Synthesis method of 2-chloro-3-fluoro-6-methylpyridine-4-amine

Abstract

The invention discloses a synthesis method of 2-chloro-3-fluoro-6-methylpyridine-4-amine, which comprises the following steps: by taking 2-chloro-3-fluoro-6-methylpyridine as an initial raw material, sequentially carrying out oxidation in the step I, nitration in the step II and reduction in the step III to synthesize the product 2-chloro-3-fluoro-6-methylpyridine-4-amine. According to the invention, the synthetic method of 2-chloro-3-fluoro-6-methylpyridine-4-amine in the prior art is improved, so that the synthetic route is greatly shortened, 2-chloro-3-fluoro-6-methylpyridine-4-amine can be synthesized from 2-chloro-3-fluoro-6-methylpyridine only through three steps, each step of reaction is simple and convenient to operate, reactants are cheap and easy to obtain, and the method is suitable for industrial production. The method is high in total yield, can be suitable for industrial production, and has good economic value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a method for synthesizing 2-chloro-3-fluoro-6-methylpyridine-4-amine. Background Art

[0002] 2-Chloro-3-fluoro-6-methylpyridine-4-amine is a key molecular building block in drugs for treating KRas-G12-D related diseases, and the existing patent report on the synthesis method of 2-chloro-3-fluoro-6-methylpyridine-4-amine requires 7 steps. Patent document CN 115304623 A discloses a pyrimidine cyclic derivative and its application in medicine, and reports a synthesis method using 2-bromo-5-fluoroisonicotinic acid as a raw material, first esterifying to obtain compound 2, then methylating to obtain compound 3, and then undergoing oxidation, transchlorination, hydrolysis, rearrangement and Boc removal for a total of seven steps to obtain the target compound 2-chloro-3-fluoro-6-methylpyridine-4-amine (see attached Figure 1 ). Although the raw materials used in the prior art are cheaper than 2-chloro-3-fluoro-6-methylpyridine, the synthesis steps are longer, and greater manpower and time costs are required in the actual production process. Therefore, the prior art route is relatively long, the total cost is high, and industrial production is not economical. In summary, 2-chloro-3-fluoro-6-methylpyridine-4-amine is a very practical molecular building block for KRas target drugs, and the synthesis route of this molecular building block needs to be improved urgently. Summary of the invention

[0003] In view of the above defects of the prior art, the present invention discloses a method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine, which is simple to operate and can effectively solve the above technical problems. The specific technical solution is: A method for synthesizing 2-chloro-3-fluoro-6-methylpyridine-4-amine, using 2-chloro-3-fluoro-6-methylpyridine as a starting material, sequentially undergoing step one of oxidation, step two of nitration, and step three of reduction, to obtain the final target product 2-chloro-3-fluoro-6-methylpyridine-4-amine in three steps, and the synthetic process route is as follows:

[0004] In some specific embodiments, the solvent of step 1 is selected from one or more of dichloromethane (DCM), tetrahydrofuran (THF), 1,2-dichloroethane (DCE), and dimethyl sulfoxide (DMSO), and the oxidant is selected from one or more of meta-chloroperbenzoic acid (m-CPBA), hydrogen peroxide (H2O2), and potassium persulfate (KHSO5).

[0005] More preferably, the solvent in step 1 is DCM and the oxidant is m-CPBA.

[0006] In some specific embodiments, the solvent in step 2 is selected from sulfuric acid, and the nitrating agent is selected from one or more of fuming nitric acid, concentrated nitric acid, and dilute nitric acid.

[0007] More preferably, the solvent in step 2 is sulfuric acid, and the nitrating agent is fuming nitric acid.

[0008] In some specific embodiments, the solvent in step three is selected from one or more of ethanol / water, methanol / water, and acetic acid, and the reducing agent is selected from one or more of iron powder and zinc powder.

