A process for the synthesis of 2-isopropyl-4-methylpyridin-3-amine

Abstract

The present application relates to a kind of 2-isopropyl-4-methylpyridine-3-amine synthesis process, with nickel catalyst, Grignard reagent, to carry out one-step Kumada coupling reaction to obtain product 2-isopropyl-4-methylpyridine-3-amine with 2-chloro-3-amino-4-methylpyridine as starting material.The synthesis process of 2-isopropyl-4-methylpyridine-3-amine of the present application, step is short, raw material is easy to obtain, and does not need to use expensive palladium metal catalyst, cost is low, yield is high, process is simple, three wastes are less, suitable for industrial amplification production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a synthesis process of 2-isopropyl-4-methylpyridine-3-amine. Background Technology

[0002] RAS proteins are a class of small G proteins that bind to GTP / GDP and possess GTP-hydrolyzing activity. Because RAS proteins occupy central positions on the axes of many important cellular signaling networks, they are associated with numerous cancer markers, and mutations causing RAS protein activation have been found in approximately one-fifth of all human tumors. There are three families of RAS proteins: HRAS, KRAS, and NRAS. KRAS mutations are the most common type of mutation in the RAS family, accounting for 85% of RAS mutations. Approximately 30% of tumors have KRAS mutations, including 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers. There are various types of KRAS mutations, one of the most common being the G12C mutation, occurring in approximately 14% of non-small cell lung cancers, approximately 4% of colon cancers, and approximately 2.9% of pancreatic cancers. In recent years, clinical treatment options have been quite limited for KRAS G12C mutation-positive NSCLC patients who have failed first-line therapy or have discontinued treatment, resulting in a significant gap in medical demand. On May 28, 2021, sotorasib (AMG-510) received accelerated approval from the FDA for the treatment of patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy. This was the world's first targeted therapy against KRAS, marking a significant milestone.

[0003] 2-Isopropyl-amino-4-methylpyridine is a key intermediate in the synthesis of sotorasidib and is also an intermediate for many current drug molecules, such as O-GlcNAc hydrolase (OGA) inhibitors. OGA inhibitors can be used to prevent or treat tau diseases, particularly those selected from the following group: Alzheimer's disease, progressive supranuclear palsy, Down syndrome, frontotemporal dementia, frontotemporal dementia with Parkinson's syndrome-17, Pick's disease, corticobasal degeneration and argyrophilic granulation disease; or neurodegenerative diseases with tau pathology, especially those selected from neurodegenerative diseases caused by C9ORF72 mutations leading to amyotrophic lateral sclerosis or frontotemporal dementia.

[0004] Currently, there are few reports on the industrial synthesis of 2-isopropyl-4-methylpyridin-3-amine. The patented synthetic routes are mainly the following two: Method 1: The original drug, Amgen's US20190374542A, follows the following route:

[0005] The process involves using 2-bromo-3-amino-4-methylpyridine as a raw material, adding Pd(dppf)Cl2 and isopropyl zinc bromide, and then reacting via a Negishi coupling reaction to obtain 2-isopropyl-4-methylpyridine-3-amine. This method uses expensive palladium catalysts and organozinc reagents, resulting in high costs; furthermore, the raw material 2-bromo-3-amino-4-methylpyridine is not a commercially available commodity, making it difficult to obtain and expensive.

[0006] Method 2: Johnson & Johnson's WO2019243535A, the synthesis route is as follows:

[0007] The process involves using 2-bromo-3-amino-4-methylpyridine as a raw material, which is then Suzuki coupled with pinacol isopropenylborate to obtain compound IV, followed by palladium carbon hydrogenation to yield the product 2-isopropyl-4-methylpyridine-3-amine. This method also uses 2-bromo-3-amino-4-methylpyridine as a raw material, and both steps utilize palladium catalysts, resulting in high metal catalyst consumption, high raw material costs, high levels of waste, and significant environmental pollution.

[0008] Therefore, for the preparation of 2-isopropyl-4-methylpyridine-3-amine, it is necessary to develop a new route and process that avoids the use of expensive metal catalysts, has readily available raw materials, is environmentally friendly, easy to operate, and is suitable for industrial production. Summary of the Invention

[0009] The purpose of this invention is to overcome the problems of difficult-to-obtain raw materials and high cost of using expensive metal catalysts in the prior art, and to provide a synthesis process for 2-isopropyl-4-methylpyridine-3-amine, which uses readily available raw materials, has low cost, and produces less waste.

[0010] The technical solution adopted by this invention to solve the above problems is: a synthetic process for 2-isopropyl-4-methylpyridine-3-amine, the synthetic route being as follows:

[0011] The synthesis steps are as follows: Starting with 2-chloro-3-amino-4-methylpyridine, a solvent and a catalyst were added, and then a Grignard reagent was added dropwise to obtain 2-isopropyl-4-methylpyridine-3-amine.

[0012] The reaction temperature is 50-120℃, and the reaction time is 2-16h.

[0013] Preferably, the catalyst in the step is a nickel catalyst such as Ni(dppp)Cl2, Ni(acac)2, or Ni(dppe)Cl2, and the molar ratio of Ni(dppp)Cl2 to compound II is 0.01-0.2:1.

