Preparation method for electrochemical synthesis of N-substituted pyridine-2-formamide

Abstract

The invention relates to the field of organic electrochemistry and medicine synthesis, in particular to a preparation method for electrochemical synthesis of N-substituted pyridine-2-formamide. The method has the following technical advantages that an oxidizing agent or a reducing agent does not need to be additionally used in electrochemical synthesis, environmental pollution and reaction danger are reduced, and the method has the advantages of being mild in reaction condition, short in technological process, good in reaction selectivity, high in yield, environmentally friendly and the like. Specifically, a cheap pyridine compound and N-substituted oxamic acid are taken as raw materials, under the electrochemical reaction condition, formamide is directly activated on a pyridine ring in a hydrocarbon mode, N-substituted pyridine-2-formamide is obtained, 4-chlorine-N-methylpyridine-2-formamide is a key intermediate of anti-tumor drugs regorafenib and sorafenib, and 4-chlorine-N-methylpyridine-2-formamide is a key intermediate of anti-tumor drugs regorafenib and sorafenib. Reaction equation: # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the fields of organic electrochemistry and pharmaceutical synthesis, and particularly relates to a preparation method for electrochemically synthesizing N-substituted pyridine-2-carboxamide. Background Art

[0002] N-substituted pyridine-2-carboxamide is a class of important pharmaceutical intermediates, and among them, 4-chloro-N-methylpyridine-2-carboxamide is a key intermediate for the anti-tumor drugs regorafenib and sorafenib. Both regorafenib and sorafenib are small molecule multi-target receptor tyrosine kinase inhibitors developed by Bayer Pharmaceutical Company of Germany. Sorafenib was approved by the US FDA for marketing on December 20, 2005, for the treatment of advanced renal cell carcinoma. This is the first new drug approved for the treatment of advanced renal cancer in the world in the past decade or more, representing a major progress in the treatment of advanced renal cancer. As a modified new drug of sorafenib, regorafenib was approved by the US FDA for marketing on September 27, 2012, was launched in China in March 2017, and was included in the medical insurance reimbursement catalog in 2018. It is a novel oral-active, multi-target, broad-spectrum diphenylurea tyrosine kinase inhibitor that can inhibit kinases including VEGFR1-2, PDGFR-β, FGFR1, KIT, etc., thereby exerting an anti-tumor effect. Clinically, it is used for the treatment of hepatocellular carcinoma, metastatic colorectal cancer, gastrointestinal stromal tumors, etc.

[0003] Regarding the synthesis of 4-chloro-N-methylpyridine-2-carboxamide, there are mainly the following two methods reported in the current literature and patents:

[0004] Method 1:

[0005]

[0006] Chinese Patent CN103408488 discloses an optimized synthesis method for sorafenib. Using 2-pyridinecarboxylic acid as a raw material, reacting with an excessive amount of thionyl chloride to obtain 4-chloro-2-pyridinecarbonyl chloride, or derivatizing the acyl chloride to obtain methyl 4-chloro-2-pyridinecarboxylate, and then aminolyzing with methylamine to obtain the target product 4-chloro-N-methylpyridine-2-carboxamide. This method generates a large amount of waste gases (such as sulfur dioxide, hydrogen chloride, hydrogen sulfide, etc.), and elemental sulfur will also be generated, resulting in great environmental protection pressure and difficult equipment cleaning.

[0007] Method 2:

[0008]

[0009] Chinese Patent CN101302193 discloses an environmentally friendly preparation method of sorafenib intermediate. Using 4-chloropyridine hydrochloride as the raw material, reacting with formamide under Minisci reaction conditions to obtain 4-chloro-2-pyridinecarboxamide, then undergoing amide methylation reaction under acidic conditions to obtain methyl 4-chloro-2-pyridinecarboxylate, and finally reacting with methylamine by aminolysis to obtain the target product 4-chloro-N-methylpyridine-2-carboxamide. This route is relatively long, does not meet the atom economy, and uses hydrogen peroxide, increasing the safety risk of the reaction.

