* 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 hydrogenchloride; NaOH; ammonium formate In methanol; water; ethyl acetate
Example 17 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method C) (MeOH/water and ammonium formate) A suspension of palladium on 5percent wet charcoal (50percent water) (1.065 g) and ammonium formate (2.52 g) in methanol (30 ml) is stirred for 20 minutes in an inert atmosphere; a solution of 2.52 g of ammonium formate in 5 ml of water and a solution consisting of 2.26 g of 3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid (18), 70 ml of methanol and 10 ml of 1N NaOH is then added. The mixture is kept under reflux stirring in an inert atmosphere for 15 hours. 0.425 g of Pd/C (5percent wet) is then added, and the reaction mixture is again maintained under reflux for 24 hours. The mixture is then cooled, diluted with methanol, filtered through a Celite bed, and the catalyst is washed with further methanol. The filtrate is then evaporated until dry at low pressure and the residue treated with 70 ml of 1N HCl and 250 ml of ethyl acetate. The organic phase is washed with brine (3*) and evaporated until dry, to obtain 1.82 g of compound (1) in the form of a white solid; HPLC purity=98.2percent, yield=94.7percent.
Reference：
[1] Patent: US2012/65370, 2012, A1,
2
[ 34576-96-0 ]
[ 1467-86-3 ]
Yield
Reaction Conditions
Operation in experiment
96.4%
Stage #1: With hydrogen; sodium hydroxide In tetrahydrofuran; methanol at 20℃; Inert atmosphere Stage #2: With hydrogenchloride In water; ethyl acetate
A suspension of 0.745 g of palladium on 5percent wet charcoal (50percent water) in 5 ml of methanol is added in an inert atmosphere to a mixture of 1.133 g of 3-chloro-6-methyl-benzo(b)thiophene-2-carboxylic acid (18) in 17.5 ml of tetrahydrofuran, 5 ml of IN NaOH and 17.5 ml of methanol. The suspension is then maintained under stirring in a hydrogen atmosphere at ambient temperature for 18-20 hours. The mixture is rendered inert and filtered through a Celite bed, and the catalyst washed with 30 ml of methanol. The filtrate is then evaporated until dry at low pressure, and 30 ml of IN HCl and 150 ml of ethyl acetate are added to the residue. The organic phase is washed with brine (2 x) and evaporated until dry. 0.927 g of compound (1) is obtained in the form of a white solid; HPLC purity = 97percent, yield = 96.4percent.
90.6%
With palladium on activated charcoal; hydrogen; sodium hydroxide In ethanol; water; N,N-dimethyl-formamide at 20℃; Inert atmosphere
8.5 g of palladium on 5percent wet charcoal (50percent water) is added in an inert atmosphere to a mixture of 11.33 g of 3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid (18), 135 ml of N,N-dimethylformamide, 15 ml of 3.3 M NaOH and 40 ml of methanol/water 9/1. After repeated vacuum-hydrogen cycles, the suspension is maintained under stirring in a hydrogen atmosphere at ambient temperature for 20-24 hours. The mixture is then rendered inert and filtered through a Celite bed, and the catalyst is washed with 150 ml of methanol. The filtrate is evaporated until dry; 500 ml of water and 40 ml of 1N HCl are added, and the solution is maintained under stirring for 1 hour. The suspension is filtered and the solid washed with 200 ml of water and dried. After drying, 8.71 g of compound (I) is obtained in the form of a white solid; yield=90.6percent. HPLC purity=99.3percent. MS m/z: 191 (M−H)− . 1H-NMR (DMSO-d6, 600 MHz): δ (ppm) 13.35 (broad singlet, 1H), 8.04 (s, 1H), 7.88 (d, 1 H, J=8.2), 7.84 (s, 1 H), 7.30 (dd, 1 H, J=1.0 Hz, J=8.2 Hz).
With hydrogenchloride; NaOH In tetrahydrofuran; methanol; ethyl acetate
Example 16 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method B) A suspension of 0.745 g of palladium on 5percent wet charcoal (50percent water) in 5 ml of methanol is added in an inert atmosphere to a mixture of 1.133 g of 3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid (18) in 17.5 ml of tetrahydrofuran, 5 ml of 1N NaOH and 17.5 ml of methanol. The suspension is then maintained under stirring in a hydrogen atmosphere at ambient temperature for 18-20 hours. The mixture is rendered inert and filtered through a Celite bed, and the catalyst washed with 30 ml of methanol. The filtrate is then evaporated until dry at low pressure, and 30 ml of 1N HCl and 150 ml of ethyl acetate are added to the residue. The organic phase is washed with brine (2*) and evaporated until dry. 0.927 g of compound (I) is obtained in the form of a white solid; HPLC purity=97percent, yield=96.4percent.
