* 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.
In the reaction vessel was added 1,4-butanediol (2) 0.15mol, triethylamine 170ml, the temperature of the solution is reduced to 5 , controlling the stirring speed 160rpm, methanesulfonic acid was slowly added to the amine (3) 0.38mol, dropwise Upon completion, the solution temperature rises to 40 , stirred for 4h, the temperature of the solution is reduced to 20 , the precipitated solid was filtered, washed with sodium nitrite solution, dried over anhydrous magnesium sulfate, recrystallized from cyclohexane to 95percent (mass fraction), as a white solid of 1,4-bis-methyl sulfonate polybutyleneterephthalate 33.58g, yield 91percent.
Reference：
[1] Patent: CN105566173, 2016, A, . Location in patent: Paragraph 0014; 0015
5
[ 3144-09-0 ]
[ 99-90-1 ]
[ 5317-89-5 ]
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 43, p. 7295 - 7298
[2] Organic Letters, 2011, vol. 13, # 10, p. 2564 - 2567
[3] Green Chemistry, 2014, vol. 16, # 3, p. 1480 - 1488
With triethylamine In dichloromethane at 25℃; for 2 h;
e) Boc-N-(4-Benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)-methanesulfonamide Triethylamine (22.0 mL, 158 mmol), di-tert-butyl dicarbonate (27.5 g, 126 mmol), and 4-(N,N-dimethylamino)pyridine (1.28 g, 10.5 mmol) were added sequentially to a solution of methanesulfonamide (10.0 g, 105 mmol) in dichloromethane (300 mL) at 25° C. The mixture was stirred at 25° C. for 2 h, and then was concentrated in vacuo to ~40 mL volume. Ethyl acetate (350 mL) was added and the mixture was washed with 1.0 M aqueous hydrochloric acid solution (300 mL). The aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford Boc-N-methanesulfonamide (17.1 g, 87.6 mmol, 83percent) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.53 (9H, s), 3.27 (3H, s).
81%
With dmap; triethylamine In dichloromethane at 20℃; for 3 h;
A solution of Boc20 (41.2 g, 189.2 mmol) in DCM (200 mL) was added dropwise to a stirred suspension of methane sulfonamide (15.0 g, 157.7 mmol), Et3N (23.6 mL, 173.5 mmol) and DMAP (1.9 g, 15.8 mmol) in DCM (200 mL). The resulting suspension was stirred for 3 h at room temperature and concentrated under vacuum. The resulting residue was diluted with EtOAc (300 mL) and acidified with 1 N HCI (200 mL). The organic layer was washed with water followed by brine, dried over Na2S04 and concentrated under reduced pressure to obtain a crude mixture, which was triturated with 10percent EtOAc in petroleum ether to obtain B1 as a white solid (25.0 g, 81 percent). Rf: 0.6 (50percent EtOAc in petroleum ether). LCMS m/z = 194.3 (M - H). 1H NMR (400 MHz, CDCI3): δ 1.44 (s, 9H), 3.19 (s, 3H), 7.19 (s, 1 H).
49%
With triethylamine In dichloromethane at 20℃;
To a 500 mL row1d bottom f1ask \vas added a solution of methanesulfonamide (1 0 g,105.13 mmol, l.OO equiv.) in dichloromeHume (300 mL) follo·wed by TEA (22 g, 217.4120 mmol, 1.50 equiv.), Boc20 (27.5 g, 126.00 mmoL 1.20 equiv.), and 4-dimethylaminopyridine(1.28 g, 10.48 mmol, 0.10 equiv.). The reaction mixture v.·as stirred at room temperatmeovernight and then concentrated under vacuurn. 200 mL ofFhO vvas added, the pFf value of the solution was adjusted to 3 using a 1M hydrogen chloride aqueous solution, and thernixture was extracted with ethyl acetate (200 mL x 3). The combined organic extracts werew·ashed vvith brine (300 mL x 2), dried over anhydrous sodium sulfate and concentratedunder vacuum to give oftert-butyl N-methanesulfonylcarbamate 216b (10.06 g, 49percent) as a5 ·white solid.
85%
With hydrogenchloride; dmap; triethylamine In hexane; dichloromethane; water; ethyl acetate
A. N-(t-butoxycarbonyl)methanesulfonamide
To a solution of 15.0 g (157.7 mmol) of methanesulfonamide, 17.6 g (173.5 mmol) of triethylamine and 1.9 g (15.8 mmol) of 4-dimethylaminopyridine in 200 mL of dichloromethane was added of 37.9 g (173.5 mmol) of di-t-butyldicarbonate in 200 mL of dichloromethane over ten minutes. The mixture was stirred at ambient temperature for 2.25 hours and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate and washed once with 200 mL of 1 N hydrochloric acid, once with 100 mL of water and once with 100 mL of saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in 100 mL of hexane, filtered and dried in vacuo to afford 26.1 g (85percent) of the title compound. Analysis calculated for C7H13NO4S: percentC, 36.91; percentH, 6.71; percentN, 7.17. Found: percentC, 36.97; percentH, 6.79; percentN, 7.04. Mass Spectrum: M+1=196.
1 g
With dmap; triethylamine In dichloromethane at 20℃; for 2 h;
Triethylamine (2.2 mL, 16 mmol), di-tert-butyldicarbonate (2.65 g, 12.1 mmol) and 4-dimethylaminopyridine (0.096 g, 0.79 mmol) were added sequentially to a solution of methanesulfonamide (0.75 g, 7.9 mmol) in methylene chloride (20 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated. EtOAc was added, and the resultant mixture was washed with 1N aq. HCl solution, dried over MgSO4 and concentrated to give the desired product (1 g) to be used in the next step directly.
85%
With hydrogenchloride; dmap; triethylamine In hexane; dichloromethane; water; ethyl acetate
A. N-(t-Butoxycarbonyl)Methanesulfonamide: To a solution of 15.0 g (157.7 mmol) of methanesulfonamide, 17.6 g (173.5 mmol) of triethylamine and 1.9 g (15.8 mmol) of 4-dimethylaminopyridine in 200 mL of dichloromethane was added of 27.9 g (173.5 mmol) of di-t-butyldicarbonate in 200 mL of dichloromethane over ten minutes. The mixture was stirred at ambient temperature for 2.25 hours and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate and washed once with 200 mL of 1 N hydrochloric acid, once with 100 mL of water and once with 100 mL of saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in 100 mL of hexane, filtered and dried in vacuo to afford 26.1 g (85percent) of the title compound. Analysis calculated for C7H13NO4S: percentC, 36.91; percentH, 6.71; percentN, 7.17. Found: percentC, 36.97; percentH, 6.79; percentN, 7.04. Mass Spectrum: M+1=196.