[0010] The electrochemical Minisci reaction has obvious advantages. Since it avoids the use of oxidation reagents and can directly activate the C-H bond of electron-deficient aromatic rings by passing an electric current, the reaction is safer and more controllable, and has higher atom economy.

[0011] In 2017, Professor Zeng Chengchu of Beijing University of Technology et al. reported the direct acetylation of heteroaromatic rings 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.). Both the positive and negative electrodes are glassy carbon electrodes, using LiClO 4 as the electrolyte, acetonitrile as the solvent, and ammonium iodide as the catalyst, with the highest yield reaching 69%.

[0012]

[0013] In 2020, Professor Xu Haichao of Xiamen University et al. reported the photoelectrochemical Minisci carbamoylation reaction (Lai, X.-L.; Shu, X.-M.; Song, J.-S.; Xu, H.-C. Angew. Chem., Int. Ed. 2020, 59, 10626.), combining organic electrochemistry and photocatalysis to achieve the Minisci carbamoylation reaction of heteroarenes. Using 4-CzIPN as the photoredox catalyst, under the action of a 455 nm LED light source, constant current electrolysis can well introduce a carbamoyl group at the 2-position of 4-methylquinoline (86% isolated yield). The research shows that both light and electricity are indispensable for this reaction.

[0014]

[0015] In view of the fact that in the prior art, the conditions for implementing photoelectrochemistry are relatively harsh, it is necessary to conduct further research and development to obtain a simpler and more operable electrochemical process. Summary of the Invention

[0016] To solve the problems encountered in the current production of 4-chloro-N-methylpyridine-2-carboxamide, the present invention provides a green process for electrochemical Minisci carbamoylation. 4-Chloropyridine is directly activated by C-H under the action of an electrode and reacts with 2-(methylamino)-2-oxoacetic acid to obtain the target product. Then, through process optimization, it has been scaled up to 5 g scale. Next, attempts will be made to continue scaling up, and at the same time, this type of reaction will be extended to the synthesis of N-substituted pyridine-2-carboxamides.

[0017] To achieve the technical objectives of the present invention, the technical solution of the present invention is as follows:

[0018] The present invention uses pyridine compounds as raw materials and N-substituted oxamic acid as a decarboxylative coupling reagent. Under the action of an electrode, an electrolyte, and a catalyst, an electric current is passed to obtain N-substituted pyridine-2-carboxamide. The reaction equation is expressed as:

[0019]

[0020] In the electrochemical synthesis process of the present invention, R is selected from hydrogen, chlorine, bromine, hydroxyl, etc.; R 1 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, etc.; R 2 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, etc.

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

[0022] In the electrochemical synthesis process of the present invention, 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 invention, 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 invention, the solvent used is any one or a mixture of two or more of acetonitrile, hexafluoroisopropanol, trifluoroethanol, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, or water, and a mixed solvent of acetonitrile and hexafluoroisopropanol is preferred.

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

[0026] In the electrochemical synthesis process of the present invention, the reaction current is 5 to 30 mA, the reaction temperature is 30 to 60 °C, and the reaction time is 3 to 36 hours.

[0027] The process of electrochemically synthesizing N-substituted pyridine-2-carboxamide of the present invention has the following technical advantages: N-substituted pyridine-2-carboxamide is directly obtained by the direct C-H activation of cheap and easily available pyridine compounds and N-substituted oxamic acid through electrochemical synthesis. N-substituted formamide is directly introduced into the pyridine molecule in an environmentally friendly way, avoiding the use of highly toxic reagents and strong oxidants. Electro-catalytic oxidative dehydrogenation is used, and the by-product is only hydrogen, which fully meets the concept of environmental protection. Therefore, compared with the existing technology process, this project has the advantages of high efficiency, simplicity, environmental friendliness, low cost, and good industrial applicability, and has obvious process reliability and technical advancement. Brief Description of the Drawings

[0028] Figure 1 1H NMR spectrum of 4-chloro-N-methylpyridine-2-carboxamide prepared in Example 1;

