Preparation process of specific mesoionic insecticides

Abstract

A process for the preparation of intermediates for the production of mesoionic insecticides, in particular N-(pyrimidin-5-ylmethyl)pyridin-2-amine, a key intermediate, is disclosed.

Description

[Background technology]

[0001] Mesoionic insecticides and methods for preparing them have been previously disclosed, for example, in International Publication No. 2009 / 099929 A1, International Publication No. 2011 / 017334 A1, International Publication No. 2011 / 017342 A1, International Publication No. 2011 / 017347 A1, International Publication No. 2011 / 017351 A1, International Publication No. 2012 / 092115 A1, International Publication No. 2013 / 090547 A1, International Publication No. 2017 / 189339 A1, and International Publication No. 2019 / 173173 A1. In addition, N-(pyrimidine-5-ylmethyl)pyridine-2-amine has been previously disclosed as an important intermediate for preparing certain mesoionic insecticides. However, certain synthesis steps previously disclosed may not be suitable for large-scale production. Therefore, alternative methods for preparing certain mesoionic insecticides are still needed. [Modes for carrying out the invention]

[0002] The following is a process related to the formation of N-(pyrimidine-5-ylmethyl)pyridine-2-amine.

[0003] Scheme 1 is exemplified as follows: [ka] (In the formula, X 1 is Cl, Br, or I; X 2 is F, Cl, Br, I, or OH; Each R 1 (The compound is methyl, ethyl, or n-propyl.)

[0004] In Scheme 1, S1a, N,N-dialkylformamide (hereinafter referred to herein as "DAF"), and oxalyl chloride ((COCl)2) are mixed under conditions for producing S1b. Generally, about 2 to 20 moles of DAF per mole of S1a, preferably about 3 to 15 moles of DAF per mole of S1a, and more preferably about 4 to 10 moles of DAF per mole of S1a may be used. The N,N-dialkylformamide may be N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide, and mixtures thereof. Also, about 0.5 to 5 moles of oxalyl chloride per mole of S1a, preferably about 0.8 to 4 moles of oxalyl chloride per mole of S1a, and more preferably about 1 to 3 moles of oxalyl chloride per mole of S1a may be used. In Scheme 1, additional conditions include ambient temperature and ambient pressure. However, higher and lower temperatures and pressures may be used at different stages of the reaction. Currently, temperatures of about -10°C to about 80°C may be used; preferably, temperatures of about -5°C to about 60°C may be used. Currently, pressures of about 10 kilopascals (kPa) to about 1000 kPa may be used; preferably, pressures of 50 kPa to about 150 kPa may be used.

[0005] In Scheme 1, S1a can be 3-chloropropanoyl chloride, 3-chloropropanoyl bromide, 3-chloropropanoyl fluoride, 3-chloropropanoyl iodide, 3-bromopropanoyl chloride, 3-bromopropanoyl bromide, 3-bromopropanoyl fluoride, 3-bromopropanoyl iodide, 3-iodopropanoyl chloride, 3-iodopropanoyl iodide, 3-iodopropanoyl bromide, 3-chloropropanoic acid, 3-bromopropanoic acid, or 3-iodopropanoic acid. However, mixtures thereof can be used. When the corresponding acid is used, more oxalyl chloride is used. Currently, 3-chloropropanoyl chloride is preferred. For example, other modifications of Scheme 1 can be used, such as using an alternative to oxalyl chloride. Such alternatives to oxalyl chloride can be selected from phosphorus oxychloride (POCl3), thionyl chloride (SOCl2), and phthaloyl chloride (C6H4-1,2-(COCl)2). As another example, an alternative to N,N-dialkylformamide can be used. Such alternatives to N,N-dialkylformamide can be piperidine-1-carbaldehyde, pyrrolidine-1-carbaldehyde, and morpholine-4-carbaldehyde.

Chemical formula

[0006] However, when such an alternative to DAF is used, an alternative to S1b is produced

Chemical formula

[0007] Alternative Scheme 1

Chemical formula

[0008] In Alternative Scheme 1, acrylic acid, N,N-dialkylformamide (hereinafter referred to herein as "DAF"), and oxalyl chloride ((COCl)2) are mixed under conditions for producing S1b. Generally, about 2 to 20 moles of DAF per mole of acrylic acid, preferably about 3 to 15 moles of DAF per mole of acrylic acid, and more preferably about 4 to 10 moles of DAF per mole of acrylic acid may be used. The N,N-dialkylformamide may be N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide, and mixtures thereof. However, it is preferable that about 1.5 to 5 moles of oxalyl chloride per mole of acrylic acid, preferably about 1.8 to 4 moles of oxalyl chloride per mole of acrylic acid, and more preferably about 2 to 3 moles of oxalyl chloride per mole of acrylic acid may be used. In Alternative Scheme 1, additional conditions include ambient temperature and ambient pressure. However, higher and lower temperatures and pressures may be used at different stages of the reaction. Currently, temperatures of about -10°C to about 80°C may be used; preferably, temperatures of about -5°C to about 60°C may be used. Currently, pressures of about 10 kilopascals (kPa) to about 1000 kPa may be used; preferably, pressures of 50 kPa to about 150 kPa may be used.