Reference：
[1] Tetrahedron Letters, 1994, vol. 35, # 3, p. 379 - 380
[2] Patent: US2009/306057, 2009, A1, . Location in patent: Page/Page column 44
[3] Journal of the American Chemical Society, 2015, vol. 137, # 17, p. 5638 - 5641
[4] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286
[5] Organic Letters, 2006, vol. 8, # 21, p. 4707 - 4710
[6] Patent: WO2015/181676, 2015, A1, . Location in patent: Page/Page column 136-137
[7] Patent: WO2018/39386, 2018, A1, . Location in patent: Page/Page column 356; 357
[8] Patent: US6303816, 2001, B1,
[9] Patent: WO2008/85300, 2008, A1, . Location in patent: Page/Page column 85
[10] Patent: EP1553074, 2005, A1, . Location in patent: Page/Page column 44
[11] Patent: US2010/256092, 2010, A1, . Location in patent: Page/Page column 109
[12] Patent: US2012/316156, 2012, A1,
[13] Patent: US2014/121198, 2014, A1, . Location in patent: Paragraph 0642; 0643
[14] Patent: US6387954, 2002, B1,
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 10, p. 2900 - 2903
11
[ 3144-09-0 ]
[ 79-04-9 ]
[ 202658-88-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 65℃; for 12 h; Large scale
In a 2-liter reaction flask, 1 liter of ethyl acetate and 66 grams of methylsulfonamide were added, and 109 grams of chloroacetyl chloride was gradually added; the temperature was gradually increased to 65°C for 12 hours until the end of the reaction.The reaction solution gradually cooled to 0 degree, and a large amount of white solid precipitated; it was filtered and dried to obtain 112 g of solid SLP-10b (X=Cl).Yield: 94percent.H NMR (400MHz, CDCl3): δ 4.02 (s, 2H), 3.28s, 3H)ESI/MS+(m/z):171
74%
for 8 h; Heating / reflux
26.8 mol of chloroacetyl chloride and 25.5 mol of methanesulfonamide in 10.2 L of butyl acetate are slowly boiled at reflux. After 8 h, the mixture is cooled to 20° C. The precipitated solid is filtered off and stirred in 4 L of butyl acetate. The precipitated solid is dried at 50° C. in a fan-assigned drying cabinet. Yield 74percent
14 g
at 125℃; for 16 h;
Methane sulfonamide (10 gm) and n-butylacetate (80 mL) were charged into a 250 mL round bottom flask at 30°C. Chloroacetylchloride (21 .37 gm) was added slowly over a period of 10 minutes at 30°C. Temperature of the reaction mass was raised to 125°C and maintained reflux for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20°C and stirred for 1 hour at 20°C. Reaction mass was filtered and the wet solid was washed with n- butylacetate (10 mL). The wet solid was taken into another 100 mL round bottom flask and n-butylacetate (50 mL) was added and stirred for 30 minutes at 20°C. The precipitation was filtered and the solid was suck dried. The material was dried at 45° under vacuum for 5 hours to yield 14 gm of title compound.
With triethylamine;dmap; In dichloromethane; at 25℃; for 2h;
e) Boc-N-(4-Benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)-methanesulfonamide Triethylamine (22.0 mL, 158 mmol), di-tert-butyl dicarbonate (27.5 g, 126 mmol), and 4-(N,N-dimethylamino)pyridine (1.28 g, 10.5 mmol) were added sequentially to a solution of methanesulfonamide (10.0 g, 105 mmol) in dichloromethane (300 mL) at 25 C. The mixture was stirred at 25 C. for 2 h, and then was concentrated in vacuo to ~40 mL volume. Ethyl acetate (350 mL) was added and the mixture was washed with 1.0 M aqueous hydrochloric acid solution (300 mL). The aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford Boc-N-methanesulfonamide (17.1 g, 87.6 mmol, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) delta: 1.53 (9H, s), 3.27 (3H, s).
81%
With dmap; triethylamine; In dichloromethane; at 20℃; for 3h;
A solution of Boc20 (41.2 g, 189.2 mmol) in DCM (200 mL) was added dropwise to a stirred suspension of methane sulfonamide (15.0 g, 157.7 mmol), Et3N (23.6 mL, 173.5 mmol) and DMAP (1.9 g, 15.8 mmol) in DCM (200 mL). The resulting suspension was stirred for 3 h at room temperature and concentrated under vacuum. The resulting residue was diluted with EtOAc (300 mL) and acidified with 1 N HCI (200 mL). The organic layer was washed with water followed by brine, dried over Na2S04 and concentrated under reduced pressure to obtain a crude mixture, which was triturated with 10% EtOAc in petroleum ether to obtain B1 as a white solid (25.0 g, 81 %). Rf: 0.6 (50% EtOAc in petroleum ether). LCMS m/z = 194.3 (M - H). 1H NMR (400 MHz, CDCI3): delta 1.44 (s, 9H), 3.19 (s, 3H), 7.19 (s, 1 H).
49%
With triethylamine; In dichloromethane; at 20℃;
To a 500 mL row1d bottom f1ask vas added a solution of methanesulfonamide (1 0 g,105.13 mmol, l.OO equiv.) in dichloromeHume (300 mL) follo·wed by TEA (22 g, 217.4120 mmol, 1.50 equiv.), Boc20 (27.5 g, 126.00 mmoL 1.20 equiv.), and 4-dimethylaminopyridine(1.28 g, 10.48 mmol, 0.10 equiv.). The reaction mixture v.·as stirred at room temperatmeovernight and then concentrated under vacuurn. 200 mL ofFhO vvas added, the pFf value of the solution was adjusted to 3 using a 1M hydrogen chloride aqueous solution, and thernixture was extracted with ethyl acetate (200 mL x 3). The combined organic extracts werew·ashed vvith brine (300 mL x 2), dried over anhydrous sodium sulfate and concentratedunder vacuum to give oftert-butyl N-methanesulfonylcarbamate 216b (10.06 g, 49%) as a5 ·white solid.