90.6%
With hydrogenchloride; NaOH In methanol; water; N,N-dimethyl-formamide
Example 15 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method A) 8.5 g of palladium on 5percent wet charcoal (50percent water) is added in an inert atmosphere to a mixture of 11.33 g of 3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid (18), 135 ml of N,N-dimethylformamide, 15 ml of 3.3 M NaOH and 40 ml of methanol/water 9/1. After repeated vacuum-hydrogen cycles, the suspension is maintained under stirring in a hydrogen atmosphere at ambient temperature for 20-24 hours. The mixture is then rendered inert and filtered through a Celite bed, and the catalyst is washed with 150 ml of methanol. The filtrate is evaporated until dry; 500 ml of water and 40 ml of 1N HCl are added, and the solution is maintained under stirring for 1 hour. The suspension is filtered and the solid washed with 200 ml of water and dried. After drying, 8.71 g of compound (I) is obtained in the form of a white solid; yield=90.6percent. HPLC purity=99.3percent. MS m/z: 191 (M-H)- 1H-NMR (DMSO-d6, 600 MHz): δ (ppm) 13.35 (broad singlet, 1H), 8.04 (s, 1H), 7.88 (d, 1H, J=8.2), 7.84 (s, 1H), 7.30 (dd, 1H, J=1.0 Hz, J=8.2 Hz).
A suspension of 0.745 g of palladium on 5% wet charcoal (50% water) in 5 ml of methanol is added in an inert atmosphere to a mixture of 1.133 g of 3-chloro-6-methyl-benzo(b)thiophene-2-carboxylic acid (18) in 17.5 ml of tetrahydrofuran, 5 ml of IN NaOH and 17.5 ml of methanol. The suspension is then maintained under stirring in a hydrogen atmosphere at ambient temperature for 18-20 hours. The mixture is rendered inert and filtered through a Celite bed, and the catalyst washed with 30 ml of methanol. The filtrate is then evaporated until dry at low pressure, and 30 ml of IN HCl and 150 ml of ethyl acetate are added to the residue. The organic phase is washed with brine (2 x) and evaporated until dry. 0.927 g of compound (1) is obtained in the form of a white solid; HPLC purity = 97%, yield = 96.4%.
90.6%
With palladium on activated charcoal; hydrogen; sodium hydroxide; In ethanol; water; N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere;
8.5 g of palladium on 5% wet charcoal (50% water) is added in an inert atmosphere to a mixture of 11.33 g of <strong>[34576-96-0]3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid</strong> (18), 135 ml of N,N-dimethylformamide, 15 ml of 3.3 M NaOH and 40 ml of methanol/water 9/1. After repeated vacuum-hydrogen cycles, the suspension is maintained under stirring in a hydrogen atmosphere at ambient temperature for 20-24 hours. The mixture is then rendered inert and filtered through a Celite bed, and the catalyst is washed with 150 ml of methanol. The filtrate is evaporated until dry; 500 ml of water and 40 ml of 1N HCl are added, and the solution is maintained under stirring for 1 hour. The suspension is filtered and the solid washed with 200 ml of water and dried. After drying, 8.71 g of compound (I) is obtained in the form of a white solid; yield=90.6%. HPLC purity=99.3%. MS m/z: 191 (M-H)- . 1H-NMR (DMSO-d6, 600 MHz): δ (ppm) 13.35 (broad singlet, 1H), 8.04 (s, 1H), 7.88 (d, 1 H, J=8.2), 7.84 (s, 1 H), 7.30 (dd, 1 H, J=1.0 Hz, J=8.2 Hz).
With hydrogenchloride; NaOH; In tetrahydrofuran; methanol; ethyl acetate;
Example 16 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method B) A suspension of 0.745 g of palladium on 5% wet charcoal (50% water) in 5 ml of methanol is added in an inert atmosphere to a mixture of 1.133 g of <strong>[34576-96-0]3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid</strong> (18) in 17.5 ml of tetrahydrofuran, 5 ml of 1N NaOH and 17.5 ml of methanol. The suspension is then maintained under stirring in a hydrogen atmosphere at ambient temperature for 18-20 hours. The mixture is rendered inert and filtered through a Celite bed, and the catalyst washed with 30 ml of methanol. The filtrate is then evaporated until dry at low pressure, and 30 ml of 1N HCl and 150 ml of ethyl acetate are added to the residue. The organic phase is washed with brine (2*) and evaporated until dry. 0.927 g of compound (I) is obtained in the form of a white solid; HPLC purity=97%, yield=96.4%.