[0009] In some specific embodiments, step three further comprises adding ammonium chloride More preferably, the solvent in step three is ethanol / water, the reducing agent is iron powder, and ammonium chloride is also added.

[0010] In some specific embodiments, Step 1: 95 g of compound 1 (2-chloro-3-fluoro-6-methylpyridine) was added to 1000 mL of DCM, and 225.25 g of m-CPBA was added. After the addition, the mixture was stirred at 15°C for 20 h. The reaction solution was filtered to remove excess m-CPBA, and the filtrate was poured into a sodium sulfite solution. The organic phase was collected, washed with a sodium bicarbonate solution, and dried over anhydrous sodium sulfate to separate compound 2 (2-chloro-3-fluoro-6-methylpyridine 1-oxide). The reaction yield was 84.30%; Step 2: 70 g of compound 2 (2-chloro-3-fluoro-6-methylpyridine 1-oxide) was dissolved in 200 mL of sulfuric acid, and 60 mL of fuming nitric acid was added. The temperature was controlled below 20°C during the addition. After the addition was completed, the temperature was raised to 100°C and stirred for 1 h. After cooling, a solid was precipitated, which was filtered and dried to obtain compound 3 (2-chloro-3-fluoro-6-methyl-4-nitropyridine 1-oxide). The reaction yield was 100%; Step 3: Add 60 grams of compound 3 (2-chloro-3-fluoro-6-methyl-4-nitropyridine 1-oxide) and 123.10 grams of ammonium chloride to an ethanol / water (450 mL / 150 mL) solution, and add 128.53 grams of iron powder. After the addition, heat to 80°C and stir to react for 12 hours. Cool, filter, wash, remove the solvent, and separate compound 4 (2-chloro-3-fluoro-6-methylpyridin-4-amine), with a reaction yield of 43.30%.

[0011] The present invention has the following beneficial effects: (1) Step 2 of the present invention is a nitration reaction on the aromatic ring, which is an electrophilic substitution reaction. Generally speaking, the reduced electron density of the C atom on the aromatic ring will make the nitration reaction difficult to proceed. The aromatic ring of compound 2 is connected with electron-withdrawing groups such as chlorine and fluorine, which reduces the electron density and makes the nitration reaction more difficult. The present invention overcomes the corresponding technical difficulties. In some embodiments, the present invention utilizes the positioning effect of nitrogen oxides to selectively nitrate at the 4th position of pyridine, and can achieve 100% selective nitration at the 4th position of the pyridine ring (nitrogen oxides have good regioselectivity for nitration, and the reaction is clean and does not require purification), thereby improving the overall yield of the synthetic route of the present invention.

[0012] (2) It can be seen from the above examples and comparative examples that the present invention not only improves the synthesis method of 2-chloro-3-fluoro-6-methylpyridine-4-amine in the prior art, but also greatly shortens the synthesis route of the present invention. 2-chloro-3-fluoro-6-methylpyridine can be synthesized from 2-chloro-3-fluoro-6-methylpyridine in only three steps. Moreover, each step of the reaction is simple to operate, the reactants are cheap and readily available, and can be suitable for industrial production.

[0013] The concept, specific synthesis steps and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 It is a schematic diagram of the synthesis route of the prior art.

[0015] Figure 2 It is a schematic diagram of the synthesis route of the technology of the present invention. DETAILED DESCRIPTION

[0016] In order to better understand the purpose, technical means, creative features and effects of the present invention, the present invention is described below by way of embodiments in conjunction with the accompanying drawings, but the present invention is not limited to the following implementation cases.

