A method for electrochemically synthesizing N-substituted pyridine-2-carboxamides

Abstract

The present application relates to the field of organic electrochemistry and medical synthesis, and particularly relates to a preparation method of electrochemical synthesis of N-substituted pyridine-2-formamide. The method has the following technical advantages: no additional oxidizing agent or reducing agent is needed in the electrochemical synthesis, the environmental pollution and the reaction danger are reduced, the reaction condition is mild, the process flow is short, the reaction selectivity is good, the yield is high, and the method is environment-friendly. Specifically, in the present application, pyridine compounds and N-substituted oxamic acid are used as raw materials, and under the electrochemical reaction condition, the pyridine ring is directly activated on the carbon hydrogen to obtain N-substituted pyridine-2-formamide, wherein 4-chloro-N-methyl pyridine-2-formamide is a key intermediate of the antitumor drugs regorafenib and sorafenib, and the reaction equation is represented as:

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic electrochemistry and pharmaceutical synthesis, and in particular to a method for electrochemically synthesizing N-substituted pyridine-2-formamide. BACKGROUND

[0002] N-substituted pyridine-2-formamide is an important pharmaceutical intermediate, and 4-chloro-N-methyl pyridine-2-formamide is a key intermediate of anti-tumor drugs regorafenib and sorafenib. Regorafenib and sorafenib are both small molecule multi-target receptor tyrosine kinase inhibitors developed by Bayer Pharmaceuticals in Germany. Sorafenib was approved for marketing by the US FDA on December 20, 2005, and is used for the treatment of advanced renal cell carcinoma. It is the first new drug approved for the treatment of advanced renal cell carcinoma in the world in the past ten years, and is a major advance in the treatment of advanced renal cell carcinoma. Regorafenib, as an improved new drug of sorafenib, was approved for marketing by the US FDA on September 27, 2012, and was approved for marketing in China in March 2017 and was included in the medical insurance reimbursement directory in 2018. It is a new type of diphenylurea tyrosine kinase inhibitor with oral activity, multi-target and broad spectrum, which can inhibit enzymes including VEGFRI-2, PDGFR-β, FGFR1, KIT, etc., thereby exerting an anti-tumor effect. It is clinically used for the treatment of hepatocellular carcinoma, metastatic colorectal cancer and gastrointestinal stromal tumor, etc.

[0003] As for the synthesis of 4-chloro-N-methyl pyridine-2-formamide, the following two methods are mainly reported in the literature and patents:

[0004] Method 1:

[0005]

[0006] Chinese patent CN103408488 discloses an optimized synthesis method of sorafenib. 2-pyridine carboxylic acid is used as a raw material to react with excess thionyl chloride to obtain 4-chloro-2-pyridine carboxylic acid chloride, or the acid chloride is derivatized to obtain 4-chloro-2-pyridine methyl ester, which is then aminated with methylamine to obtain the target product 4-chloro-N-methyl pyridine-2-formamide. This method produces a large amount of waste gas (sulfur dioxide, hydrogen chloride, hydrogen sulfide, etc.), and elemental sulfur is also produced, which has a great environmental pressure and is difficult to clean the equipment.

[0007] Method 2:

[0008]

[0009] Chinese patent CN101302193 discloses an environmentally friendly preparation method of sorafenib intermediate. 4-Chloropyridine hydrochloride is used as raw material to react with formamide under Minisci reaction conditions to obtain 4-chloro-2-pyridine carboxamide, then amide methyl esterization reaction occurs under acidic conditions to obtain 4-chloro-2-pyridine carboxylate, and finally aminolysis with methylamine to obtain the target product 4-chloro-N-methylpyridine-2-carboxamide. The route is relatively long, does not meet the atomic economy, and hydrogen peroxide is used, which increases the safety risk of the reaction.

[0010] The electrochemical Minisci reaction has obvious advantages, because it avoids the use of oxidizing reagents, and direct current can activate the electron-deficient aromatic ring C-H, making the reaction more safe and controllable, and having higher atomic economy.

[0011] In 2017, Professor Zeng Chengchun of Beijing University of Technology reported the realization of direct acetylation of heteroaromatic ring under electrochemical conditions (Wang, Q.-Q.; Xu, K.; Jiang, Y.-Y.; Liu, Y.-G.; Sun, B.-G.; Zeng, C.-C. Org. Lett. 2017, 19, 5517.). The positive and negative electrodes are both glassy carbon electrodes, LiClO4 is used as electrolyte, acetonitrile is used as solvent, and ammonium iodide is used as catalyst, and the highest yield can reach 69%.

