* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h;
To the reaction flask was added llg (4-methylthio) phenylacetate, 200 mL of anhydrous THF, and the mixture was heated to 65-70The (: Maintaining T = 65-70 ° C while adding 88 ml of a solution of 1.0 M t-BuMgCl in THF and 5.7 g of 6-methylpyridine-3-carboxylic acid methylEster in 50 ml of THF. Dropping to complete the incubation reaction for 1 hour. Cooled to room temperature, dropping 50 ml of 4 M hydrochloric acid, layered, organic layerAnd then 50ml of 4M hydrochloric acid extraction, the water layer, the water layer by adding 50g sodium hydroxide, heated to 40-50 ° C stirring 3 hours, cooling toAt room temperature and filtered to give 8.3 g of a pale yellow solid, 87.7percent yield, 98.6percent pure
With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h;
To the reaction flask was added llg (4-methylthio) phenylacetate, 200 mL of anhydrous THF, and the mixture was heated to 65-70 The (: Maintaining T = 65-70 ° C while adding 88 ml of a solution of 1.0 M t-BuMgCl in THF and 5.7 g of 6-methylpyridine-3-carboxylic acid methyl Ester in 50 ml of THF. Dropping to complete the incubation reaction for 1 hour. Cooled to room temperature, dropping 50 ml of 4 M hydrochloric acid, layered, organic layer And then 50ml of 4M hydrochloric acid extraction, the water layer, the water layer by adding 50g sodium hydroxide, heated to 40-50 ° C stirring 3 hours, cooling to At room temperature and filtered to give 7.4 g of a pale yellow solid, yield 78.5percent, purity 98.1
With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h;
To the reaction flask was added llg (4-methylthio) phenylacetic acid,200 mL of anhydrous THF, and the mixture was heated to 65-70 ° C.Maintain T = 65-70 ° C while dropping175 Mll. 0 M t-BuMgCl in THF and5.7g6-methylpyridine-3-carboxylate50 ml of THF solution. Dropping to complete the incubation reaction for 1 hour.Cooling to room temperature, dropping 50ml4M hydrochloric acid quenching reaction, stratification, organic layer and then 50ml4M hydrochloric acid extraction,The aqueous layer was added and the aqueous layer was added with 50 g of sodium hydroxide,Heated to 40-50 ° C for 3 hours, cooled to room temperature,Filtration gave 6.9 g of a pale yellow solid, 72.0percent yield, 97.3percent pure
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 25, p. 8415 - 8420
7
[ 321913-54-6 ]
[ 221615-72-1 ]
Yield
Reaction Conditions
Operation in experiment
5.2 g
With hydrogenchloride In water; acetic acid; toluene at 20℃;
Example-6 Preparation of 1-(6-methyl-3-pyridinyl)-2-[(4-Methylthio)phenyl]ethanone (V) [0068] To compound ( VI) (10 gm) (as per process described above in Example-4) was added a mixture of concentrate hydrochloric acid (75 ml) and Glacial acetic acid (25 ml) After completion of reaction it was cooled to room temperature and extracted with (12 ml) Toluene. [0069] The above reaction mass was added in to a mixture of (31.75 ml) ammonia solution and water (10.00 ml) and stirred. Reaction mass was adjusted to pH between 6.9 to 7.1 using sodium carbonate solution (5percent w/v) at 0-5° C. temperature. It was stirred for 60 minutes and filtered to obtain wet cake. Wet product was washed twice with (10 ml) water. Product wet cake was dissolved in (70 ml) dichloromethane followed by addition of (20 ml) water, stirred for 10 minutes and layers were separated. Aqueous layer was extracted twice with dichloromethane. Combined organic layer containing the product was washed with water (10.00 ml), dried over anhydrous sodium sulphate and purified by activated carbon treatment. [0070] Product layer was concentrated by distilling out dichloromethane at atmospheric pressure to obtain a semi-solid residue. The residue mass was degassed under vacuum for 30 minutes. Isopropyl alcohol (7.5 ml) was added to the mass and it was cooled to 8-10° C. temperature. After stirring for 1 hour at 8-10° C. temperature, it was filtered, and washed with chilled isopropyl alcohol (2.00 ml). The product was dried in a vacuum oven at 45°-50° C. to give dried product (7 gm, purity by HPLC 93.24percent) [0071] Dried product obtained (7 gm) was purified by treatment with methyl iso butyl ketone (17.5 ml). The product slurry was stirred for 30 minutes, filtered and washed with methyl iso butyl ketone (2 ml), and dried under vacuum oven at 40-45° C. temperature. The purified product (5.2 gm) showed HPLC purity 95.40percent.