26.1 g (85%)
With hydrogenchloride; dmap; triethylamine; In hexane; dichloromethane; water; ethyl acetate;
A. N-(t-butoxycarbonyl)methanesulfonamide To a solution of 15.0 g (157.7 mmol) of methanesulfonamide, 17.6 g (173.5 mmol) of triethylamine and 1.9 g (15.8 mmol) of 4-dimethylaminopyridine in 200 mL of dichloromethane was added of 37.9 g (173.5 mmol) of di-t-butyldicarbonate in 200 mL of dichloromethane over ten minutes. The mixture was stirred at ambient temperature for 2.25 hours and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate and washed once with 200 mL of 1 N hydrochloric acid, once with 100 mL of water and once with 100 mL of saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in 100 mL of hexane, filtered and dried in vacuo to afford 26.1 g (85%) of the title compound. Analysis calculated for C7H13NO4S: %C, 36.91; %H, 6.71; %N, 7.17. Found: %C, 36.97; %H, 6.79; %N, 7.04. Mass Spectrum: M+1=196.
Methanesulfonamide (4.4g; 46.26 mmol), triethylamine (7.1 ml; 50.88 mmol) and DMAP (565 mg; 4.626 mmol) were dissolved in dry CH2CI2 (50 ml) and stirred at room temperature. A solution of di-tert-butyl dicarbonate (1 l.lg; 53.196 mmol) in dry CH2CI2 (100 ml) was slowly added drop by drop over 10 minutes. After the addition was complete the reaction mixture was stirred a further 1 hour, then the volatiles were removed under reduced pressure. The residues were carefully partitioned with 2N hydrochloric acid (150 ml) and diethyl ether (2 x 150 ml). The ether extracts were combined and washed with brine (150 ml) and the extract dried over anhydrous MgSO4 powder, filtered and the filtrates concentrated under reduced pressure. The solid residues obtained from evaporation was triturated with hexanes, the hexane layer was filtered off and discarded. The remaining solid was crystalized from hexane and diethyl ether to give the title compound. 1H-NMR (400 MHz, CDCl3) delta: 1.53 (s, 9H), 3.28 (s.,3H).
With dmap; triethylamine; In dichloromethane; at 20℃; for 2.5h;
Reference Example 42 To a mixture of methane sulfonamide (1.96 g), triethylamine (3.2 mL), 4-(dimethylamino)pyridine (252 mg), and dichloromethane (30 mL) was added a mixture of di-tert-butyl dicarbonate (5.17 g) and dichloromethane (40 mL) at room temperature for 30 minutes. The mixture was concentrated after stirring for 2 hours, and the residue was distributed with ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl methylsulfonyl carbamate (2.44 g). 1H-NMR (300 MHz, CDCl3) delta: 1.52 (9H, s), 3.28 (3H, s).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred suspension of methylsulfonamide (6 g, 62 mmol) in DCM at 0 C. was added DMAP (760 mg, 6.2 mmol), triethylamine (10.4 ml, 74.4 mmol) and (Boc)2O (14.2 g, 65.1 mmol). The reaction mixture was warmed up to room temperature and stirred overnight. The solution was concentrated and the residue was diluted with ethyl acetate, washed consecutively with 1N HCl and water, dried with Na2SO4, filtered and evaporated to afford a colorless oil. The oil was refluxed in hexane for 1 hour then cooled to room temperature and filtered to afford the target compound as a white solid (12.1 g, 42.1% yield). 1H NMR (DMSO-d6, 300 MHz) delta ppm 11.22 (s, 1H), 3.18 (s, 3H), 1.42 (s, 9H).
With dmap; triethylamine; In dichloromethane; ethyl acetate;
Triethylamine (22.0 mL, 158 mmol), di-tert-butyl dicarbonate (27.5 g, 126 mmol), and 4-(N,N-dimethylamino)pyridine (1.28 g, 10.5 mmol) were added sequentially to a solution of methanesulfonamide (10.0 g, 105 mmol) in dichloromethane (300 mL) at 25 C. The mixture was stirred at 25 C. for 2 h, and then was concentrated in vacuo to ~40 mL volume. Ethyl acetate (350 mL) was added and the mixture was washed with 1.0 M aqueous hydrochloric acid solution (300 mL). The aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford Boc-N-methanesulfonamide (17.1 g, 87.6 mmol, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) delta: 1.53 (9H, s), 3.27 (3H, s).
1 g
With dmap; triethylamine; In dichloromethane; at 20℃; for 2h;
Triethylamine (2.2 mL, 16 mmol), di-tert-butyldicarbonate (2.65 g, 12.1 mmol) and 4-dimethylaminopyridine (0.096 g, 0.79 mmol) were added sequentially to a solution of methanesulfonamide (0.75 g, 7.9 mmol) in methylene chloride (20 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated. EtOAc was added, and the resultant mixture was washed with 1N aq. HCl solution, dried over MgSO4 and concentrated to give the desired product (1 g) to be used in the next step directly.
26.1 g (85%)
With hydrogenchloride; dmap; triethylamine; In hexane; dichloromethane; water; ethyl acetate;
A. N-(t-Butoxycarbonyl)Methanesulfonamide: To a solution of 15.0 g (157.7 mmol) of methanesulfonamide, 17.6 g (173.5 mmol) of triethylamine and 1.9 g (15.8 mmol) of 4-dimethylaminopyridine in 200 mL of dichloromethane was added of 27.9 g (173.5 mmol) of di-t-butyldicarbonate in 200 mL of dichloromethane over ten minutes. The mixture was stirred at ambient temperature for 2.25 hours and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate and washed once with 200 mL of 1 N hydrochloric acid, once with 100 mL of water and once with 100 mL of saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in 100 mL of hexane, filtered and dried in vacuo to afford 26.1 g (85%) of the title compound. Analysis calculated for C7H13NO4S: %C, 36.91; %H, 6.71; %N, 7.17. Found: %C, 36.97; %H, 6.79; %N, 7.04. Mass Spectrum: M+1=196.