[0009] Other modifications to Alternative Scheme 1 may be used, for example, by using a substitute for oxalyl chloride. Such oxalyl chloride substitutes may be selected from phosphorus oxychloride (POCl3), thionyl chloride (SOCl2), and phthaloyl chloride (C6H4-1,2-(COCl)2).

[0010] Scheme 2 is exemplified as follows: [ka] (In the formula, X 1 is Cl, Br, or I; Each R1 (The compound is methyl, ethyl, or n-propyl.)

[0011] In Scheme 2, S1b, pyridine-2-amine (also known as 2-aminopyridine), and a base are mixed in the presence of a solvent under conditions for producing S2b. Generally, about 0.8 to 2 moles of pyridine-2-amine per mole of S1b, preferably about 0.9 to 1.8 moles of pyridine-2-amine per mole of Sb1, more preferably about 1 to 1.5 moles of pyridine-2-amine per mole of Sb1 may be used. Also, about 0.8 to 4 moles of base per mole of S1b, preferably about 0.9 to 3 moles of base per mole of S1b, more preferably about 1 to 2 moles of base per mole of S1b may be used. In Scheme 2, additional conditions include ambient temperature and ambient pressure. However, higher and lower temperatures and pressures may be used. Currently, temperatures of about -100°C to about 50°C may be used; preferably, temperatures of about -80°C to about 20°C may be used. Currently, pressures of approximately 10 kilopascals (kPa) to approximately 1000 kPa can be used; preferably, pressures of 50 kPa to approximately 150 kPa can be used.

[0012] In Scheme 2, S1b can be N-(2-(chloromethyl)-3-(dimethylamino)allylidene)-N-methylmethanaminium chloride, N-(2-(bromomethyl)-3-(dimethylamino)allylidene)-N-methylmethanaminium chloride or N-(2-(iodomethyl)-3-(dimethylamino)allylidene)-N-methylmethanaminium chloride. If necessary, mixtures of these three can be used. Currently, N-(2-(chloromethyl)-3-(dimethylamino)allylidene)-N-methylmethanaminium chloride is preferably used. For example, many types of bases such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine; aromatic amines such as pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, and 3,5-lutidine; lithium diisopropylamide, n-butyllithium, s-butyllithium, sodium amide, sodium hydride, lithium 2,2,6,6-tetramethylpiperidide, and lithium bis(trimethylsilyl)amide can be used. Moreover, an organomagnesium halide (R 2b MgX 2b ) can be used as the base; where R 2b is alkyl or aryl such as, for example, methyl, ethyl, propyl, isopropyl, and phenyl, and X 2b is halo such as, for example, Cl, Br, or I. If necessary, mixtures of these bases can be used. The base could be mixed with pyridyl-2-amine before mixing with S1b. Further, other modifications to Scheme 2 can be used.

[0013] Many types of solvents can be used, such as aromatic hydrocarbons (e.g., toluene and xylene), halogenated benzenes (e.g., chlorobenzene and 1,2-dichlorobenzene), haloalkanes (e.g., dichloromethane and 1,2-dichloroethane), ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), methyl tert-butyl ether (MTBE), and 1,4-dioxane); esters (e.g., ethyl acetate or propyl acetate); and / or other solvents including DMF, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, or benzonitrile.

[0014] R is such that S2b is (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)alilidene)-N-methylmethaneaminium chloride 1 It is preferable that it is methyl.

[0015] If an S1b substitute is used, an S2b substitute is generated using the conditions shown above and as shown in the following scheme. [ka] (In the formula: X 1 is Cl, Br, or I; Each Y is independent of (CH2) n or O; n is either 0 or 1.

[0016] Scheme 3 is illustrated as follows: [ka] (In the formula, X 3 These are Cl, Br, I, F, OC(=O)CH3, OCO(O)H, OC(O)CH2CH3, H2PO4, or HSO4; Each R1 (The compound is methyl, ethyl, or n-propyl.)

[0017] In Scheme 3, S2b and S3a are mixed under conditions for producing S3b (also known as N-(pyrimidine-5-ylmethyl)pyridine-2-amine). Generally, about 0.1 to about 10 moles of S3a per mole of S2b, preferably about 0.5 to about 5 moles of S3a per mole of S2b, and more preferably about 1 to about 2 moles of S3a per mole of S2b may be used. A base is typically used in this mixture. Generally, when a base is used, about 0.01 to about 6 moles of base per mole of S2b, preferably about 0.05 to about 4 moles of base per mole of S2b, and more preferably about 0.5 to about 2.5 moles of base per mole of S2b may be used. For example, many bases can be used, such as triethylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, and 3,5-lutidine, sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium methoxide (NaOCH3), sodium ethoxide (NaOCH2CH3), and potassium tert-butoxide (KOC(CH3)3), and mixtures of such bases can be used if necessary. Acids can also be used, such as p-toluenesulfonic acid monohydrate. In Scheme 3, additional conditions include ambient temperature and ambient pressure. However, higher and lower temperatures and pressures can be used. Currently, temperatures of about 0°C to about 100°C can be used; preferably, temperatures of about 25°C to about 80°C can be used. Currently, pressures of approximately 10 kilopascals (kPa) to approximately 1000 kPa can be used; preferably, pressures of 50 kPa to approximately 150 kPa can be used. S3a can be selected from formamidine acetate, formamidine hydrochloride, formamidine hydrobromide, formamidine sulfate (H2N-CH=NH·H2SO4), and mixtures thereof. This mixing is preferably carried out in the presence of a solvent such as methanol, ethanol, isopropanol, DMF, DMA, NMP, benzonitrile, DMSO, acetonitrile, THF, and mixtures thereof.