Stage #1: at 5 - 10℃; Stage #2: at 5 - 25℃; for 6 h;
100 g 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfanyl)phenyl]ethanone of formula (VI) (1.0 equiv.), 150 mL ice-cold acetic acid (1.5 vol) and 30 mL methanesulfonic acid (1.2 equiv, 0.3 vol-96.11 g/mol; 1.481 g/ml) are introduced into a 3000 ml flask provided with high-temperature thermometer, coolant and dropping funnel.The reaction mixture is quenched to 5-10 ° C.120 mL hydrogen peroxide 30percent w/w (3 equiv, 1.20 vol; 34.02 g/mol: 1.13 g/ml) are added under stirring at 5-10° C. The reaction mixture is stirred at 20-25° C. for at least 6 hours. At the end of the reaction, it is quenched to 0-5° C. and a solution consisting of 300 g sodium thiosulfate (3 wt) and water (10 vol) is added in portions.Approximately 180-260 ml of an aqueous solution of 30percent sodium hydroxide are added up to reach a pH of about 5.5-6.5.It is stirred at 20-25° C. for 2 h and the suspension is filtered. The solid is washed with 2x400 mL water, then the solid is dried at 40° C. in a vacuum for at least 12 h. 105.7 g product are obtained, for a molar yield of 94percent HPLC purity, equal to 97.5percent (A percent).
80.4%
With sodium tungstate; sulfuric acid; dihydrogen peroxide In methanol at 55℃; for 1 h;
To the reaction flask was added C50g, 2N sulfuric acid 3.7ml and 500ml methanol, 1. Lg sodium tungstate, heated to 55 degrees, droppingAfter stirring, the mixture was stirred for 1 hour, 500 ml of water was added, cooled to room temperature, filtered, and the filter cake was washed with 500 ml of water and dried to obtain 45.2 g, yield: 80.4percent purity: 98.1percent.
72%
With sodium tungstate; dihydrogen peroxide In ethyl acetate at 30℃; for 1 h; Flow reactor
In a continuous flow reactor, enter the first material input port with 1-(6-methylpyridin-3-yl)-2-(4-methanesulfonylphenyl)ethanone in ethyl acetate (1 mol /L concentration, 1mL/s flow rate), The second input port was fed with an aqueous solution of sodium tungstate (0.1 mol/L concentration, 0.1 mL/s flow rate) and heated to 30 degrees via a heat exchanger. Enter a 10.5percent hydrogen peroxide solution (1 mL/s flow rate, 3 equivalents) at the third material input port and mix with the solution shown in the first inlet. After mixing the two solutions, pass 20-30 degrees in 60 minutes. Cooler, Then, a sodium thiosulfate solution (2 mol/L concentration, 1 mL/s flow rate) was input from the fourth material input port, and the upper organic phase was collected and output in a continuous flow dispenser. The organic phase was collected into a container and, after reaching 20 liters, a post-treatment of concentration and crystallization was carried out. The yield of the two-step reaction was 72percent and the purity was 98.5percent.
21 g
With sodium tungstate; sulfuric acid; dihydrogen peroxide; Aliquat 336 In dichloromethane; water at 18 - 20℃;
Product (wet) mass of 1-(6-methyl-3-pyridinyl)-2-[(4-Methylthio)phenyl]ethanone (V) was dissolved in dichloromethane (185 ml), stirred allowed to settle and aqueous layer was separated. Dichloromethane solution of the product was directly forwarded to the subsequent synthetic stage of oxidation with a mixture of concentrate Sulphuric acid (4.10 gm.)+water (4.50 ml) and stirred for 15-20 minutes. A solution of sodium tungstate (0.74 gm) in water (14.0 ml) was also charged and reaction mass was stirred for 10 minutes followed by addition of mixture of methyl-tri-n-octyl chloride (0.80 gm) in dichloromethane (8.0 ml). The reaction mixture was stirred for 10 minutes, and cooled to 18°-20° C. Mixture of 50percent Hydrogen peroxide (19.50 gm) and water (12.50 ml) was gradually added within 45 minutes at 18°-20° C. temp. Reaction mass was maintained for several hours and monitored by TLC examination, till the spot corresponding to 1-(6-methyl-3-pyridinyl)-2-[(4-methylthio)phenyl]ethanone (V) was practically absent by TLC. Reaction mass pH was set between 6.95 to 7.10 using mixture of diluted ammonia solution under string within 30 minutes at 25°-30° C. It was stirred for 10 minutes, aqueous layer separated and extracted with dichloromethane (130 ml). Combined dichloromethane layer containing product was washed with water (110 ml), dried over anhydrous sodium sulphate and filtered. Dichloromethane at atmospheric pressure to obtained. Vacuum was finally applied and the mass was degassed Then isopropyl alcohol (96 ml) was added, stirred mass and cooled to 25°-30° C. followed by chilling to 0°-5° C. temp, maintained for an hour, filtered, washed with chilled isopropyl alcohol and dried at 50°-60° C. (yield 21 gms, m.p. 176°-180° C., purity by HPLC-92.50percent).