[0017] It should be noted that the drawings in this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with this technology, and are not used to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any structural modification, change or adjustment of the proportional relationship, without affecting the effects and purposes that can be achieved by the present invention, should still fall within the scope of the technical contents disclosed by the present invention. Example 1

[0018] like Figure 2 As shown, 2-chloro-3-fluoro-6-methylpyridine is used as the starting material, and the target product is synthesized through three steps of oxidation, nitration and reduction. Step 1 is as follows: Compound 1 (95 g, 652.64 mmol) was added to 1000 mL DCM, and m-CPBA (225.25 g, 1.31 mol) was slowly added (addition was completed in 30 min). After addition, the mixture was stirred at room temperature at 15°C for 20 h. Thin layer chromatography (TLC) (volume ratio PE / EA = 3 / 1) showed that the raw materials were basically reacted. The reaction solution was filtered to remove excess m-CPBA. The filtrate was poured into a sodium sulfite solution, and the organic phase was collected, washed with a sodium bicarbonate solution, dried over anhydrous sodium sulfate, mixed with silica gel, and the solvent was removed by rotary evaporation. The mixture was separated by column chromatography (tetrahydrofuran / petroleum ether = 1 / 1 as the eluent) to obtain compound 2 (90.00 g, 550.20 mmol) as a white solid with a calculated yield of 84.30%.

[0019] The compound detection results are as follows: 1 H NMR (400 MHz, Chloroform- d ) d 7.18 - 7.12 (m, 1H), 7.05 (dd, J =8.8, 6.6 Hz, 1H), 2.51 (s, 3H). LC-MS[M+1] + =162.10

[0020] Step 2 is as follows: Compound 2 (70 g, 427.93 mmol) was dissolved in 200 mL of sulfuric acid, and 60 mL of fuming nitric acid was slowly added dropwise. The temperature was controlled below 20°C during the addition. After the addition was completed, the temperature was raised to 100°C and stirred for 1 h. LC-MS detection showed that the raw material was completely reacted. The reaction solution was cooled to room temperature and slowly added to ice water while stirring. A yellow solid precipitated, which was filtered and dried to obtain compound 3 (90.00 g, 431.51 mmol) as a yellow solid with a calculated yield of 100%.

[0021] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 8.22 - 8.14 (m, 2H), 3.92 (s, 3H). LC-MS[M+1] + =207.0

[0022] Step three is as follows: Compound 3 (60 g, 287.67 mmol) and ammonium chloride (123.10 g, 2.30 mol) were added to ethanol / water (450 mL / 150 mL), and iron powder (128.53 g, 2.30 mol) was added. After the addition, the temperature was raised to 80°C and stirred for 12 hours. LC-MS detection showed that the raw materials reacted completely. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed by rotary evaporation. Column chromatography was used for separation (tetrahydrofuran / petroleum ether = 1 / 5-1 / 1 as eluent) to obtain the target compound 2-chloro-3-fluoro-6-methylpyridin-4-amine (20.00 g, 124.55 mmol) as a brown solid with a calculated yield of 43.30%.

[0023] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 6.47 (dd, J = 6.1, 0.5 Hz, 1H), 6.43 (s, 2H), 2.16 (s, 3H). LC-MS[M+1] + =161.10 The total yield of Example 1 is 36.50%. Example 2

[0024] like Figure 2 As shown, 2-chloro-3-fluoro-6-methylpyridine is used as the starting material, and the target product is synthesized through three steps of oxidation, nitration and reduction. Step 1 is as follows: Compound 1 (87 g, 597.68 mmol) was added to 1000 mL DMSO, and KHSO5 (802.44 g, 1.20 mol) was slowly added (addition was completed over 30 min). After addition, the mixture was stirred at room temperature at 30°C for 16 h. Thin layer chromatography (TLC) (volume ratio PE / EA = 3 / 1) showed that the raw materials were basically reacted. The mixture was washed three times with ethyl acetate / water = 1 / 1, and the ethyl acetate phase was extracted and collected, dried over anhydrous sodium sulfate, mixed with silica gel, and the solvent was removed by rotary evaporation. The mixture was separated by column chromatography (tetrahydrofuran / petroleum ether = 1 / 1 as eluent) to obtain compound 2 (78.40 g, 479.34 mmol) as a white solid with a calculated yield of 80.20%.