[0012]

[0013] In 2020, Professor Xu Haichao of Xiamen University reported a photoelectric Minisci carbamoylation reaction (Lai, X.-L.; Shu, X.-M.; Song, J.-S.; Xu, H.-C. Angew. Chem., Int. Ed. 2020, 59, 10626.). The Minisci carbamoylation reaction of heteroarenes was realized by combining organic electrochemistry and photocatalysis together. 4-CzIPN was used as a photo-redox catalyst, and under the action of 455 nm LED light source, constant current electrolysis could well introduce carbamoyl group at the 2 position of 4-methylquinoline (86% isolated yield). Studies have shown that the reaction requires both light and electricity.

[0014]

[0015] In view of the fact that the existing technology requires relatively harsh conditions for implementing photo and electrochemistry, it is necessary to further develop a more simple and operable electrochemical process. SUMMARY

[0016] In order to solve the problems encountered in the production of 4-chloro-N-methyl pyridine-2-carboxamide at present, the present application provides a green process of electrochemical Minisci carbamoylation, 4-chloropyridine is directly activated by hydrogen under the action of an electrode, reacts with 2-(methylamino)-2-oxoacetic acid to obtain the target product, and then through process optimization, it has been scaled up to 5g scale, and the following attempts continue to scale up, and at the same time, the reaction is expanded to synthesize N-substituted pyridine-2-carboxamide.

[0017] In order to achieve the technical purpose of the present application, the technical scheme of the present application is:

[0018] The present application uses pyridine compounds as raw materials, N-substituted oxaline acid as decarboxylation coupling reagent, and obtains N-substituted pyridine-2-carboxamide under the action of electrode, electrolyte and catalyst by passing current, and the reaction equation is represented as:

[0019]

[0020] In the electrochemical synthesis process of the present application, R is selected from hydrogen, chlorine, bromine, hydroxyl and the like; R1 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and the like; and R2 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and the like.

[0021] In the electrochemical synthesis process of the present application, the anode is any one of carbon rod, carbon sheet, carbon plate, carbon cloth and graphite, the cathode is any one of platinum sheet, nickel sheet, copper sheet and iron sheet, and the electrochemical device is an undivided electrolytic cell.

[0022] In the electrochemical synthesis process of the present application, the electrolyte used is any one of tetra-n-butylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium perchlorate or lithium perchlorate.

[0023] In the electrochemical synthesis process of the present application, the catalyst used is any one of tetrabutylammonium bromide, tetrabutylammonium iodide, ammonium bromide, ammonium iodide, potassium iodide or sodium iodide.

[0024] In the electrochemical synthesis process of the present application, the solvent used is any one of acetonitrile, hexafluoroisopropanol, trifluoroethanol, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol or water, or a mixed solvent of two or more thereof, and the mixed solvent of acetonitrile and hexafluoroisopropanol is preferred.

[0025] In the electrochemical synthesis process of the present application, the molar ratio of the raw material pyridine compound, N-substituted oxaline acid, electrolyte and catalyst is 1:1~3:0.25~1:0.1~0.5.

[0026] In the electrochemical synthesis process of the present application, the reaction current is 5~30mA, the reaction temperature is 30~60℃, and the reaction time is 3~36 hours.

[0027] The process for electrochemically synthesizing N-substituted pyridine-2-formamide has the following technical advantages: N-substituted pyridine-2-formamide is directly obtained by carbon-hydrogen activation through electrochemical synthesis of pyridine compounds and N-substituted oxalamic acid, N-substituted formamide is directly introduced into a pyridine molecule in a green and environmentally friendly manner, the use of highly toxic reagents and strong oxidants is avoided, electrocatalytic oxidation dehydrogenation is used, and the only by-product is hydrogen, which fully meets the concept of green environmental protection. Therefore, compared with the prior art process, the project has the advantages of high efficiency, simplicity, green environmental protection, low cost, good industrial applicability, obvious process reliability and technical advancement. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The hydrogen spectrum of 4-chloro-N,N-dimethylpyridine-2-carboxamide prepared in Example 4;

[0029] Figure 2 The hydrogen spectrum of 4-chloro-N,N-dimethylpyridine-2-carboxamide prepared in Example 4;

[0030] Figure 3 The hydrogen spectrum of 4-chloro-N-ethyl-N-methylpyridine-2-carboxamide prepared in Example 5;

[0031] Figure 4 The hydrogen spectrum of N-methylpyridine-2-carboxamide prepared in Example 6;

[0032] Figure 5 The hydrogen spectrum of N-methylpyridine-2-carboxamide prepared in Example 6; DETAILED DESCRIPTION

[0033] In order to better understand the content of the present application, the following will be further described in combination with specific examples, but the specific embodiments are not limitations to the content of the present application.