With acetamide; potassium carbonate; at 90 - 145℃; for 0.5h;
Example 13 2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL-N- (5- METHANESULFONYLAMINO-PYRAZIN-2-YL)-PROPIONAMIDE [000164] A solution of molten acetamide (1.58 g, 26.7 mmol) heated to 90C was treated with a mixture of <strong>[117103-53-4]2-bromo-5-nitropyrazine</strong> (1.34 g, 6.58 MMOL), METHANESULFONAMIDE (1.88 g, 19.7 mmol), and potassium carbonate (2.30 g, 16.6 mmol). The resulting mixture was quickly brought to 145C. The resulting solution was stirred at 145C for 30 min. At this time, the reaction was cooled to 25C and then was treated with water (4 mL). This solution was cooled to 0C and then was treated with a IN aqueous hydrochloric acid solution until the pH of the solution was adjusted to pH=8. This solution was treated with charcoal and was filtered through a pad of celite (90/10 methylene chloride/methanol wash). The filtrate was partitioned, and the aqueous layer was extracted with a solution of 90/10 methylene CHLORIDE/METHANOL. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, ethyl acetate) afforded N- (5-nitro- PYRAZIN-2-YL)-METHANESULFONAMIDE (583.9 mg, 40.6%) as a yellow solid: mp 204-207C ; EI-HRMS m/e calcd for C5H6N404S (M+H) + 219. 0183, found 219.0185.
In a 2-liter reaction flask, 1 liter of ethyl acetate and 66 grams of methylsulfonamide were added, and 109 grams of chloroacetyl chloride was gradually added; the temperature was gradually increased to 65C for 12 hours until the end of the reaction.The reaction solution gradually cooled to 0 degree, and a large amount of white solid precipitated; it was filtered and dried to obtain 112 g of solid SLP-10b (X=Cl).Yield: 94%.H NMR (400MHz, CDCl3): delta 4.02 (s, 2H), 3.28s, 3H)ESI/MS+(m/z):171
74%
In acetic acid butyl ester; for 8h;Heating / reflux;
26.8 mol of chloroacetyl chloride and 25.5 mol of methanesulfonamide in 10.2 L of butyl acetate are slowly boiled at reflux. After 8 h, the mixture is cooled to 20 C. The precipitated solid is filtered off and stirred in 4 L of butyl acetate. The precipitated solid is dried at 50 C. in a fan-assigned drying cabinet. Yield 74%
14 g
In acetic acid butyl ester; at 125℃; for 16h;
Methane sulfonamide (10 gm) and n-butylacetate (80 mL) were charged into a 250 mL round bottom flask at 30C. Chloroacetylchloride (21 .37 gm) was added slowly over a period of 10 minutes at 30C. Temperature of the reaction mass was raised to 125C and maintained reflux for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the mass was cooled to 20C and stirred for 1 hour at 20C. Reaction mass was filtered and the wet solid was washed with n- butylacetate (10 mL). The wet solid was taken into another 100 mL round bottom flask and n-butylacetate (50 mL) was added and stirred for 30 minutes at 20C. The precipitation was filtered and the solid was suck dried. The material was dried at 45 under vacuum for 5 hours to yield 14 gm of title compound.
[5-(Methanesulfonylamino-methyl)-thiophen-2-yl]-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With hydrogenchloride; formaldehyd;Zinc chloride; In 1,4-dioxane;
PREPARATION JJ1 5-(Methanesulfonylamino-methyl)-thiophen-2-yl-acetic acid methyl ester To a solution of thiophen-2-yl-acetic acid methyl ester (2 mL, 12.8 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL, 4.8 mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) was added and the reaction was lowered into a pre-heated water bath at 45 C. and was stirred for 15 minutes. HCl (g) was bubbled into the solution for 2-3 minutes. The temperature of the reaction rose to about 60 C. Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was added dropwise and the temperature rose to 70 C. The reaction was cooled to room temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added in portions. The reaction was stirred for 3 h and was poured into EtOAc (60 mL). The organic solution was washed with water and the aqueous solution was washed with EtOAc (60 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3) provided the title compound (69%) as a gold oil. 1H NMR (400 MHz, CDCl3) delta 6.85 (d, 1H), 6.70 (d, 1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s, 3H).
2-[[5-{2,8-Dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-N-methylsulphonyl-4-oxazolecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; N-ethyl-N,N-diisopropylamine; In aqueous ammonium acetate; N,N-dimethyl-formamide;
i 2-[[5-{2,8-Dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl}-3,4-dihydro-2-oxo-4-thioxo-1(2H)-pyrimidinyl]methyl]-N-methylsulphonyl-4-oxazolecarboxamide The product of example 37(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.38 g), 4-dimethylaminopyridine (0.07 g), methanesulphonamide (0.095 g) and N,N-diisopropylethylamine (0.43 ml) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 h. The mixture was partitioned between aqueous tartaric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Purification was by reverse phase silica gel chromatography (C18-sep-pak) eluding with 50% methanol in 0.1% aqueous ammonium acetate. Yield 0.032 g. MS: APCI(-ve): 547(M-1, 100%). 1H NMR: delta (DMSO) 12.71(s, 1H), 12.1-12.2(br s, 1H), 8.88(s, 1H), 7.46(d, 2H), 7.1-7.2(m, 4H), 7.08(s, 1H), 6.82(s, 2H), 5.76(s, 1H), 5.11(s, 2H), 3.35(s, 3H), 3.0-3.1(m, 4H), 2.27(s, 6H), 1.7-1.8(m, 4H).