[0025] The compound detection results are as follows: 1 H NMR (400 MHz, Chloroform- d ) d 7.18 - 7.12 (m, 1H), 7.05 (dd, J =8.8, 6.6 Hz, 1H), 2.51 (s, 3H). LC-MS[M+1] + =162.10

[0026] Step 2 is as follows: Compound 2 (60 g, 366.80 mmol) was dissolved in 180 mL of sulfuric acid, and 60 mL of concentrated nitric acid (mass fraction 68%) was slowly added dropwise. The temperature was controlled below 20°C during the addition. After the addition was completed, the temperature was raised to 85°C and stirred for 2 h. LC-MS detection showed that the raw material reacted completely. The reaction solution was cooled to room temperature and slowly added to ice water while stirring. A yellow solid precipitated, which was filtered and dried to obtain compound 3 (77.14 g, 366.78 mmol) as a yellow solid with a calculated yield of 97%.

[0027] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 8.22 - 8.14 (m, 2H), 3.92 (s, 3H). LC-MS[M+1] + =207.0

[0028] Step three is as follows: Compound 3 (55 g, 263.70 mmol) and ammonium chloride (112.84 g, 2.11 mol) were added to methanol / water (450 mL / 150 mL), and iron powder (116.96 g, 2.11 mol) was added. After the addition, the temperature was raised to 70°C and stirred for 16 hours. LC-MS detection showed that the raw materials reacted completely. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, washed with ethyl acetate, and the solvent was removed by rotary evaporation. Column chromatography was used for separation (tetrahydrofuran / petroleum ether = 1 / 5-1 / 1 as eluent) to obtain the target compound 2-chloro-3-fluoro-6-methylpyridin-4-amine (19.72 g, 122.80mmol) as a brown solid with a calculated yield of 42.70%.

[0029] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 6.47 (dd,J = 6.1, 0.5 Hz, 1H), 6.43 (s, 2H), 2.16 (s, 3H). LC-MS[M+1] + =161.10 The total yield of Example 2 is 33.21%. Example 3

[0030] like Figure 2 As shown, 2-chloro-3-fluoro-6-methylpyridine is used as the starting material, and the target product is synthesized through three steps of oxidation, nitration and reduction. Step 1 is as follows: Compound 1 (80 g, 549.59 mmol) was added to 1000 mL THF, and 30% H2O2 (113.33 g, 1.10 mol) was slowly added (addition was completed in 30 min). After addition, the mixture was stirred at room temperature at 20°C for 10 h. Thin layer chromatography (TLC) (volume ratio PE / EA = 3 / 1) showed that the raw material was basically reacted. The mixture was washed three times with ethyl acetate / water = 1 / 1, and the ethyl acetate phase was extracted and collected, dried over anhydrous sodium sulfate, mixed with silica gel, and the solvent was removed by rotary evaporation. The mixture was separated by column chromatography (tetrahydrofuran / petroleum ether = 1 / 1 as eluent) to obtain compound 2 (73.80 g, 451,16 mmol) as a white solid with a calculated yield of 82.10%.

[0031] The compound detection results are as follows: 1 H NMR (400 MHz, Chloroform- d ) d 7.18 - 7.12 (m, 1H), 7.05 (dd, J =8.8, 6.6 Hz, 1H), 2.51 (s, 3H). LC-MS[M+1] + =162.10

[0032] Step 2 is as follows: Compound 2 (50 g, 305.66 mmol) was dissolved in 200 mL of sulfuric acid, and 60 mL of fuming nitric acid was slowly added dropwise. The temperature was controlled below 20°C during the addition. After the addition was completed, the temperature was raised to 70°C and stirred for 3 h. LC-MS detection showed that the raw material was completely reacted. The reaction solution was cooled to room temperature and slowly added to ice water while stirring. A yellow solid precipitated, which was filtered and dried to obtain compound 3 (35.50 g, 170.21 mmol) as a yellow solid with a calculated yield of 95%.