Reference：
[1] Patent: US2012/232281, 2012, A1, . Location in patent: Page/Page column 7
[2] Journal of Organic Chemistry, 2000, vol. 65, # 25, p. 8415 - 8420
[3] Patent: US6369275, 2002, B1, . Location in patent: Page column 17
[4] Patent: CN104045596, 2017, B, . Location in patent: Paragraph 0056-0057
[5] Patent: CN108689917, 2018, A, . Location in patent: Paragraph 0036; 0044; 0051-0054; 0062-0065
[6] Patent: WO2012/66570, 2012, A2, . Location in patent: Page/Page column 21
[7] Patent: EP2497767, 2012, A1, . Location in patent: Page/Page column 100-11
[8] Patent: US2013/245272, 2013, A1, . Location in patent: Paragraph 0100
100 g 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfanyl)phenyl]ethanone of formula (VI) (1.0 equiv.), 150 mL ice-cold acetic acid (1.5 vol) and 30 mL methanesulfonic acid (1.2 equiv, 0.3 vol-96.11 g/mol; 1.481 g/ml) are introduced into a 3000 ml flask provided with high-temperature thermometer, coolant and dropping funnel.The reaction mixture is quenched to 5-10 C.120 mL hydrogen peroxide 30% w/w (3 equiv, 1.20 vol; 34.02 g/mol: 1.13 g/ml) are added under stirring at 5-10 C. The reaction mixture is stirred at 20-25 C. for at least 6 hours. At the end of the reaction, it is quenched to 0-5 C. and a solution consisting of 300 g sodium thiosulfate (3 wt) and water (10 vol) is added in portions.Approximately 180-260 ml of an aqueous solution of 30% sodium hydroxide are added up to reach a pH of about 5.5-6.5.It is stirred at 20-25 C. for 2 h and the suspension is filtered. The solid is washed with 2x400 mL water, then the solid is dried at 40 C. in a vacuum for at least 12 h. 105.7 g product are obtained, for a molar yield of 94% HPLC purity, equal to 97.5% (A %).
92%
With sodium tungstate; dihydrogen peroxide; In methanol; at 40 - 50℃; for 2h;
1.1) A compound AYTKX17 (800.0 g, 3.109 mol), methanol (7200 ml) and sodium tungstate (20.51 g, 0.062 mol) were added to a 20 L reactor, and stirred to obtain a yellow suspension. Slowly add 10% hydrogen peroxide (2325.9g, 6.840mol), and control the temperature below 50 C. After the completion of the dropwise addition, the reaction was carried out at a temperature of 40-50 C for 2 h. TLC showed that the reaction was almost complete. A solution of sodium sulfite (78.4 g, 0.622 mol) dissolved in 800 ml of water was added, stirred for 20 min, and then cooled to 5-10 C for 1 h. After suction filtration, the filter cake was washed with purified water (500 ml × 2), and dried at 45-55 C to constant weight to give a pale yellow solid, 827.1 g, yield 92.0%. The pale yellow solid (825.0 g) obtained in the step 1.1) was added to a 10 L three-necked flask, and acetonitrile (3300 ml) and purified water (2475 ml) were added thereto, and the mixture was heated to reflux under stirring for 0.5 h, and the solution was suspended and crystallized. The temperature was controlled at 5-10 C for 1 h, suction filtration, and the filter cake was washed with a mixture of 900 ml of acetonitrile/water (1:2 (v/v)), and dried at 45-55 C to constant weight to obtain 706.0 g of a pale yellow solid. That is, the compound AYTKX01 has a yield of 78.5%.
80.4%
With sodium tungstate; sulfuric acid; dihydrogen peroxide; In methanol; at 55℃; for 1h;
To the reaction flask was added C50g, 2N sulfuric acid 3.7ml and 500ml methanol, 1. Lg sodium tungstate, heated to 55 degrees, droppingAfter stirring, the mixture was stirred for 1 hour, 500 ml of water was added, cooled to room temperature, filtered, and the filter cake was washed with 500 ml of water and dried to obtain 45.2 g, yield: 80.4% purity: 98.1%.