EXAMPLE 16 METHANESULFONAMIDE, N-[2'-(DIMETHYLAMINO)-1,4-DIHYDROSPIRO[3H-2-BENZOPYRAN-3'-CYCLOHEXAN]-7-YL]-,CIS-ISOMER STR22 A solution of methyltoluamide 1 (8.95 grams, 60 mmol) in 240 mL of dry THF cooled to 0 C. was treated with n-Butyl lithium (75 mL, 120 mmol) and stirred for 30 minutes. This mixture was cooled to -70 C. and a solution of 2-dimethylaminocyclohexanone (2.82 grams, 20 mmol) in 3 mL of THF was added and stirred for 1.5 hrs. The reaction was warmed to 0 C. and quenched with saturated aqueous NaCl. After extraction with ethyl acetate, the organic portion was extracted with 2N HCl. The aqueous was washed with ethyl acetate and then basified with 40% NaOH in water. Extraction of the aqueaous with ethylacetate, drying with sodium sulfate and concentration gave a crude alcohol intermediate which was treated with 34 mL of 50% acetic acid in water followed by 8 mL of concentrated sulfuric acid. The mixture was heated at 100 C. for 24 hrs. This was diluted with water and extracted with ethyl acetate. The aqueous was basified with 40% NaOH and extracted with ethyl acetate. The organic portions from the basic extractions were combined dried over sodium sulfate and concentrated. Filtration of the residue through silica gel eluted with ethyl acetate, concentration and crystalization from hexane gave 2.55 grams (50%) of 3 as a white solid mp=95-96 C. 1 H NMR (CDCl3, partial): 4.25 (d, J=8 Hz, 1H); 8.07(d, J=8 Hz, 1H) ppm. STR23
23
[ 3144-09-0 ]
[ 56961-30-9 ]
[ 77227-81-7 ]
N-methanesulphonyl-5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-chloro-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In thionyl chloride; hexane; dimethyl sulfoxide;
EXAMPLE 21 This Example illustrates the preparation of N-methanesulphonyl-5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-chloro-benzamide (compound 56 of Table I). 3,5-Dichloro-4-fluorobenzotrifluoride (2.0 g), potassium carbonate (6.0 g) and <strong>[56961-30-9]2-chloro-5-hydroxybenzoic acid</strong> (1.5 g) were heated and stirred in dry dimethylsulphoxide (25 ml) at 80° C. for 2.5 hours. The mixture was cooled and agitated with ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer was washed with water, dried (MgSO4), and evaporated under reduced pressure. The brown oil which remained was triturated with petroleum (b.p. 60°-80°) to give a white solid (2.3 g) identified as 2-chloro-5-(2,6-dichloro-4-trifluoromethylphenoxy) benzoic acid, with a melting point of 158°-159° C. The benzoic acid derivative so prepared (1.0 g) was heated under reflux in thionyl chloride (15 ml) for 3 hours and the excess of thionyl chloride then removed under reduced pressure. The remaining oil was taken up in dry pyridine, the solution cooled to 0° C. and methanesulphonamide (0.8 g) added. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature, and stirred for another 2 hours. The mixture was then agitated with ether and dilute hydrochloric acid. The ether layer was separated, dried (MgSO4) and evaporated to give an oil. This was triturated with a mixture of hexane and ether to give a white solid. This was taken up in ether and the solution washed three times with water, dried (MgSO4) and evaporated to give an oil. This was triturated with hexane to give a solid. The solid was recrystallized from ether/hexane to give a white solid with a melting point of 195°-196° C. (melts and re-solidifies at 162° C.) identified as compound 56.
Preparation of N-[3-(4-aminophenyl)-propionyl]-methanesulfonamide To a solution of 3-(4-nitrophenyl)-propionic acid (205 mg, 1.0 mmol) in 3 mL of DMF was added carbonyl diimidazole (190 mg, 1.13 mmol). The mixture was stirred at rt for 1 h followed by addition of methanesulfonamide (120 mg, 1.2 mmol) and 0.17 mL of DBU. The reaction mixture was stirred overnight at rt, then quenched with water. The reaction mixture was extracted with CH2Cl2, and the organic fractions were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated. The residue and 10 mg of Pd/C (10%) in 5 mL of MeOH was stirred under 1 atm of H2 for 1 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give 90 mg (35% yield in 2 steps) of N-[3-(4-aminophenyl)-propionyl]-methanesulfonamide. The title compound was prepared by reacting N-[3-(4-aminophenyl)-propionyl]-methanesulfonamide with 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methoxy-amide. 1H NMR (400 MHz, CD3OD) delta (ppm): 9.30 (s, 1H), 8.76 (s, 1H), 7.36 (d, 1H), 7.20 (br, 2H), 7.10 (d, 2H), 6.95 (d, 1H), 6.84 (br, 1H), 6.56 (br, 1H), 3.83 (s, 3H), 3.13 (s, 3H), 2.92-2.80 (m, 6H), 2.47 (m, 2H), 2.19 (m, 2H).
N-(4-Chloro-2-nitro-benzoyl)-methanesulfonamide (H, Scheme 3)To a suspension of <strong>[6280-88-2]4-chloro-2-nitrobenzoic acid</strong> (5 g, 1 eq) in DCM (100 ml), EDC HCI (9.5 g, 2 eq) and DMAP (9 g, 3 eq) are added. The resulting brown solution is stirred for 10 min and methanesulfonamide (2.35 g, 1 eq) is then added.The reddish solution is stirred at room temperature overnight, diluted with DCM (100 ml), washed with 1.5 N HCI (2 x 50 ml) and water (50 ml), dried and evaporated to <n="25"/>dryness, to give a yellowish solid (4.6 g, 67% yield). This crude material is suspended in DCM (15 ml), stirred for 15 min, filtered and dried, to afford the title compound as white solid (2 g, 29%, purity 98%), which is used as such for the next step
29%
N-(4-Chloro-2-nitro-benzoyl)-methanesulfonamide (INT-1) (Scheme 1 )To a suspension of <strong>[6280-88-2]4-chloro-2-nitrobenzoic acid</strong> (5 g, 1 eq) in DCM (100 ml), EDC HCI (9.5 g, 2 eq) and DMAP (9 g, 3 eq) are added. The resulting brown solution is stirred for 10 min and methanesulfonamide (2.35 g, 1 eq) is then added. The reddish solution is stirred at room temperature overnight, diluted with DCM (100 ml), washed with 1.5 N HCI (2 x 50 ml) and water (50 ml), dried and evaporated to dryness, to give a yellowish solid (4.6 g, 67% yield). This crude material is suspended in DCM (15 ml), stirred for 15 min, filtered and dried, to afford the title compound as white solid (2 g, 29%, purity 98%), which is used as such for the next step.
2,3-dichloro-5-methylsulfonamidomethylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium tris(acetoxy)borohydride; acetic acid; triethylamine; In dichloromethane; at 0 - 25℃; for 15h;
2,3-dichloro-5-methylsulfonamidylmethyl pyridine. To a suspension of methyl sulfonamide (1.08 g, 1 1.35 mmol), 2,3-dichloropyridinyl aldehyde, (79, 3.0 g, 17.03 mmol), AcOH (1.35 mL), and NaBH(OAc)3 in dry dichloromethane (70 mL) at O0C, TEA (3.18 mL, 22.7 mmol) was added. The reaction mixture was heated to a temperature of about 250C and stirred for 15 h. Thereafter, saturated NaHCO3 (2 mL) was added. The mixture was extracted twice with ethyl acetate (8OmL for each extraction). The organic portions were combined, washed twice with brine (5OmL for each wash), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The oily residue was chromatographed using a COMBIFLASH apparatus with a 40 g REDISEP column with eluent of 40% ethyl acetate in hexanes to provide 2.8 g of 105 (65% yield) and 20% recovered starting material. 1H NMR (CDCl3): delta 8.38 (s, IH), 8.27 (s, IH), 5.03 (bs, NH), 4.35 (d, J=17Hz, 2H), 3.0 (s, 3H).
