylnicotinamide, potassium hydroxide and bromine is 1:1 to 5:1 to 3, the dropping temperature is between 0 and 10°C, and the reaction temperature is 40 to 80°C; the post-treatment operation in step (5) is: cooling to room temperature, adding EA and stirring for 5 minutes, separating the layers, extracting the aqueous phase with EA once more, combining the organic phases, adding activated carbon, heating to reflux for decolorization, filtering, and distilling under reduced pressure to obtain a crude product, cooling the crude product with cyclohexane for pulping, and filtering to obtain 2-isopropyl-3-amino-4-methylpyridine.

2. The method for preparing the key intermediate of Sotolacib according to claim 1, characterized in that The specific steps include: (1) Add 0.77 mol of ethyl acetoacetate to a 500 mL reaction flask, then add 600 g of toluene and 0.92 mol of magnesium ethoxide, heat to 60 ° C and react for 1 hour, finally add 0.85 mol of isobutyryl chloride dropwise, then heat to T = 90 ° C and react for 4 hours, add 100 g of hydrochloric acid dropwise to quench the reaction, add 150 g of ammonia water to the organic phase, stir at 1-10 ° C for 1 hour, separate the organic phase, adjust the pH to 7 with acetic acid, stir for 1 hour, separate the organic phase, evaporate the toluene, and obtain the product ethyl isobutyryl acetate after distillation; (2) Add 0.63 mol of ethyl isobutyryl acetate, 600 g of acetone, and 0.13 mol of L-proline to the reaction flask, raise the temperature to reflux reaction, and keep the temperature for 5 hours. After the reaction of the raw materials is complete, cool down, add hydrochloric acid to adjust the pH to 3-4, filter, and rotary evaporate the organic phase to obtain 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester; (3) Add 0.45 mol of 2-isobutyryl-3-methyl-2-butenoic acid ethyl ester, 450 g of ethanol, and 0.68 mol of DMF-DMA to the reaction flask, heat and reflux for 2 hours, and after the reaction of the raw materials is completed, add 0.09 mol of ammonium acetate and 1.13 mol of ammonia water, heat and reflux for 8 hours, and after the intermediate disappears, evaporate the ethanol, add 300 g of water and 300 g of dichloromethane, wash the dichloromethane with saturated sodium chloride, dry it, and spin dry it to obtain the product 2-isopropyl-4-methylnicotinate; (4) Add 0.41 mol of 2-isopropyl-4-methylnicotinic acid ethyl ester, 300 g of ethanol, and 3.3 mol of ammonia water to a reaction flask, heat to 40°C and react overnight, cool to room temperature to precipitate a solid, and filter to obtain 2-isopropyl-4-methylnicotinamide; (5) Add 600 g of water, 0.79 mol of potassium hydroxide, 0.31 mol of 2-isopropyl-4-methylnicotinamide to the reaction flask, and add 0.38 mol of bromine dropwise while stirring. Keep the dropping temperature between T = 0 and 10 ° C. After detecting the disappearance of the control raw material, quickly raise the temperature to 60 ° C and keep the reaction for 2 hours. Detect the disappearance of the raw material and the intermediate state, cool to room temperature, add 300 g of ethyl acetate and stir for 5 minutes, separate the layers, and extract the aqueous phase with 100 g of ethyl acetate once. Combine the organic phases, add 2 g of activated carbon, raise the temperature to reflux for decolorization, filter, and distill under reduced pressure to obtain a crude product. The crude product is cooled and slurried with cyclohexane, and filtered to obtain the fine product 2-isopropyl-3-amino-4-methylpyridine.

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