[0018] If the substitute for S2b is used under the conditions discussed above for S2b, it will also produce S3b. [ka] (In the formula, X 3 These are Cl, Br, I, F, OC(=O)CH3, OCO(O)H, OC(O)CH2CH3, H2PO4, or HSO4; Each Y is independent of (CH2) n or O; n is either 0 or 1. [Examples]

[0019] Example 1: Preparation of A-N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride [ka]

[0020] Example 1.1 - A 100 ml (mL) three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, a thermocouple, and a pressure-equalizing dropper funnel was charged with anhydrous dimethylformamide (DMF, 11.50 g, 157.32 mmol, 4.0 equivalents). 3-Chloropropanoyl chloride (5.00 g, 39.38 mmol) was added over 2 minutes at ambient temperature (25°C). The mixture was cooled to 0-5°C; oxalyl chloride (5.0 g, 39.39 mmol, 1.0 equivalent) was added over 30 minutes. The reaction mixture was maintained at a temperature below 10°C by dropwise addition over several minutes. After the addition was complete, the reaction mixture was warmed to 25°C by removing the cooling bath. The reaction mixture was slowly heated to 55-60°C and stirred for an additional 3 hours at 55-60°C. The reaction mixture was cooled to 25°C; DMF (9.44 g) was added. The resulting mixture was cooled to -5°C. After stirring at -5°C for 2 hours, the mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of anhydrous DMF and ethyl acetate and dried in a vacuum oven at ambient temperature to obtain the title compound (3.80 g, 45.7% yield): 1 H NMR(600MHz,CD3CN)δ 8.16(s,2H),4.64(s,2H),3.48(s,6H),3.37(s,6H).

[0021] Example 1.2 - Anhydrous DMF (11.50 g, 157.32 mmol, 4.0 equivalents) was charged into a 100 mL three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, a thermocouple, and a pressure-equalizing dropper funnel. 3-chloropropanoyl chloride (5.00 g, 39.38 mmol) was added over 2 minutes at ambient temperature (25°C). The mixture was cooled to 0-5°C; while maintaining the temperature of the reaction mixture below 10°C, oxalyl chloride (7.5 g, 59.09 mmol, 1.5 equivalents) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was warmed to 25°C by removing the cooling bath. The reaction mixture was slowly heated to 50°C and stirred for an additional 5 hours at 50°C. The reaction mixture was cooled to 25°C and DMF (10 mL, 9.44 g) was added. The resulting mixture was cooled to -5°C. After stirring at -5°C for 2 hours, the reaction mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of anhydrous DMF and ethyl acetate, and dried in a vacuum oven at ambient temperature to obtain the title compound (4.40 g, 52.9% yield): 1 H NMR(600MHz,CD3CN)δ 8.16(s,2H),4.64(s,2H),3.48(s,6H),3.37(s,6H).

[0022] Example 1.3 - Anhydrous DMF (11.50 g, 157.32 mmol, 4.0 equivalents) was placed in a 100 mL three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, a thermocouple, and a pressure-equalizing dropper funnel. 3-Chloropropanoyl chloride (5.00 g, 39.38 mmol) was added over 2 minutes at ambient temperature (25°C). The mixture was cooled to 0-5°C, and while maintaining the temperature of the reaction mixture below 10°C, oxalyl chloride (7.5 g, 59.09 mmol, 1.5 equivalents) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was warmed to 25°C by removing the cooling bath. The reaction mixture was heated and stirred at 40-45°C for 22 hours. The reaction mixture was cooled to 25°C, and DMF (10 mL, 9.44 g) was added. The resulting mixture was cooled to -5°C. After stirring at -5°C for 2 hours, the reaction mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of cold anhydrous DMF and ethyl acetate, and dried in a vacuum oven at ambient temperature to obtain the title compound (4.80 g, 57.7% yield): 1 H NMR(600MHz,CD3CN)δ 8.16(s,2H),4.64(s,2H),3.48(s,6H),3.37(s,6H).

[0023] Example 1.4 - Anhydrous DMF (22.89 g, 313.13 mmol, 7.95 equivalents) and 3-chloropropanoyl chloride (5.00 g, 39.38 mmol) were added to a 100 mL three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, a thermocouple, and a pressure-equalizing dropper funnel over 2 minutes at ambient temperature (25°C). The mixture was cooled to 0-5°C, and while maintaining the temperature of the reaction mixture below 10°C, oxalyl chloride (5.92 g, 46.64 mmol, 1.2 equivalents) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was warmed to 25°C by removing the cooling bath. The reaction mixture was heated and stirred at 40-45°C for 22 hours. The reaction mixture was cooled and stirred at 25°C for 1 hour and at -5°C for 2 hours, and then filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of cold, anhydrous DMF and ethyl acetate, and dried in a vacuum oven at ambient temperature to obtain the title compound (4.30 g, 51.7% yield): 1H NMR(600MHz,CD3CN)δ 8.16(s,2H),4.64(s,2H),3.48(s,6H),3.37(s,6H).