[0033] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 8.22 - 8.14 (m, 2H), 3.92 (s, 3H). LC-MS[M+1] + =207.0

[0034] Step three is as follows: Compound 3 (30 g, 143.84 mmol) and ammonium chloride (61.55 g, 1.15 mol) were added to acetic acid (300 mL), and zinc powder (64.27 g, 1.15 mol) was added. After the addition, the temperature was raised to 60°C and stirred for 20 hours. LC-MS detection showed that the raw materials reacted completely. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed by rotary evaporation. Column chromatography was used for separation (tetrahydrofuran / petroleum ether = 1 / 5-1 / 1 as eluent) to obtain the target compound 2-chloro-3-fluoro-6-methylpyridin-4-amine (9,40 g, 57.53 mmol) as a brown solid with a calculated yield of 40.70%.

[0035] The compound detection results are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) d 6.47 (dd, J = 6.1, 0.5 Hz, 1H), 6.43 (s, 2H), 2.16 (s, 3H). LC-MS[M+1] + =161.10 The total yield of Example 3 is 31.74%.

[0036] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine, characterized in that 2-Chloro-3-fluoro-6-methylpyridine is used as the starting material, and the product 2-chloro-3-fluoro-6-methylpyridine-4-amine is synthesized in three steps through step one oxidation, step two nitration, and step three reduction. The synthesis process route is as follows:

2. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The solvent of step 1 is selected from one or more of dichloromethane (DCM), tetrahydrofuran (THF), 1,2-dichloroethane (DCE), and dimethyl sulfoxide (DMSO), and the oxidant is selected from one or more of meta-chloroperbenzoic acid (m-CPBA), hydrogen peroxide (H2O2), and potassium persulfate (KHSO5).

3. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The solvent of step 2 is sulfuric acid, and the nitrating agent is selected from one or more of fuming nitric acid, concentrated nitric acid, and dilute nitric acid.

4. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The solvent in step three is selected from one or more of ethanol / water, methanol / water, and acetic acid, and the reducing agent is selected from one or more of iron powder and zinc powder.

5. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 4, characterized in that: The step three also includes adding ammonium chloride.

6. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The step 1 is as follows: 95 grams of compound 1 (2-chloro-3-fluoro-6-methylpyridine) is added to 1000 mL of DCM, and 225.25 grams of m-CPBA is added. After the addition, the mixture is stirred at 15° C. for 20 hours. The reaction solution is filtered to remove excess m-CPBA, the filtrate is poured into a sodium sulfite solution, the organic phase is collected, washed with a sodium bicarbonate solution, and dried over anhydrous sodium sulfate to separate compound 2 (2-chloro-3-fluoro-6-methylpyridine 1-oxide), and the reaction yield is 84.30%.

7. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The second step is: 70 grams of compound 2 (2-chloro-3-fluoro-6-methylpyridine 1-oxide) is dissolved in 200 mL of sulfuric acid, and 60 mL of fuming nitric acid is added. The temperature is controlled below 20°C during the addition process. After the addition is completed, the temperature is raised to 100°C and stirred for 1 h. After cooling, a solid is precipitated, which is filtered and dried to obtain compound 3 (2-chloro-3-fluoro-6-methyl-4-nitropyridine 1-oxide), and the reaction yield is 100%.

8. The method for synthesizing 2-chloro-3-fluoro-6-methylpyridin-4-amine according to claim 1, characterized in that: The step three is as follows: 60 grams of compound 3 (2-chloro-3-fluoro-6-methyl-4-nitropyridine 1-oxide) and 123.10 grams of ammonium chloride are added to an ethanol / water (450 mL / 150 mL) solution, and 128.53 grams of iron powder are added. After the addition, the temperature is raised to 80°C and stirred for 12 hours. After cooling, filtering, washing, and removing the solvent, compound 4 (2-chloro-3-fluoro-6-methylpyridine-4-amine) is isolated, and the reaction yield is 43.30%.

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