To a suspension of 2-(1 ,2-benzisoxazol-3-yl)acetic acid (0.250 g, 1 eq) in DCM (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.325 g, 1.2 eq) and 4- dimethylaminopyridine (0.207 g, 1.2 eq) are added. The resulting brown solution is stirred for 10 min and methanesulfonamide (0.161 g, 1.2 eq) is then added. The reaction mixture is stirred at room temperature overnight, diluted with DCM, washed with 5% KHSO4 and water, dried over MgSO4 and evaporated to dryness, to give a yellowish solid (0.272 mg, 76%). This crude material is purified by crystallisation from a mixture of ethyl acetate and petroleum ether, to afford a white to pale yellow crystalline powder with a melting point of 167-1710C. LC-ESI-HRMS of [M+H]+ shows 255.0436 Da. CaIc. 255.043954 Da, dev. -1.4 ppm.
With potassium carbonate; In dimethyl sulfoxide; at 120℃;
Example 46; 5-chloro-1-{5-fluoro-2-[(methylsulfonyl)amino]benzyl}-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride; (Step 1); A suspension of <strong>[64248-64-2]2,5-difluorobenzonitrile</strong> (12.4 g), methanesulfonamide (9.3 g) and potassium carbonate (13.6 g) in DMSO (360 ml) was stirred overnight at 120 C. The reaction solution was poured into 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-(2-cyano-4-fluorophenyl]methanesulfonamide (6.57 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta ppm 3.09 (3H, s), 7.49-7.57 (1H, m), 7.58-7.68 (1H, m), 10.02 (1H, s).
With caesium carbonate;copper(l) iodide; In water; N,N-dimethyl-formamide; at 105℃; for 20.0h;
EXAMPLE 119; N-(2-Methoxy-5-(4-morpholinoquinolin-6-yl)pyridin-3- yl)methanesulfonamide; (1) N-(5-Bromo-2-methoxypyridin-3-yl)methanesulfonamide.; To a 5 mL microwave vial, <strong>[578007-66-6]5-bromo-3-iodo-2-methoxypyridine</strong> (0.317 g, 1.01 mmol, Alfa Aesar, Ward Hill, MA), methanesulfonamide (0.100 g, 1.06 mmol), cesium carbonate (0.829 g, 2.54 mmol) and copper(I) iodide (0.0211 g, 0.111 mmol) were mixed into DMF (1 mL). water (0.1 mL) was added and the mixture was heated at 105 0C for 20 h. The reaction mixture was poured into water/Tris-lM HCl pH 7 buffer then IN HCl was added to bring pH to ~5. The aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: EtOAc in hexanes 0 % - 50 %) to afford an off white solid (0.135 g) as the desired product. MS (ESI pos. ion) m/z calcd for C7H9BrN2O3S: 280.0; found 280.8/282.8 [M+l/M+3]. 1H NMR (300 MHz, CHLOROFORM-^), delta ppm 3.04 (s, 3 H) 3.92 - 4.07 (m, 3 H) 6.74 (br. s., 1 H) 7.89 (d, J=2.19 Hz, 1 H) 7.97 (d, J=2.19 Hz, 1 H).
Step 1: Methanesulfonamide (0.476 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), and 60% sodium hydride (0.275 g, 5.00 mmol) was added at 0C, then the mixture was stirred at the same temperature for 20 minutes. Subsequently, to the mixture was added 3-chloropropiophenone (843 mg, 5.00 mol), and the mixture was stirred at the same temperature for 2 hours, and then further stirred at room temperature for 15 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol = 20/1) to give N-methanesulfonyl-3-aminopropiophenone (240 mg, 21%).
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Intermediate 49: ((1 S, 3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4- oxo-butyl)-carbamic acid tert-butyl ester; To a solution of (2R, 4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1 .304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDCHCI (450 mg, 2.347 mmol), 1 -hydroxy-7- azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN-H2O (0.1 % NH4OH) over 10 min by X-bridge phenyl column] provides ((1 S, 3R)-1 - Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333mg, 55%). HPLC retention time = 1 .03 minutes (condition D), MS (m-1 ) = 495.5, MS (m-55) = 405.3, MS (m-99) = 361 .3.
With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 65℃;
l-{4'-[3-Methyl-4-((R)-l-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4- yl}-cyclopropanecarboxylic acid (O.lg, 0.2mmol), methanesulfonamide (0.08g, 0.8mmol), and N,N'-carbonyldiimidazole (0.15g, O.betammol) were combined in THF (4mL). Diisopropylethylamine (0.5mL) was added, and the reaction was stirred at 650C overnight. The mixture was acidified and extracted with CH2Cl2. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃;Inert atmosphere;
General procedure for Pd-mediated carbon-nitrogen bond formation: a microwave vial was charged with Pd2(dba)3 or Pd2(dba)3.CHCl3 (0.1 equiv) and Xantphos (0.11 equiv) followed by 1,4-dioxane. The mixture was stirred at room temperature for 15 min. To this vial was then added acetamide or sulfonamide (1.5 equiv), and Cs2CO3 (1.5 equiv) followed by dichloro benzenes (1.0 equiv) in 1,4-dioxane. The vial was flushed with N2 gas and heated in a microwave reactor at 120 C for 1 h. The mixture was diluted with EtOAc. The organic phase was washed with water and brine, then dried, and concentrated. The product was purifed by flash chromatography to provide the desired product.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Inert atmosphere; Reflux;
Preparation 32,5-Difluoro-4-methyl-N-(methylsulfonyl)benzamideA mixture of <strong>[103877-80-1]2-5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 34.9 mmol), diisopropylethylamine (13.5 g, 105.0 mmol), propanephosphonic acid cyclic anhydride (50 mL, 50% w/w solution in ethyl acetate, 84.0 mmol) and methyl sulphonamide (6.6 g, 69.7 mmol) in tetrahydrofuran (200 mL) was heated under reflux with stirring under N2 for 18 hours. After cooling, the solution was evaporated in vacuo and the residue suspended in water. The mixture was extracted with ethyl acetate (300 mL) and the organic extract then washed with brine (2 x 80 mL). The organic solution was then dried over sodium sulphate and evaporated in vacuo to give a solid. Trituration with hexane gave the title compound (7.6 g, 87%) as an off white solid after drying.1H NMR (400 MHz, d6-DMSO): delta 2.26 (s, 3H), 3.34 (s, 3H), 7.33 (m, 1 H), 7.44 (m, 1 H). LCMS Rt = 1 .24 minutes MS m/z 248 [M-H]-