[0024] Example 1.5 - Anhydrous DMF (29.20 g, 400 mmol, 4.0 equivalents) was charged into a 125 mL four-neck flask equipped with an overhead stirrer, a condenser with a nitrogen bubbler at the top, a thermocouple, and a syringe pump, and cooled to 0-5°C. While maintaining the temperature of the reaction mixture below 10°C, oxalyl chloride (2.78 g, 21.9 mmol, 0.22 equivalents) was added by syringe pump over 20 minutes. The reaction mixture was warmed to 25°C and heated to 44-45°C. A mixture of 3-chloropropanoyl chloride (12.70 g, 100 mmol, 1.0 equivalent) and oxalyl chloride (12.60 g, 100 mmol, 1.0 equivalent) was added by syringe pump over 5 hours at 44-46°C. The resulting reaction mixture was stirred at 44-46°C until the reaction was complete (overnight). An additional 19.63 g of DMF (268.5 mmol, approximately 2.7 equivalents) was added. The reaction mixture was cooled to 25°C, stirred at 200 rpm for 1 hour, cooled to 0°C, stirred for 2 hours, and filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of cold anhydrous DMF and ethyl acetate, and dried in a vacuum oven at ambient temperature to obtain the title compound (9.76 g, 46.2% yield). 1 H NMR(600MHz,CD3CN)δ 8.16(s,2H),4.64(s,2H),3.48(s,6H),3.37(s,6H).

[0025] Example 1.6 - Anhydrous DMF (116.94 g, 1.6 mol, 4.0 equivalents) was charged into a 250 mL four-necked jacketed reactor equipped with an overhead stirrer, a condenser with a nitrogen bubbler at the top, a thermocouple, and a peristaltic pump. The solvent was heated to 44-45°C while stirring at 300 rpm under a nitrogen atmosphere. A mixture of 3-chloropropanoyl chloride (50.78 g, 400 mmol, 1 equivalent) and oxalyl chloride (60.9 g, 480 mmol, 1.2 equivalents) was added by peristaltic pump at a rate (approximately 13 ml / h) that maintained the reaction temperature within the range of 44-46°C. After the addition was complete (6-8 hours), the resulting mixture was stirred overnight (10-15 hours) at 44-46°C. An additional amount of anhydrous DMF (87.71 g, 1.2 mol, 3 equivalents) was added to the reaction mixture. The reaction mixture was heated at 44–46°C until the reaction was complete (4–8 hours). The reaction mixture was cooled to 20°C over 1 hour and then to -5°C over 1 hour. After stirring at -5°C for 2 hours, the reaction mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with cold anhydrous DMF (-5°C, 20–30 mL), then with anhydrous ethyl acetate (50 mL), and dried in a vacuum oven at ambient temperature (20–25°C) to obtain the title compound (45.54 g, 53.9% yield).

[0026] Example 1.7 - Anhydrous DMF (204.6 g, 2.8 mol, 7.0 equivalents) was charged into a 250 mL four-necked jacketed reactor equipped with an overhead stirrer, a condenser with a nitrogen bubbler at the top, a thermocouple, and a peristaltic pump. The solvent was heated to 44-45°C while stirring at 300 rpm under a nitrogen atmosphere. A mixture of 3-chloropropanoyl chloride (50.78 g, 400 mmol, 1 equivalent) and oxalyl chloride (76.0 g, 600 mmol, 1.5 equivalents) was added by peristaltic pump at a rate (approximately 13 mL / h) that maintained the reaction temperature within the range of 44-46°C. After the addition was complete (6-8 hours), the resulting mixture was stirred overnight (15 hours) at 44-46°C. The reaction mixture was cooled to 20°C over 1 hour and to 0 to -5°C over 1 hour. After stirring at 0 to -5°C for 1 hour, the reaction mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with cold anhydrous DMF (-5°C, 30 mL) and dried in a vacuum oven at ambient temperature (20 to 25°C) to obtain the title compound (59.3 g, which contained approximately 5 wt percent (wt%) of DMF, with 95% purity and 66.6% yield).

[0027] Example 1: Preparation of B-N-(2-(bromomethyl)-3-(dimethylamino)arylidene)-N-methylmethaneaminium chloride [ka]

[0028] Example 1.8 - Anhydrous DMF (8.50 g, 116.22 mmol, 4.0 equivalents) was placed in a 100 mL three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, a thermocouple, and a pressure-equalizing dropper funnel. 3-bromopropanoyl chloride (5.00 g, 29.17 mmol, 1.0 equivalent) was added over 2 minutes at ambient temperature (25°C). The mixture was cooled to 0-5°C, and while maintaining the temperature of the reaction mixture below 10°C, oxalyl chloride (5.50 g, 43.3 mmol, 1.48 equivalents) was added dropwise over 60 minutes. After the addition was complete, the reaction mixture was warmed to 25°C by removing the cooling bath. The reaction mixture was heated and stirred at 40°C for 20 hours. The resulting mixture was cooled to 20°C, stirred for 1 hour, cooled to -5°C, stirred for 1 hour, and filtered under a nitrogen atmosphere. The wet cake was rinsed with a small amount of cold, anhydrous DMF and ethyl acetate, and dried in a vacuum oven at ambient temperature to obtain the title compound (3.50 g, 46.95% yield): 1 H NMR(300MHz,CD3CN)δ 7.95(s,2H),4.64(s,2H),3.49(s,6H),3.36(s,6H).