72%
With sodium tungstate; dihydrogen peroxide; In ethyl acetate; at 30℃; for 1h;Flow reactor;
In a continuous flow reactor, enter the first material input port with 1-(6-methylpyridin-3-yl)-2-(4-methanesulfonylphenyl)ethanone in ethyl acetate (1 mol /L concentration, 1mL/s flow rate), The second input port was fed with an aqueous solution of sodium tungstate (0.1 mol/L concentration, 0.1 mL/s flow rate) and heated to 30 degrees via a heat exchanger. Enter a 10.5% hydrogen peroxide solution (1 mL/s flow rate, 3 equivalents) at the third material input port and mix with the solution shown in the first inlet. After mixing the two solutions, pass 20-30 degrees in 60 minutes. Cooler, Then, a sodium thiosulfate solution (2 mol/L concentration, 1 mL/s flow rate) was input from the fourth material input port, and the upper organic phase was collected and output in a continuous flow dispenser. The organic phase was collected into a container and, after reaching 20 liters, a post-treatment of concentration and crystallization was carried out. The yield of the two-step reaction was 72% and the purity was 98.5%.
Product (wet) mass of l-(6-methyl-3-pyridinyl)-2-[(4-Methylthio) phenyl] ethanone (V) was dissolved in dichloromethane (185 ml), stirred allowed to settle and aqueous layer was separated. Dichloromethane solution of the product was directly forwarded to the subsequent synthetic stage of oxidation with a mixture of concentrate Sulphuric acid (4.10 gm.) + water (4.50 ml) and stirred for 15-20 minutes. A solution of sodium tungstate (0.74 gm) in water (14.0 ml) was also charged and reaction mass was stirred for 10 minutes followed by addition of mixture of methyl-tri-n-octyl chloride (0.80 gm) in dichloromethane (8.0 ml).. The reaction mixture was stirred for 10 minutes, and cooled to 18-20C Mixture of 50% Hydrogen peroxide (19.50 gm) and water (12.50 ml) was gradually added within 45 minutes at 18-20C temp. Reaction mass was maintained for several hours and monitored by TLC examination, till the spot corresponding to l-(6- methyl-3-pyridinyl)-2-[(4-methylthio) phenyl] ethanone (V) was practically absent by TLC. Reaction mass pH was set between 6.95 to 7.10 using mixture of diluted ammonia solution under string within 30 minutes at 25-30C It was stirred for 10 minutes, aqueous layer separated and extracted with dichloromethane (130 ml). Combined dichloromethane layer containing product was washed with water (1 10 ml), dried over anhydrous sodium sulphate and filtered. Dichloromethane at atmospheric pressure to obtained. Vacuum was finally applied and the mass was degassed Then isopropyl alcohol (96 ml) was added, stirred mass and cooled to 25-30C followed by chilling to 0-5C temp, maintained for an hour, filtered, washed with chilled isopropyl alcohol and dried at 50-60C(yield 21 gms, m.p. 176o-180C,purity by HPLC-92.50%)
Example 8 - Synthesis of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of formula (I) - Exemplary variation of the invention 100 g 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfanyl)phenyl]ethanone of formula (VI) (1.0 equiv.), 150 mL ice-cold acetic acid (1.5 vol) and 30 mL methanesulfonic acid (1.2 equiv, 0.3 vol - 96.11 g/mol; 1.481 g/ml) are introduced into a 3000 ml flask provided with high-temperature thermometer, coolant and dropping funnel. The reaction mixture is quenched to 5-10 C. 120 mL hydrogen peroxide 30% w/w (3 equiv, 1.20 vol; 34.02 g/mol: 1.13 g/ml) are added under stirring at 5-10C. The reaction mixture is stirred at 20-25 C for at least 6 hours. At the end of the reaction, it is quenched to 0-5C and a solution consisting of 300 g sodium thiosulfate (3 wt) and water (10 vol) is added in portions. Approximately 180-260 ml of an aqueous solution of 30% sodium hydroxide are added up to reach a pH of about 5.5-6.5. It is stirred at 20-25C for 2 h and the suspension is filtered. The solid is washed with 2 x 400 mL water, then the solid is dried at 40C in a vacuum for at least 12 h. 105.7 g product are obtained, for a molar yield of 94% HPLC purity, equal to 97.5% (A%).