[0034] Example 1: Preparation of 4-chloro-N-methylpyridine-2-carboxamide

[0035]

[0036] Take 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2- oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) dissolved in a mixed solvent containing dimethyl sulfoxide (80 mL) and water (8 mL), and stirred under the protection of N2. The reaction temperature was controlled at 45-50°C, the anode was graphite electrode (35 mm x 15 mm x 0.5 mm), and the cathode was platinum electrode (10 mm x 10 mm x 0.1 mm). The constant current was controlled at 15 mA, and the reaction time was 15-18 h. The reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate. After concentration, the crude product was separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 502 mg of the target product 4-chloro-N-methylpyridine-2-carboxamide with a yield of 58.9%. 1 H-NMR (400 MHz, CDCl3): δ 8.44 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.43 (d, J = 5.2 Hz, 1H), 3.05 (d, J = 5.2 Hz, 3H).

[0037] Example 2: Preparation of 4-chloro-N-methylpyridine-2-carboxamide

[0038]

[0039] Take 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2- oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) dissolved in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL), and the reaction was stirred under the protection of N2 by passing current, the reaction temperature was controlled at 45-50°C, the positive electrode was selected as a graphite electrode (35 mm x 15 mm x 0.5 mm), and the negative electrode was selected as a platinum electrode (10 mm x 10 mm x 0.1 mm), the constant current was controlled at 15 mA, the reaction time was 15-18 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 704 mg of the target product 4-chloro-N-methylpyridine-2-carboxamide with a yield of 82.5%.

[0040] Example 3: Preparation of 4-chloro-N-methylpyridine-2-carboxamide

[0041]

[0042] Take 4-chloropyridine (5.68 g, 50.00 mmol, 1.0 equiv), 2-(methylamino)-2- oxoacetic acid (10.31 g, 100.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (4.12 g, 12.50 mmol, 0.25 equiv) and tetrabutylammonium iodide (3.69 mg, 10.00 mmol, 0.2 equiv) dissolved in a mixed solvent containing acetonitrile (600 mL) and hexafluoropropanol (200 mL), and the reaction was stirred under the protection of N2 by passing current, the reaction temperature was controlled at 45-50°C, the positive electrode was selected as a graphite electrode (35 mm x 15 mm x 0.5 mm), and the negative electrode was selected as a platinum electrode (10 mm x 10 mm x 0.1 mm), the constant current was controlled at 15 mA, the reaction time was 24-36 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (800 mL x 2) and water (800 mL x 2), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was recrystallized with petroleum ether / ethyl acetate to obtain 6.89 g of the target product 4-chloro-N-methylpyridine-2-carboxamide with a yield of 80.7%.

[0043] Example 4: Preparation of 4-chloro-N,N-dimethylpyridine-2-carboxamide

[0044]

[0045] Weigh 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), N,N-dimethyl oxamic acid (1171 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) into a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL), and stir the reaction under the protection of N2, with a constant current of 15 mA, and a graphite electrode (35 mm x 15 mm x 0.5 mm) as the anode and a platinum electrode (10 mm x 10 mm x 0.1 mm) as the cathode, and control the reaction temperature at 45-50°C. The reaction time is 15-18 h, and the reaction progress is detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction is completed, the reaction solution is extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), the organic phases are combined and dried over anhydrous sodium sulfate, and the crude product is separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 785 mg of the target product 4-chloro-N,N-dimethylpyridine-2-carboxamide, with a yield of 85.0%. 1 H-NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.37 (t, J = 2.8 Hz, 1H), 3.14 (t, J = 2.4 Hz, 3H), 3.09 (t, J = 2.0 Hz, 3H).

[0046] Example 5: Preparation of 4-chloro-N-ethyl-N-methylpyridine-2-carboxamide

[0047]

[0048] Take 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), 2-(ethyl(methyl)amino)-2- oxoacetic acid (1311 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) dissolved in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL), and the reaction was stirred under the protection of N2 by passing current, with the reaction temperature controlled at 45-50°C, a graphite electrode (35 mm x 15 mm x 0.5 mm) was selected for the anode and a platinum electrode (10 mm x 10 mm x 0.1 mm) was selected for the cathode, a constant current of 15 mA was controlled, and the reaction time was 15-18 h. The reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 825 mg of the target product 4-chloro-N-ethyl-N-methylpyridine-2-carboxamide with a yield of 83.1%. 1 H-NMR (400 MHz, CDC13): δ 8.49 (s, 1H), 7.64 (d, J = 10.4 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 3.60 (q, J = 7.2 Hz, 1H), 3.41 (q, J = 7.2 Hz, 1H), 3.07 (d, J = 22.8 Hz, 1H).