[0029] Example 2: Preparation of (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)arylidene)-N-methylmethaneaminium chloride [ka]

[0030] Example 2.1: A solution of pyridine-2-amine (447 mg, 4.74 mmol) in anhydrous THF (10 mL) was cooled to -78°C under a nitrogen atmosphere. 2.4 M n-butyllithium (n-BuLi, 2.0 mL, 4.80 mmol, 1.0 equivalent) in hexane was added dropwise over 30 minutes. The resulting mixture was stirred at -60°C for 1.5 hours and added over 30 minutes under nitrogen to a suspension of N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride (1.0 g, 4.74 mmol) in acetonitrile (10 mL) at -45°C. The resulting mixture was stirred at -45°C for 1.5 hours, warmed to 0°C, and stirred for 40 minutes. The mixture was filtered, and the wet cake was rinsed with a small amount of acetonitrile. The wet cake was dried in a vacuum oven to obtain the title compound (0.70 g, 55% yield): 1 H NMR(500MHz,DMSO-d6)δ 8.01(d,J=6.0Hz,1H),7.72(s,2H),7.42(t,J=7.1Hz,1H),7.05(s,1H),6.61 (d,J=7.1Hz,1H),6.56(t,J=6.0Hz,1H),4.02(d,J=3.7Hz,2H),3.28(s,12H). 1 As estimated by 1H NMR spectroscopy, 10% of the title compound was lost in the filtrate.

[0031] Example 2.2: To a suspension of N-(2-(chloromethyl)-3-(dimethylamino)arylidene)-N-methylmethaneaminium chloride (0.48 g, 2.27 mmol) in acetonitrile (10 mL) at 0°C, triethylamine (460 mg, 4.55 mmol, 2.0 equivalents) and pyridine-2-amine (213 mg, 2.27 mmol) were added under nitrogen. The reaction mixture was stirred at 0°C for 17 hours. The resulting mixture was filtered and rinsed with a small amount of acetonitrile. The wet cake was dried in a vacuum oven to obtain the title compound (0.270 g, 44% yield): 1H NMR(500MHz,DMSO-d6)δ 8.01(d,J=6.0Hz,1H),7.72(s,2H),7.42(t,J=7.1Hz,1H),7.05(s,1H),6.61 (d,J=7.1Hz,1H),6.56(t,J=6.0Hz,1H),4.02(d,J=3.7Hz,2H),3.28(s,12H).

[0032] Example 2.3: Pyridine-2-amine (1.035 g, 11 mmol) and anhydrous THF (8 mL) were charged into a 50 mL flask under nitrogen. The solution was cooled to -15°C using an ice salt bath. While maintaining a reaction temperature of -15 to -10°C, a solution of 2.15 M n-butyllithium (4.65 mL, 10.0 mmol) was slowly added over 30 minutes. After stirring at -10°C for 30 minutes, the resulting solution was added dropwise over 20 minutes to a suspension of N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride (2.111 g, 10.00 mmol) in anhydrous acetonitrile (10 mL) at -13°C to -10°C, yielding an orange slurry. The reaction mixture was stirred at -10°C for 1 hour, warmed to 0°C, and filtered under a nitrogen atmosphere. The wet cake was rinsed with anhydrous water (20 mL) and hexane (10 mL). The wet cake was dried under vacuum to obtain the title compound (1.97 g, 71.9% yield and Q- 1 We obtained a purity of 98% (estimated by 1H NMR).

[0033] Example 2.4: A solution of pyridine-2-amine (2.23 g, 23.7 mmol, 1.0 equivalent) in anhydrous THF (50 mL) was cooled to -10°C under a nitrogen atmosphere, and a solution of n-BuLi in hexane (2.4 M, 8.9 mL, 21.3 mmol, 0.9 equivalent) was added dropwise over 20 minutes. After stirring at -10°C for 1.5 hours, the resulting solution was added over 30 minutes to a stirred suspension of N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride (5.00 g, 23.7 mmol) in anhydrous acetonitrile (50 mL) at -10°C. The resulting yellow suspension was stirred at -10°C for 3 hours and filtered under a nitrogen atmosphere. The wet cake was rinsed with cold THF (20 mL) and dried to obtain a yellow solid (5.30 g, which contained 89 wt% of the title compound and 11 wt% of lithium chloride (LiCl)). The yield of the title compound was 74.3%. [ka]

[0034] Example 2.5: To a suspension of N-2-(bromomethyl)-3-(dimethylamino)arylidene)-N-methylmethaneaminium chloride (0.48 g, 1.88 mmol) in acetonitrile (10 mL) at 0°C, triethylamine (380 mg, 3.76 mmol, 2.0 equivalents) and pyridine-2-amine (177 mg, 1.88 mmol) were added under nitrogen. The reaction mixture was stirred at 0°C for 16 hours. The resulting mixture was filtered and rinsed with a small amount of acetonitrile. The wet cake was dried in a vacuum oven to obtain the title compound (0.140 g, 28% yield): 1 H NMR(500MHz,DMSO-d6)δ 8.01(d,J=6.0Hz,1H),7.72(s,2H),7.42(t,J=7.1Hz,1H),7.05(s,1H),6.61 (d,J=7.1Hz,1H),6.56(t,J=6.0Hz,1H),4.02(d,J=3.7Hz,2H),3.28(s,12H).