[0014] Preferably, the catalyst in the step is a mixture of a nickel catalyst and a ligand; the ligand is tris(1-adamantyl)phosphine, and the molar ratio of the ligand to the nickel catalyst is 0.1-1:1.

[0015] Preferably, the Grignard reagent in the step is isopropyl magnesium chloride or isopropyl magnesium bromide, and the molar ratio of it to compound II is 1.0-3.0:1.

[0016] Preferably, the step is carried out in a solvent system, wherein the solvent is at least one of toluene, dichloromethane, tetrahydrofuran, dioxane, or organic ether solvents.

[0017] Compared with the prior art, the advantages of the present invention are as follows: The raw material used in this invention, 2-chloro-3-amino-4-methylpyridine, is an industrial product that is readily available and inexpensive.

[0018] The catalyst used in this invention is a nickel catalyst, which is inexpensive and requires a small amount, avoiding the need for the previously expensive palladium catalyst and significantly reducing raw material costs. Furthermore, the Grignard reagent used is either widely used isopropyl magnesium chloride or isopropyl magnesium bromide, which is simple and economical.

[0019] The ligand used in this invention is tris(1-adamantyl)phosphine, which can improve the reaction yield upon addition. Furthermore, tris(1-adamantyl)phosphine is safer than the commonly used tri-tert-butylphosphine, because tri-tert-butylphosphine is spontaneously combustible when exposed to air and is not suitable for large-scale production.

[0020] The route of this invention is a one-step Kumada coupling reaction, which is short, has a high yield, few byproducts, and is easy to separate and purify. It overcomes the shortcomings of existing technologies, such as high cost and difficulty in obtaining raw materials, thereby achieving the goal of commercial production.

[0021] In summary, this invention uses 2-chloro-3-amino-4-methylpyridine as the starting material, and reacts it with a nickel catalyst and a Grignard reagent in a one-step Kumada coupling reaction to obtain the product 2-isopropyl-4-methylpyridine-3-amine. The synthesis process of 2-isopropyl-4-methylpyridine-3-amine in this invention is short, uses readily available raw materials, does not require expensive palladium metal catalysts, has low cost, high yield, simple process, and produces little waste, making it suitable for industrial-scale production. Attached Figure Description

[0022] Figure 1 The 2-isopropyl-4-methylpyridine-3-amine obtained in Example 1 of this invention1 H NMR. Implementation

[0023] The present invention will be further described in detail below with reference to the embodiments.

[0024] Example 1 Add 200 g (1403 mmol) of 2-chloro-3-amino-4-methylpyridine and 1000 mL of toluene to a 3 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 38 g (70.2 mmol) of Ni(dppp)Cl2 and stir. Cool the system using an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 1403 mL (2806 mmol, 2 M in THF) of isopropyl magnesium chloride under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 110 °C and react for 10 h. Sampling was conducted to confirm the completion of the reaction; the temperature was lowered to 10-20℃, and 1L of water was added dropwise to the reaction system. Phase separation was performed, and anhydrous sodium sulfate was added to the organic phase for drying and filtration. After concentration to dryness, 170g of a pale yellow oily liquid, 2-isopropyl-4-methylpyridin-3-amine (theoretical yield 210.7g), was obtained, with a yield of 81%. The NMR spectrum of the obtained product is shown below. Figure 1 As shown.

[0025] 1 HNMR (DMSO-d6,400 MHz, ppm): δ7.66(d, J =4.0 Hz, 1H), 6.78(d, J =4.0Hz, 1H), 4.74 (s, 2H), 3.21-3.17 (m, 1H), 2.08 (s, 3H), 1.14 (s, 6H).

[0026] Example 2 Add 100 g (701 mmol) of 2-chloro-3-amino-4-methylpyridine and 1000 mL of toluene to a 3 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 3.8 g (7.01 mmol) of Ni(dppp)Cl2 and 3.1 g (7.01 mmol) of tris(1-adamantyl)phosphine. Stir and cool with an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 421 mL (841 mmol, 2 M in THF) of isopropyl magnesium chloride under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 110 °C and react for 10 h. Sampling and control were performed to confirm that the reaction of the raw materials was complete; the temperature was lowered to 10-20℃, 1L of water was added dropwise to the reaction system, the phases were separated, anhydrous sodium sulfate was added to the organic phase, dried and filtered, and concentrated to dryness to obtain 95g of pale yellow oily liquid 2-isopropyl-4-methylpyridin-3-amine (theoretical amount 105.3g), yield 90%.

[0027] Example 3 Add 50 g (351 mmol) of 2-chloro-3-amino-4-methylpyridine and 500 mL of tetrahydrofuran to a 1 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 0.9 g (3.5 mmol) of Ni(acac)2 and stir. Cool the system using an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 401 mL (421 mmol, 1.05 M in THF) of isopropyl magnesium bromide under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 60 °C and react for 8 h. After the reaction was complete, the temperature was lowered to 10-20℃, and 500 mL of water was added dropwise to the reaction system. The mixture was then concentrated until almost no liquid was dripping out. 500 mL of methyl tert-butyl ether was added to dissolve the mixture, followed by the addition of another 500 mL of water. The phases were separated, and the organic phase was concentrated to dryness to obtain 42.2 g of a pale yellow oily liquid, 2-isopropyl-4-methylpyridin-3-amine (theoretical amount 52.7 g), with a yield of 80%.