87%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; for 18h;Reflux; Inert atmosphere;
Preparation 92,5-Difluoro- -methyl-N-(methylsulfonyl)benzamideA mixture of <strong>[103877-80-1]2-5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 34.9 mmol), diisopropylethylamine (1 3.5 g, 1 05.0 mmol), propanephosphonic acid cyclic anhydride (50 mL, 50% w/w solution in ethyl acetate, 84.0 mmol) and methyl sulphonamide (6.6 g, 69.7 mmol) in THF (200 ml_) was heated under reflux with stirring under N2 for 18 hours. After cooling, the solution was evaporated in vacuo and the residue suspended in water. The mixture was extracted with ethyl acetate (300 ml_) and the organic extract then washed with brine (2 x 80 ml_). The organic solution was then dried over sodium sulphate and evaporated in vacuo to give a solid. Trituration with hexane gave the title compound (7.6 g, 87%) as an off white solid after drying.1H NMR (400 MHz, DMSO-d6): delta 2.26 (s, 3H), 3.34 (s, 3H), 7.33 (m, 1 H), 7.44 (m, 1 H). LCMS Rt = 1 .24 minutes. MS m/z 248 [M-H]-
Preparation 1082,4,5-Trifluoro-N-(methylsulfonyl)benzamide<strong>[446-17-3]2,4,5-Trifluorobenzoic acid</strong> (3.00 g, 17.0 mmol), N-ethyl-N-/'sopropylpropan-2-amine (8.9 m L, 6.6 g , 51 .1 m mol ), 2 ,4 ,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6- triox id e 50 % so l u t io n i n EtOAc/D M F ( 1 2.7 m L , 1 3.6 g , 42 .6 m m o l ) a n d methanesulfonamide (3.24 g, 34.1 mmol) were suspended in THF (40 mL) and stirred under a nitrogen atmosphere at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo and the residue suspended in water (pH = 4). The mixture was acidified to pH = 2 with an aqueous solution of potassium hydrogen sulfate (0.5 M). The mixture was extracted with EtOAc (1 x 100 mL). The organic layer was washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated to yield the crude solid. The crude solid was triturated with hexane to yield the title compound as an off- white crystalline solid (3.08 g, 72%). 1H NMR (400 MHz, CDCI3): delta 3.45 (s, 3H), 7.10-7.13 (m, 1 H), 7.97-8.02 (m, 1 H), 8.74 (br, 1 H). 19FNMR (400 MHz, CDCI3): delta -1 12.4, -121 .9, -138.5.
72%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide; for 18h;Inert atmosphere; Reflux;
<strong>[446-17-3]2,4,5-Trifluorobenzoic acid</strong> (3.00 g, 17.0 mmol), N-ethyl-N-isopropylpropan-2-amine (8.9 mL, 6.6 g, 51.1 mmol), 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide 50% solution in EtOAc/DMF (12.7 mL, 13.6 g, 42.6 mmol) and methanesulfonamide (3.24 g, 34.1 mmol) were suspended in THF (40 mL) and stirred under a nitrogen atmosphere at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo and the residue suspended in water (pH=4). The mixture was acidified to pH=2 with an aqueous solution of potassium hydrogen sulfate (0.5 M). The mixture was extracted with EtOAc (1×100 mL). The organic layer was washed with brine (2×50 mL), dried over sodium sulfate, filtered and evaporated to yield the crude solid. The crude solid was triturated with hexane to yield the title compound as an off-white crystalline solid (3.08 g, 72%):1H NMR (400 MHz, CDCl3): delta 3.45 (s, 3H), 7.10-7.13 (m, 1H), 7.97-8.02 (m, 1H), 8.74 (br, 1H).19FNMR (400 MHz, CDCl3): delta -112.4, -121.9, -138.5.
36%
<strong>[446-17-3]2,4,5-Trifluorobenzoic acid</strong> (15 g, 85.2 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (24.45 g, 128 mmol) and 4-dimethylaminopyridine (15.6 g, 128 mmol) were stirred in dichloromethane at room temperature for 15 minutes under an atmosphere of nitrogen. Methanesulfonamide (12.15 g, 128 mmol) and triethylamine (23.8 g, 254 mmol) were added and the reaction stirred at room temperature overnight. A 1M aqueous solution of hydrogen chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting residue was recrystallised from a mixture of ethyl acetate and heptane to afford the title compound (7.8 g, 36%).1HNMR (CDCl3): delta 3.40 (s, 3H), 7.05 (m, 1H), 8.00 (m, 1H), 8.70 (s, 1H).LCMS Rt=1.70 minutes MS m/z 252 [MH]-
Preparation 162,4,5-Trifluoro-N-(methylsulfonyl)benzamide<strong>[446-17-3]2,4,5-Trifluorobenzoic acid</strong> (3.00 g, 17.0 mmol), N-ethyl-N-/'sopropylpropan-2-amine (8.9 mL, 6.6 g, 51 .1 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide 50% solution in EtOAc/DMF (12.7 mL, 13.6 g, 42.6 mmol) and methanesulfonamide (3.24 g, 34.1 mmol) were suspended in THF (40 mL) and stirred under a nitrogen atmosphere at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo and the residue suspended in water (pH = 4). The mixture was acidified to pH = 2 with an aqueous solution of potassium hydrogen sulfate (0.5 M). The mixture was extracted with EtOAc (1 x 100 mL). The organic layer was washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated to yield the crude solid. The crude solid was triturated with hexane to yield the title compound as an off-white crystalline solid (3.08 g).1H NMR (400 MHz, CDCI3): delta 3.45 (s, 3H), 7.10-7.13 (m, 1 H), 7.97-8.02 (m, 1 H), 8.74 (brs, 1 H).19FNMR (400 MHz, CDCI3): delta -1 12.4, -121 .9, -138.5.