[0035] Example 3: Preparation of N-(pyrimidine-5-ylmethyl)pyridine-2-amine [ka]

[0036] Example 3.1: To a solution of (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)arylidene)-N-methylmethaneaminium chloride (621 mg, 2.31 mmol) in ethanol (10 mL), formamidine acetate (265 mg, 2.54 mmol) was added. The mixture was stirred at 80°C for 16 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with a gradient of 0-3% methanol (MeOH) in dichloromethane (DCM) to obtain the title compound (0.250 g, 56% yield).

[0037] Example 3.2: A 50 mL three-necked round-bottom flask equipped with a stirring bar, a condenser with a nitrogen bubbler at the top, and a thermocouple was charged with anhydrous DMF (40 mL), (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)arylidene)-N-methylmethaneaminium chloride (882 mg, 3.28 mmol), formamidine acetate (341 mg, 3.28 mmol), and potassium carbonate (K2CO3, 906 mg, 6.56 mmol). The mixture was stirred at 70°C for 16 hours. After evaporation of the solvent, the residue was purified by flash column chromatography on silica gel, eluting with a gradient of 0-3% MeOH in DCM, to obtain the title compound (0.556 g, 91.0% yield).

[0038] Example 3.3: To a mixture of (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)alilidene)-N-methylmethaneaminium chloride (5.00 g, 85% by weight purity, containing 15% by weight of LiCl, 18.7 mmol) and formamidine acetate (1.94 g, 18.7 mmol) in anhydrous MeOH (50.0 mL), anhydrous potassium carbonate (K2CO3, 5.16 g, 37.4 mmol, 2 equivalents) was added under a nitrogen atmosphere. The reaction mixture was heated and stirred at 40°C for 1.5 hours until the (E)-N-(3-(dimethylamino)-2-((pyridine-2-ylamino)methyl)alilidene)-N-methylmethaneaminium chloride was consumed as shown by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to room temperature and filtered. The wet cake was rinsed with MeOH (10 mL). 1 Analysis of the filtrate by 1H NMR spectroscopy showed a 98% impotence yield of the title compound. The filtrate was concentrated under reduced pressure by rotational evaporation to obtain a residue (3.0 g). The residue was recrystallized from ethyl acetate and hexane to obtain the title compound (2.67 g, 90.5% yield).

[0039] Example 4: Preparation of N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride [ka]

[0040] Anhydrous N,N-dimethylformamide (DMF, 116.94 g, 1.6 mol, 4.0 equivalents) was charged into a 250 mL four-necked jacketed reactor equipped with an overhead stirrer, a condenser (with a nitrogen atmosphere at the top), and a thermocouple, and heated to 44-45°C with stirring at 300 rpm under a nitrogen atmosphere. Acrylic acid (28.82 g, 400 mmol, 1 equivalent) and oxalyl chloride (111.70 g, 880 mmol, 2.2 equivalents) were added simultaneously over a period of time using two syringe pumps at a rate that maintained the reaction temperature in the range of 44-46°C. After the addition was complete (6-8 hours), the resulting mixture was stirred overnight (10-15 hours) at 44-46°C. Additional anhydrous DMF (87.71 g, 1.2 mol, 3.0 equivalents) was added to the reaction mixture. The reaction mixture was kept at 44-46°C until the reaction was complete (4-8 hours). The reaction mixture was cooled to 0-5°C over 3 hours. After holding at 0-5°C for 2 hours, the reaction mixture was filtered under a nitrogen atmosphere. The wet cake was rinsed with cold anhydrous DMF (0-5°C, 20-30 mL) and then anhydrous tetrahydrofuran (50 mL), and dried in a vacuum oven at ambient temperature (20-25°C) to obtain the title compound (38.5 g, 45.6% yield).

[0041] Considering the above, the following additional details (D) are provided.

[0042] 1D. A process comprising mixing S1a, N,N-dialkylformamide ("DAF"), and oxalyl chloride ((COCl)2) under conditions for producing S1b. [ka] (In the formula, X 1 is Cl, Br, or I; X 2 is F, Cl, Br, I, or OH; Each R 1 (The compound is methyl, ethyl, or n-propyl.)

[0043] 2D. X 1The process described in 1D, where Cl is the same.

[0044] 3D. X 1 The process described in 1D is Br.

[0045] 4D. X 1 The process described in 1D, where I is.

[0046] 5D. X 2 The process described in 1D, 2D, 3D, or 4D, wherein F is the process.