[0028] Example 4 Add 50 g (351 mmol) of 2-chloro-3-amino-4-methylpyridine and 500 mL of tetrahydrofuran to a 1 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 0.9 g (3.5 mmol) of Ni(acac)2 and 1.5 g (3.5 mmol) of tris(1-adamantyl)phosphine and stir. Cool the system using an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 401 mL (421 mmol, 1.05 M in THF) of isopropyl magnesium bromide under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 60 °C and react for 8 h. After the reaction was complete, the temperature was lowered to 10-20℃, and 500 mL of water was added dropwise to the reaction system. The mixture was then concentrated until almost no liquid was dripping out. 500 mL of methyl tert-butyl ether was added to dissolve the mixture, followed by the addition of another 500 mL of water. The phases were separated, and the organic phase was concentrated to dryness to obtain 46.9 g of a pale yellow oily liquid, 2-isopropyl-4-methylpyridin-3-amine (theoretical amount 52.7 g), with a yield of 89%.

[0029] Example 5 Add 30 g (210 mmol) of 2-chloro-3-amino-4-methylpyridine and 300 mL of dioxane to a 1 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 1.1 g (2.1 mmol) of Ni(dppe)Cl2 and 0.9 g (2.1 mmol) of tris(1-adamantyl)phosphine. Stir and cool with an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 240 mL (252 mmol, 1.05 M in THF) of isopropyl magnesium bromide under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 100 °C and react for 8 h. After the reaction was complete, the temperature was lowered to 10-20℃, and 500 mL of water was added dropwise to the reaction system. The phases were separated, and anhydrous sodium sulfate was added to the organic phase for drying and filtration. After concentration, 27.7 g of pale yellow oily liquid 2-isopropyl-4-methylpyridin-3-amine (theoretical amount 31.5 g) was obtained, with a yield of 88%.

[0030] Example 6 Add 30 g (210 mmol) of 2-chloro-3-amino-4-methylpyridine and 300 mL of dioxane to a 1 L three-necked flask equipped with a magnetic stirrer. Purge and stir with nitrogen until completely dissolved. Then add 1.1 g (2.1 mmol) of Ni(dppe)Cl2 and 0.55 g (2.1 mmol) of triphenylphosphine. Stir and cool with an ice-salt bath. When the temperature of the system drops to 2 °C, slowly add 240 mL (252 mmol, 1.05 M in THF) of isopropyl magnesium bromide under nitrogen protection, controlling the temperature between 0 and 5 °C. After the addition is complete, slowly raise the temperature to 100 °C and react for 8 h. After the reaction was complete, the temperature was lowered to 10-20℃, and 500 mL of water was added dropwise to the reaction system. The phases were separated, and anhydrous sodium sulfate was added to the organic phase for drying and filtration. After concentration, 24.9 g of pale yellow oily liquid 2-isopropyl-4-methylpyridine-3-amine (theoretical amount 31.5 g) was obtained, with a yield of 79%.

[0031] In addition to the above embodiments, the present invention also includes other embodiments. All technical solutions formed by equivalent transformation or equivalent substitution should fall within the protection scope of the claims of the present invention.

Claims

1. A process for synthesizing 2-isopropyl-4-methylpyridine-3-amine, characterized in that, The process is as follows: Starting with 2-chloro-3-amino-4-methylpyridine, a solvent and a catalyst are added, followed by the dropwise addition of a Grignard reagent to obtain 2-isopropyl-4-methylpyridine-3-amine. The catalyst is a mixture of a nickel catalyst and a ligand. The ligand is tris(1-adamantyl)phosphine, and the molar ratio of the ligand to the nickel catalyst is 0.1-1:

1. The nickel catalyst is one or more of Ni(dppp)Cl2, Ni(acac)2, and Ni(dppe)Cl2. The Grignard reagent is isopropyl magnesium chloride and / or isopropyl magnesium bromide.

2. The synthesis process of 2-isopropyl-4-methylpyridine-3-amine according to claim 1, characterized in that: The molar ratio of the nickel catalyst to 2-chloro-3-amino-4-methylpyridine is 0.01-0.2:

1.

3. The synthesis process of 2-isopropyl-4-methylpyridine-3-amine according to claim 1, characterized in that: The molar ratio of the Grignard reagent to 2-chloro-3-amino-4-methylpyridine is 1.0-3.0:

1.

4. The synthesis process of 2-isopropyl-4-methylpyridine-3-amine according to claim 1, characterized in that: The solvent is at least one of toluene, dichloromethane, tetrahydrofuran, and 1,4-dioxane.

5. The synthesis process of 2-isopropyl-4-methylpyridine-3-amine according to claim 1, characterized in that: The reaction temperature is 50-120℃, and the reaction time is 2-16h.

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