90.6%
With hydrogenchloride; NaOH; In methanol; water; N,N-dimethyl-formamide;
Example 15 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method A) 8.5 g of palladium on 5% wet charcoal (50% water) is added in an inert atmosphere to a mixture of 11.33 g of <strong>[34576-96-0]3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid</strong> (18), 135 ml of N,N-dimethylformamide, 15 ml of 3.3 M NaOH and 40 ml of methanol/water 9/1. After repeated vacuum-hydrogen cycles, the suspension is maintained under stirring in a hydrogen atmosphere at ambient temperature for 20-24 hours. The mixture is then rendered inert and filtered through a Celite bed, and the catalyst is washed with 150 ml of methanol. The filtrate is evaporated until dry; 500 ml of water and 40 ml of 1N HCl are added, and the solution is maintained under stirring for 1 hour. The suspension is filtered and the solid washed with 200 ml of water and dried. After drying, 8.71 g of compound (I) is obtained in the form of a white solid; yield=90.6%. HPLC purity=99.3%. MS m/z: 191 (M-H)- 1H-NMR (DMSO-d6, 600 MHz): δ (ppm) 13.35 (broad singlet, 1H), 8.04 (s, 1H), 7.88 (d, 1H, J=8.2), 7.84 (s, 1H), 7.30 (dd, 1H, J=1.0 Hz, J=8.2 Hz).
With hydrogenchloride; NaOH; ammonium formate;palladium-carbon; In methanol; water; ethyl acetate;
Example 17 6-methyl-benzo[b]thiophene-2-carboxylic acid (1) (Method C) (MeOH/water and ammonium formate) A suspension of palladium on 5% wet charcoal (50% water) (1.065 g) and ammonium formate (2.52 g) in methanol (30 ml) is stirred for 20 minutes in an inert atmosphere; a solution of 2.52 g of ammonium formate in 5 ml of water and a solution consisting of 2.26 g of <strong>[34576-96-0]3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid</strong> (18), 70 ml of methanol and 10 ml of 1N NaOH is then added. The mixture is kept under reflux stirring in an inert atmosphere for 15 hours. 0.425 g of Pd/C (5% wet) is then added, and the reaction mixture is again maintained under reflux for 24 hours. The mixture is then cooled, diluted with methanol, filtered through a Celite bed, and the catalyst is washed with further methanol. The filtrate is then evaporated until dry at low pressure and the residue treated with 70 ml of 1N HCl and 250 ml of ethyl acetate. The organic phase is washed with brine (3*) and evaporated until dry, to obtain 1.82 g of compound (1) in the form of a white solid; HPLC purity=98.2%, yield=94.7%.
N-[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]-6-methyl-1-benzothiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane at 25℃; for 20h; Inert atmosphere;
5.1.43 General procedure of amide formation
General procedure: Acid (1.00 equiv.), triethylamine (1.5000 equiv.), and propanephosphonic acid anhydride (T3P, 1.5000 equiv.) were added to a stirred solution of amine (1.00 equiv.) in dichloromethane (2mL) at 25°C, and the reaction mixture was stirred at 25°C for 20h. The reaction was monitored by TLC, after reaction completion, the reaction mixture was diluted with dichloromethane (5mL), washed with NaOH(aq) solution (2×5mL), water (2×5mL), brine (1×5mL). The organic layer was dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The crude product was purified by Isco Combi-Flash Companion column chromatography to give the desired product.
59%
With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane at 25℃; for 20h; Inert atmosphere;
5.1.43 General procedure of amide formation
General procedure: Acid (1.00 equiv.), triethylamine (1.5000 equiv.), and propanephosphonic acid anhydride (T3P, 1.5000 equiv.) were added to a stirred solution of amine (1.00 equiv.) in dichloromethane (2mL) at 25°C, and the reaction mixture was stirred at 25°C for 20h. The reaction was monitored by TLC, after reaction completion, the reaction mixture was diluted with dichloromethane (5mL), washed with NaOH(aq) solution (2×5mL), water (2×5mL), brine (1×5mL). The organic layer was dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The crude product was purified by Isco Combi-Flash Companion column chromatography to give the desired product.
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