[0047] 6D. X 2 The process described in 1D, 2D, 3D, or 4D, wherein Cl is the same.

[0048] 7D. X 2 The process described in 1D, 2D, 3D, or 4D, wherein Br is the process.

[0049] 8D. X 2 The process described in 1D, 2D, 3D, or 4D, where I is I.

[0050] 9D. X 2 The process described in 1D, 2D, 3D, or 4D, wherein OH is present.

[0051] 10D. The process described in any of the details above, in which approximately 2 to 20 moles of DAF are used per mole of S1a.

[0052] 11D. The process described in any of the details above, in which approximately 3 to 15 moles of DAF are used per mole of S1a.

[0053] 12D. The process described in any of the details above, in which approximately 4 to 10 moles of DAF are used per mole of S1a.

[0054] 13D. The process described in any of the details above, in which approximately 0.5 to 5 moles of oxalyl chloride are used per mole of S1a.

[0055] 14D. The process described in any of the details above, in which approximately 0.8 moles to approximately 4 moles of oxalyl chloride are used per mole of S1a.

[0056] 15D. The process described in any of the details above, in which approximately 1 mole to approximately 3 moles of oxalyl chloride are used per mole of S1a.

[0057] 16D. A process described in any of the details above, where the conditions include ambient temperature and ambient pressure.

[0058] 17D. A process described in any of the details above, where the conditions include a temperature of approximately -10°C to approximately 80°C.

[0059] 18D. The process described in any of the details above, with conditions including a temperature of approximately -5°C to approximately 60°C.

[0060] 19D. A process described in any of the details above, where the conditions include a pressure of approximately 10 kilopascals (kPa) to approximately 1000 kPa.

[0061] 20D. The process described in any of the details above, where the conditions include a pressure of approximately 50 kPa to approximately 150 kPa.

[0062] 21D. The process according to any of the details above, wherein S1a is 3-chloropropanoyl chloride, 3-chloropropanoyl bromide, 3-chloropropanoyl fluoride, 3-chloropropanoyl iodide, 3-bromopropanoyl chloride, 3-bromopropanoyl bromide, 3-bromopropanoyl fluoride, 3-bromopropanoyl iodide, 3-iodopropanoyl chloride, 3-iodopropanoyl iodide, 3-iodopropanoyl bromide, 3-iodopropanoyl fluoride, 3-chloropropanoic acid, 3-bromopropanoic acid, 3-iodopropanoic acid, or a mixture thereof.

[0063] 22D. The process described in any of the details above, wherein S1a is 3-chloropropanoyl chloride.

[0064] 23D. The process described in any of the preceding details, wherein the substitute for oxalyl chloride ((COCl)2) is selected from phosphorus oxychloride (POCl3), thionyl chloride (SOCl2), phthaloyl chloride (C6H4-1,2-(COCl)2), or a mixture thereof.

[0065] 24D. The process described in any of the above details, in which a substitute for N,N-dialkylformamide is selected from piperidine-1-carbaldehyde, pyrrolidine-1-carbaldehyde, or morpholine-4-carbaldehyde and used to produce an S1b substitute. [ka] (In the formula: X 1 is Cl, Br, or I; Each Y is independent of (CH2) n or O; n is either 0 or 1.

[0066] 24.2D The process described in detail 1D and 10D-20D, wherein S1a is substituted with acrylic acid.

[0067] 24.4D The process described in detail in 24.5, in which approximately 1.5 to 5 moles of oxalyl chloride are used per mole of acrylic acid.

[0068] 24.6D The process described in detail in 24.5, in which approximately 1.8 to 4 moles of oxalyl chloride are used per mole of acrylic acid.

[0069] 24.8D The process described in detail in 24.5, in which approximately 2 to 3 moles of oxalyl chloride are used per mole of acrylic acid.

[0070] 25D. A process comprising mixing S1b, pyridine-2-amine, and a base in the presence of a solvent under conditions for producing S2b. [ka] (In the formula, X 1 is Cl, Br, or I; Each R 1 (These are methyl, ethyl, or n-propyl.)

[0071] 26D. X 1 The process described in 25D, where Cl is used.

[0072] 27D. X 1 The process described in 25D, where is Br.

[0073] 28D. X 1 The process described in 25D, where I is.

[0074] 29D. The process described in any of the details 25D to 28D above, in which approximately 0.8 moles to approximately 2 moles of pyridine-2-amine are used per mole of S1b.

[0075] 30D. The process described in any of the details 25D to 28D above, in which approximately 0.9 moles to approximately 1.8 moles of pyridine-2-amine are used per mole of S1b.

[0076] 31D. The process described in any of the details 25D-28D above, in which approximately 1 to 1.5 moles of pyridine-2-amine are used per mole of S1b.

[0077] 32D. The process described in any of the details 25D to 31D above, in which approximately 0.8 moles to approximately 4 moles of base are used per mole of S1b.

[0078] 33D. The process described in any of the details 25D to 31D above, in which approximately 0.9 moles to approximately 3 moles of base are used per mole of S1b.

[0079] 34D. The process described in any of the details 25D to 31D above, in which approximately 1 to 2 moles of base are used per mole of S1b.