[0029] Figure 2 1H NMR spectrum of 4-chloro-N,N-dimethylpyridine-2-carboxamide prepared in Example 4;

[0030] Figure 3 1H NMR spectrum of 4-chloro-N-ethyl-N-methylpyridine-2-carboxamide prepared in Example 5;

[0031] Figure 4 1H NMR spectrum of N-methylpyridine-2-carboxamide prepared in Example 6;

[0032] Figure 5 1H NMR spectrum of N,N-dimethylpyridine-2-carboxamide prepared in Example 7. Detailed Description of the Invention

[0033] For a better understanding of the content of the present invention, the following is further described in conjunction with specific examples, but the specific implementation manners do not limit the content of the present invention.

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

[0035]

[0036] Weigh 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2-oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv), and dissolve them in a mixed solvent containing dimethyl sulfoxide (80 mL) and water (8 mL). N2 Under N protection, a current was passed through for stirring reaction. The reaction temperature was controlled at 45 - 50 °C. The positive electrode was a graphite electrode (35 mm × 15 mm × 0.5 mm), and the negative electrode was a platinum electrode (10 mm × 10 mm × 0.1 mm). 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, the reaction solution was extracted with ethyl acetate (80 mL × 2) and water (80 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using 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(400MHz,CDCl 3 ): 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] Weighed 4-chloropyridine (568 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2-oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) and dissolved them in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL). Under N 2 protection, a current was passed through for stirring reaction. The reaction temperature was controlled at 45 - 50 °C. The positive electrode was a graphite electrode (35 mm × 15 mm × 0.5 mm), and the negative electrode was a platinum electrode (10 mm × 10 mm × 0.1 mm). 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, the reaction solution was extracted with ethyl acetate (80 mL × 2) and water (80 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using 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] Weigh 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), tetrabutylammonium tetrafluoroborate (4.12 g, 12.50 mmol, 0.25 equiv) and tetrabutylammonium iodide (3.69 mg, 10.00 mmol, 0.2 equiv) and dissolve them in a mixed solvent containing acetonitrile (600 mL) and hexafluoropropanol (200 mL). Under N 2 protection, pass an electric current and stir the reaction. Control the reaction temperature at 45 - 50 °C. Select a graphite electrode (35 mm × 15 mm × 0.5 mm) as the positive electrode and a platinum electrode (10 mm × 10 mm × 0.1 mm) as the negative electrode. Control the constant current at 15 mA and the reaction time at 24 - 36 h. Detect the reaction progress by TLC (petroleum ether:ethyl acetate = 1:2). After the reaction is completed, extract the reaction solution with ethyl acetate (800 mL × 2) and water (800 mL × 2). Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate, and recrystallize the crude product 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-dimethylglyoxylate (1171 mg, 10.00 mmol, 2.0 equiv), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) and dissolve them in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL). Under N 2Under protection, a current was passed through for stirring reaction. The reaction temperature was controlled at 45 - 50 °C. The positive electrode was a graphite electrode (35 mm × 15 mm × 0.5 mm), and the negative electrode was a platinum electrode (10 mm × 10 mm × 0.1 mm). 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 × 2) and water (80 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using 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(400MHz,CDCl 3 ):δ8.50(s,1H),7.66(d,J=2.0Hz,1H),7.37(t,J=2.8Hz,1H),3.14(t,J=2.4Hz,3H),3.09(t,J=2.0Hz,3H).

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

[0047]