21 g
With sodium tungstate; sulfuric acid; dihydrogen peroxide; Aliquat 336; In dichloromethane; water; at 18 - 20℃;pH 6.95-7.10;
Product (wet) mass of 1-(6-methyl-3-pyridinyl)-2-[(4-Methylthio)phenyl]ethanone (V) was dissolved in dichloromethane (185 ml), stirred allowed to settle and aqueous layer was separated. Dichloromethane solution of the product was directly forwarded to the subsequent synthetic stage of oxidation with a mixture of concentrate Sulphuric acid (4.10 gm.)+water (4.50 ml) and stirred for 15-20 minutes. A solution of sodium tungstate (0.74 gm) in water (14.0 ml) was also charged and reaction mass was stirred for 10 minutes followed by addition of mixture of methyl-tri-n-octyl chloride (0.80 gm) in dichloromethane (8.0 ml). The reaction mixture was stirred for 10 minutes, and cooled to 18-20 C. Mixture of 50% Hydrogen peroxide (19.50 gm) and water (12.50 ml) was gradually added within 45 minutes at 18-20 C. temp. Reaction mass was maintained for several hours and monitored by TLC examination, till the spot corresponding to 1-(6-methyl-3-pyridinyl)-2-[(4-methylthio)phenyl]ethanone (V) was practically absent by TLC. Reaction mass pH was set between 6.95 to 7.10 using mixture of diluted ammonia solution under string within 30 minutes at 25-30 C. It was stirred for 10 minutes, aqueous layer separated and extracted with dichloromethane (130 ml). Combined dichloromethane layer containing product was washed with water (110 ml), dried over anhydrous sodium sulphate and filtered. Dichloromethane at atmospheric pressure to obtained. Vacuum was finally applied and the mass was degassed Then isopropyl alcohol (96 ml) was added, stirred mass and cooled to 25-30 C. followed by chilling to 0-5 C. temp, maintained for an hour, filtered, washed with chilled isopropyl alcohol and dried at 50-60 C. (yield 21 gms, m.p. 176-180 C., purity by HPLC-92.50%).
Stage #1: 1-(chloromethyl)-4-methylthiobenzene With magnesium In tetrahydrofuran; toluene for 3 - 4h;
Stage #2: N-methoxy-N-methyl-6-methylnicotinamide In toluene at -20℃; for 1.5h;
62%
With magnesium; ethylene dibromide In tetrahydrofuran; toluene at 36℃;
With tert-butylmagnesium chloride; In tetrahydrofuran; at 65 - 70℃; for 1h;
To the reaction flask was added llg (4-methylthio) phenylacetic acid,200 mL of anhydrous THF, and the mixture was heated to 65-70 C.Maintain T = 65-70 C while dropping175 Mll. 0 M t-BuMgCl in THF and5.7g6-methylpyridine-3-carboxylate50 ml of THF solution. Dropping to complete the incubation reaction for 1 hour.Cooling to room temperature, dropping 50ml4M hydrochloric acid quenching reaction, stratification, organic layer and then 50ml4M hydrochloric acid extraction,The aqueous layer was added and the aqueous layer was added with 50 g of sodium hydroxide,Heated to 40-50 C for 3 hours, cooled to room temperature,Filtration gave 6.9 g of a pale yellow solid, 72.0% yield, 97.3% pure
In a continuous flow reactor, the first material input port is a solution of 4-(methylthio)phenylacetic acid in tetrahydrofuran (1 mol/L concentration, 1 mL/s flow rate). Heated to 60 degrees by heat exchanger, the second material input port was sent to a solution of tert-butylmagnesium chloride in tetrahydrofuran (2mol/L concentration, 1.5mL/s flow rate) and mixed with the solution shown in the first inlet, and the installation gas overflowed. Device. After mixing the two solutions, a 60-degree heat exchanger was passed over 60 minutes, and then a solution of 6-methyl-pyridine-3-carboxylic acid methyl ester in tetrahydrofuran (5 mol/L concentration, 0.18) was input from the third material input port. mL/s flow rate), And through a 60-degree heat exchanger (must install a gas overflow device) in 60 minutes, and concentrated to collect tetrahydrofuran, concentrated to a material solution output rate of about 1.0mL / s. Enter the toluene (1mL/s) at the fourth material input port, then enter 10% dilute hydrochloric acid (0.35mL/s) at the fifth material input port, and install a gas overflow device. In a continuous flow dispenser, the upper organic phase is collected and output. A 10% sodium bicarbonate solution (0.8 mL/s) was input to the sixth material input port, and the lower aqueous phase was collected and output in a continuous flow dispenser. Enter 10% hydrochloric acid (1.2 mL/s) in the seventh material input port, collect the lower aqueous phase and output in a continuous flow dispenser. Enter 30% sodium hydroxide (0.5 mL/s) in the eighth material input port, and output to a solid-liquid separation device to collect solids.
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