[0080] 35D. A process described in any of the details 25D to 34D above, where the conditions include ambient temperature and ambient pressure.

[0081] 36D. The process described in any of the details 25D to 34D above, with conditions including a temperature of approximately -100°C to approximately 50°C.

[0082] 37D. The process described in any of the details 25D to 34D above, with conditions including a temperature of approximately -80°C to approximately 20°C.

[0083] 38D. A process described in any of the details 25D to 34D above, where the conditions include a pressure of approximately 10 kilopascals (kPa) to approximately 1000 kPa.

[0084] 39D. The process described in any of the details 25D to 34D above, including a pressure of approximately 50 kPa to approximately 150 kPa.

[0085] 40D. The process described in any of the details 25D to 39D above, wherein S1b is N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride, N-(2-(bromomethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride, N-(2-(iodomethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride, or a mixture thereof.

[0086] 41D. The process described in any of the details 25D to 40D above, wherein S1b is N-(2-(chloromethyl)-3-(dimethylamino)alilidene)-N-methylmethaneaminium chloride.

[0087] 42D. The process according to any of the above details 25D to 40D, wherein the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, lithium diisopropylamide, n-butyllithium, s-butyllithium, sodium amide, sodium hydride, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide, and mixtures thereof.

[0088] 43D. The aforementioned base is of formula (R 2b MgX 2b )(wherein, R 2b (C1~C4) alkyl or (C6~C 10 ) is an aryl, X 2b The process is one of the details described above in 25D to 40D, and involves an organomagnesium halide (which is Cl, Br, or I).

[0089] 44D. The process according to 43D, wherein the alkyl is methyl, ethyl, propyl, or isopropyl.

[0090] 45D. The process described in any of the details 25D-44D above, in which the S1b-substitute of S1b is used to produce the S2b-substitute. [ka]

[0091] 46D. The process according to any of the details 25D to 45D above, wherein the solvent is an aromatic hydrocarbon, a halogenated benzene, a haloalkane, an ether, an ester, or a mixture thereof.

[0092] 47D. The process according to any of the details 25D to 46D above, wherein the solvent is toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, propyl acetate, DMF, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, or a mixture thereof.

[0093] 48D. A process comprising mixing S2b and S3a under conditions for producing S3b, also known as N-(pyrimidine-5-ylmethyl)pyridine-2-amine. [ka] (In the formula, X 3 These are Cl, Br, I, F, OC(=O)CH3, OCO(O)H, OC(O)CH2CH3, H2PO4, or HSO4; Each R 1 (These are methyl, ethyl, or n-propyl.)

[0094] 49D. The process described in 48D, in which approximately 0.1 moles to approximately 10 moles of S3a are used per mole of S2b.

[0095] 50D. The process described in 49D, in which approximately 0.5 moles to approximately 5 moles of S3a are used per mole of S2b.

[0096] 51D. The process described in 49D, in which approximately 1 to 2 moles of S3a are used per mole of S2b.

[0097] 52D. The process described in any of the details 48D to 51D above, in which a base is used, with approximately 0.01 moles to approximately 6 moles of base used per mole of S2b.

[0098] 53D. The process described in any of the details 48D to 52D above, in which a base is used, with approximately 0.05 moles to approximately 4 moles of base per mole of S2b.

[0099] 54D. The process described in any of the details 48D to 52D above, in which a base is used, with approximately 0.5 moles to approximately 2.5 moles of base used per mole of S2b.

[0100] 55D. The process described in detail 52D-54D, wherein the base is selected from the group consisting of triethylamine, Na2CO3, NaHCO3, K2CO3, KHCO3, NaOCH3, NaOCH2CH3, KOC(CH3)3, and mixtures thereof.

[0101] 56D. A process described in any of the details 48D to 55D above, where the conditions include a temperature of approximately 0°C to approximately 100°C.

[0102] 57D. The process described in any of the details 48D to 56D above, wherein the conditions include a temperature of approximately 25°C to approximately 80°C.

[0103] 58D. A process described in any of the details 48D to 57D above, where the conditions include a pressure of approximately 10 kilopascals (kPa) to approximately 1000 kPa.

[0104] 59D. The process described in any of the above details 48D to 57D, where the conditions include a pressure of approximately 50 kPa to approximately 150 kPa.

Claims

[Claim 1] (1) Under conditions for generating S1b, S1a, N,N-dialkylformamide and oxalyl chloride ((COCl) ２ ) Mixing 【Chemistry 1】 (In the formula, X １ is Cl, Br, or I; Each R1 is methyl, ethyl, or n-propyl; In formula S1a, X ２ is F, Cl, Br, I, or OH; In equation S1b, X² is F, Cl, Br, or I; continuation (2) Mix S1b, pyridine-2-amine, and a base in the presence of a solvent under conditions for generating S2b. 【Chemistry 2】 (In equation S2b, X2 is F, Cl, Br, or I); continuation (3) Mix S2b, S3a, and the base under conditions for generating S3b. 【Transformation 3】 (In formula S3a, X ３ is Cl, Br, I, F, OC(=O)CH ３ , OC(O)H, OC(O)CH ２ CH ３ , H ２ PO ４ , or HSO ４ ) A process that includes this.

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