[0049] Example 6: Preparation of N-methylpyridine-2-carboxamide

[0050]

[0051] The pyridine (396 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2-oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) were dissolved in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL), and the reaction was stirred under current protection under N2. The reaction temperature was controlled at 45-50°C, the anode was selected as a graphite electrode (35 mm x 15 mm x 0.5 mm), and the cathode was selected as a platinum electrode (10 mm x 10 mm x 0.1 mm). The constant current was controlled at 15 mA, the reaction time was 15-18 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), the organic phase was combined and dried over anhydrous sodium sulfate, and the crude product was separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 358 mg of the target product N-methylpyridine-2-carboxamide with a yield of 52.6%. 1 H-NMR (400 MHz, CDCl3): δ 8.54 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.10 (s, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6, 4.8 Hz, 1H), 3.04 (d, J = 5.6 Hz, 3H).

[0052] Example 7: Preparation of N,N-dimethylpyridine-2-carboxamide

[0053]

[0054] The pyridine (396 mg, 5.00 mmol, 1.0 equiv), N, N-dimethyl oxamic acid (1171 mg, 10.00 mmol, 2.0 equiv), tetra-n-butylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) were dissolved in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL), and the reaction was stirred under current protection at 45-50°C. The graphite electrode (35 mm x 15 mm x 0.5 mm) was selected as the anode, and the platinum electrode (10 mm x 10 mm x 0.1 mm) was selected as the cathode. The constant current was controlled at 15 mA, and the reaction time was 15-18 h. The reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:2). After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL x 2) and water (80 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate. After concentration, the crude product was separated by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent to obtain 615 mg of the target product N, N-dimethylpyridine-2-formamide, with a yield of 81.9%. 1 H-NMR (400 MHz, CDC13): δ 8.58 (d, J = 4.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 3.13 (s, 3H), 3.06 (s, 3H).

[0055] While the application has been fully described in connection with the specific embodiments, various modifications and changes in the specific embodiments can be made by those skilled in the art. It is intended that the scope of the application should include all such modifications and changes that fall within the scope of the appended claims.

Claims

1. A method for preparing N-substituted pyridine-2-carboxamide by electrochemical synthesis, characterized in that, Using pyridine compounds as raw materials and N-substituted oxaline as a decarboxylation coupling agent, N-substituted pyridine-2-carboxamide was obtained by passing an electric current under the action of electrodes, electrolytes and catalysts. Wherein, R is selected from hydrogen, chlorine, bromine or hydroxyl; R1 is selected from hydrogen, methyl, ethyl, isopropyl or tert-butyl; R2 is selected from hydrogen, methyl, ethyl, isopropyl or tert-butyl.

2. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the anode is any one of carbon rod, carbon sheet, carbon plate, carbon cloth and graphite, the cathode is any one of platinum sheet, nickel sheet, copper sheet and iron sheet, and the electrochemical device is an undivided electrolytic cell.

3. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the electrolyte used is any one of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium perchlorate, or lithium perchlorate.

4. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the catalyst used is any one of tetrabutylammonium bromide, tetrabutylammonium iodide, ammonium bromide, ammonium iodide, potassium iodide, or sodium iodide.

5. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the solvent used is any one or a mixture of two or more of the following: acetonitrile, hexafluoroisopropanol, trifluoroethanol, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, or water.

6. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the molar ratio of the raw material pyridine compound, N-substituted oxaline, electrolyte, and catalyst is 1:1 to 3:0.25 to 1:0.1 to 0.

5.

7. The preparation method according to claim 1, characterized in that, In the electrochemical synthesis process, the reaction current is 5–30 mA, the reaction temperature is 30–60 °C, and the reaction time is 3–36 hours.

8. A method for preparing 4-chloro-N-methylpyridine-2-carboxamide by electrochemical synthesis, characterized in that, 4-Chloro-N-methylpyridine-2-carboxylamide was prepared using 4-chloropyridine as a raw material, 2-(methylamino)-2-oxoacetic acid as a decarboxylation coupling agent, tetra-n-butyltetrafluoroborate ammonium as an electrolyte and tetrabutylammonium iodide as a catalyst, with a graphite electrode as the positive electrode and a platinum electrode as the negative electrode, by passing an electric current.

9. The preparation method according to claim 8, characterized in that, The yield of the prepared 4-chloro-N-methylpyridine-2-carboxamide is greater than 80%.

10. The preparation method according to claim 8, characterized in that, The prepared 4-chloro-N-methylpyridine-2-carboxamide was used to prepare the antitumor drugs regorafenib or sorafenib.

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