[0048] 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), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv), and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL). Under N 2 Under protection, a current was passed through for stirring reaction. The reaction temperature was controlled at 45 - 50 °C. The positive electrode was a graphite electrode (35 mm × 15 mm × 0.5 mm), and the negative electrode was a platinum electrode (10 mm × 10 mm × 0.1 mm). 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 × 2) and water (80 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using 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(400MHz,CDCl 3): 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] Weigh pyridine (396 mg, 5.00 mmol, 1.0 equiv), 2-(methylamino)-2-oxoacetic acid (1031 mg, 10.00 mmol, 2.0 equiv), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv), and dissolve them in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL). Under N 2 protection, pass an electric current and stir the reaction. The reaction temperature is controlled at 45 - 50 °C. The positive electrode is a graphite electrode (35 mm × 15 mm × 0.5 mm), and the negative electrode is a platinum electrode (10 mm × 10 mm × 0.1 mm). Control the constant current at 15 mA, and the reaction time is 15 - 18 h. Monitor the reaction progress by TLC (petroleum ether:ethyl acetate = 1:2). After the reaction is completed, extract the reaction solution with ethyl acetate (80 mL × 2) and water (80 mL × 2). Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate, and separate the crude product by silica gel column chromatography using 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, CDCl 3 ): 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] Weigh pyridine (396 mg, 5.00 mmol, 1.0 equiv), N,N-dimethyloxamic acid (1171 mg, 10.00 mmol, 2.0 equiv), tetrabutylammonium tetrafluoroborate (412 mg, 1.25 mmol, 0.25 equiv) and tetrabutylammonium iodide (369 mg, 1.00 mmol, 0.2 equiv) and dissolve them in a mixed solvent containing acetonitrile (60 mL) and hexafluoropropanol (20 mL). Under N 2 protection, pass an electric current and stir the reaction. Control the reaction temperature at 45 - 50 °C. Select a graphite electrode (35 mm × 15 mm × 0.5 mm) as the positive electrode and a platinum electrode (10 mm × 10 mm × 0.1 mm) as the negative electrode. Control the constant current at 15 mA and the reaction time at 15 - 18 h. Detect the reaction progress by TLC (petroleum ether:ethyl acetate = 1:2). After the reaction is completed, extract the reaction solution with ethyl acetate (80 mL × 2) and water (80 mL × 2). Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate, and separate the crude product by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain 615 mg of the target product N,N-dimethylpyridine-2-carboxamide, with a yield of 81.9%. 1 H-NMR (400 MHz, CDCl 3 ): 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] Although the present invention has been fully described in connection with specific embodiments, it should be noted that various changes and modifications are obvious to those skilled in the art. Such changes and modifications will be understood to be included within the scope of the present invention as defined by the appended claims.

Claims

1. A preparation method for electrochemically synthesizing N-substituted pyridine-2-carboxamide, characterized in that, using a pyridine compound as a raw material and N-substituted oxamic acid as a decarboxylative coupling reagent, and passing an electric current under the action of an electrode, an electrolyte and a catalyst to obtain N-substituted pyridine-2-carboxamide; Among them, R is selected from hydrogen, chlorine, bromine or hydroxyl group; R 1 is selected from hydrogen, methyl, ethyl, isopropyl or tert-butyl; R 2 is selected from hydrogen, methyl, ethyl, isopropyl or tert-butyl.

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

3. The preparation method according to claim 1, characterized in that, in the electrochemically synthesizing process, the electrolyte used is any one of tetra-n-butylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium perchlorate or lithium perchlorate.

4. The preparation method according to claim 1, characterized in that, in the electrochemically synthesizing 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 electrochemically synthesizing process, 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 of them.

6. The preparation method according to claim 1, characterized in that, in the electrochemically synthesizing process, the molar ratio of the raw material pyridine compound, N-substituted oxamic acid, the electrolyte and the 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 electrochemically synthesizing process, the reaction current is 5 to 30 mA, the reaction temperature is 30 to 60 °C, and the reaction time is 3 to 36 hours.

8. A preparation method for electrochemically synthesizing 4-chloro-N-methylpyridine-2-carboxamide, characterized in that, using 4-chloropyridine as a raw material, 2-(methylamino)-2-oxoacetic acid as a decarboxylative coupling reagent, tetra-n-butylammonium tetrafluoroborate as an electrolyte and tetrabutylammonium iodide as a catalyst, selecting a graphite electrode as the positive electrode and a platinum electrode as the negative electrode, and passing an electric current to prepare 4-chloro-N-methylpyridine-2-carboxamide, 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 is used for preparing the anti-tumor drugs regorafenib or sorafenib.

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