Preparation 242-Methoxy- 4-methyl-N-(methylsulfonyl)benzamide2-Methoxy-4-methyl-benzoic acid (1 .0 g. 6 mmol), methanesulphonamide (1 .14 g. 12 mmol), 1 -(3-dimethylanninopropyl)-3-ethylcarbodiinnide hydrochloride (2.31 g. 12 mmol), 4-dimethylaminopyridine (1 .47 g. 12 mmol) and DCM (50 mL) were combined and stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and the residue suspended in water and acidified with aqueous potassium hydrogen sulphate (0.5 M). The mixture was extracted with EtOAc (1 x 30 mL). The organic layer was separated, washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and evaporated to give a solid, which was triturated with hexane: diethyl ether (4:1 ) to yield the title compound as a white solid (0.92 g, 63 %).1H NMR (400 MHz, CDCI3): delta 2.43 (s, 3H), 3.41 (s, 3H), 4.03 (s, 3H), 6.83 (s, 1 H), 6.95 (d, 1 H), 8.08 (d, 1 H), 10.18 (br, 1 H).LCMS Rt = 1 .01 minutes. MS m/z 244 [MH]+
Example 632-[4-((E)-2-{2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}vinyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl]amino}-N-methylbenzamide Example 63 AN-(3-bromopyridin-2-yl)methanesulfonamide To methanesulfonamide (8.5 g, 89 mmol) in 80 ml of N,N-dimethylformamide was added potassium tert-butoxide (9.5 g, 84.8 mmol). The mixture was stirred for 20 minutes and <strong>[36178-05-9]3-bromo-2-fluoropyridine</strong> (10.0 g, 57 mmol) was added. The resulting mixture was refluxed for 2 hours. The mixture was poured into water and extracted with dichloromethane, washed with brine, dried over Na S04, filtered, and concentrated to dryness. The crude residue was put through a plug of silica (0-50percent ethyl acetate in petroleum ether) to yield the title compound. MS ESI(+) m/z 251.7 [M+H]+.
With potassium tert-butylate; In N,N-dimethyl-formamide; for 5.63h;Reflux;
Example 64-{6-[({2-[(2-methoxy-4-mophiholm-4-ylphenyl)amino]-7H-py?·olo[2,3-d]pyrimidin-4- yl} amino)methyl]pyridin-2-yl} -N-methylmethanesulfonamideExample 64AN-(6-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide To methanesulfonamide (1.870 g, 19.66 mmol) in N,N-dimethylformamide (40 ml) was added potassium tert-butoxide (2.206 g, 19.66 mmol). The mixture was stirred for 20 minutes and <strong>[3939-15-9]2-cyano-6-fluoropyridine</strong> (2.0 g, 16.38 mmol) was added. The resulting mixture was refluxed for 3.5 hours. It was poured into water and extracted with ethyl acetate, washed with brine, dried over MgS0 , filtered and concentrated to dryness. To the crude residue in a 250 ml pressure bottle was added 7M NH3-methanol (40 ml) and Ra-Ni, water-wet (6.80 g, 116 mmol) and the mixture was stirred for 4 hours at 30 psi at room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound. MS ESI(+) m/z 216 A [M+H]+.
2-Bromo-1,3-thiazole-4-carboxylic acid (0.8 g, 3.85 mmol) was initially charged in tetrahydrofuran (10 ml). N,N'-Carbonyldiimidazole (0.94 g, 5.77 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.55 g, 5.77 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 g, 5.77 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. The aqueous phase was extracted with dichloromethane; the organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. This gave a total of 1.0 g (89% of theory) of 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide.HPLC-MS: LogP(HCOOH): 0.83; mass (m/z): 284.9 (M+H)+;1H NMR (d6-DMSO): 3.33 (s, 3H), 8.61 (s, 1H), 12.00 (s, 1H)
<strong>[88982-82-5]4-Bromo-1,3-thiazole-2-carboxylic acid</strong> (1.0 g, 4.8 mmol) were initially charged in tetrahydrofuran (10 ml). N,N'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.69 g, 7.2 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.10 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. This gave 1.18 g (84% of theory) of 4-bromo-N-(methylsulphonyl)-1,3-thiazole-2-carboxamide.HPLC-MS: LogP(HCOOH): 0.63; mass (m/z): 284.9 (M+H)+;1H NMR (d6-DMSO): 3.31 (s, 3H), 8.31 (s, 1H)
General procedure: To a cooled mixture (0-5C) of proper acids (1.0 mmol) in dry dichloromethane (15 mL), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.0 mmol, 177.0 mL) and 4-dimethylaminopyridine (DMAP, 1.0 mmol, 122.2 mg) were added, under stirring in a nitrogen atmosphere. After 15 min, methanesulfonamide (1.1 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with dichloromethane (15 mL), washed with 2N HCl (3Chi30 mL), dried on Na2SO4. After evaporation of solvent under reduced pressure, crude products were purified on silica gel (eluent dichloromethane/methanol 9:1).
General procedure: To a cooled mixture (0-5C) of proper acids (1.0 mmol) in dry dichloromethane (15 mL), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.0 mmol, 177.0 mL) and 4-dimethylaminopyridine (DMAP, 1.0 mmol, 122.2 mg) were added, under stirring in a nitrogen atmosphere. After 15 min, methanesulfonamide (1.1 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with dichloromethane (15 mL), washed with 2N HCl (3Chi30 mL), dried on Na2SO4. After evaporation of solvent under reduced pressure, crude products were purified on silica gel (eluent dichloromethane/methanol 9:1).
General procedure: To a cooled mixture (0-5C) of proper acids (1.0 mmol) in dry dichloromethane (15 mL), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.0 mmol, 177.0 mL) and 4-dimethylaminopyridine (DMAP, 1.0 mmol, 122.2 mg) were added, under stirring in a nitrogen atmosphere. After 15 min, methanesulfonamide (1.1 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with dichloromethane (15 mL), washed with 2N HCl (3Chi30 mL), dried on Na2SO4. After evaporation of solvent under reduced pressure, crude products were purified on silica gel (eluent dichloromethane/methanol 9:1).
With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; at 20℃;
Preparation of <strong>[188813-02-7]3-bromo-5-fluorobenzaldehyde</strong> (XLIX) (2.03 g, 10.0 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15 0 mmol) and TEA (2.79 mL, 20.0 mmol). The solution was stirred for a few minutes before NaBH(OAc)3 (3.00 g, 14.1 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 and evaporated under vacuum to give N-(3-bromo-5-fluorobenzyl)methanesulfonamide ( L) as a clear oil (2.65 g, 9.39 mmol, 99% yield). ESIMS found C8H9BrFNO2S m/z 282 (M+H).
93.9%
With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; at 20℃;
To a solution of <strong>[188813-02-7]3-bromo-5-fluorobenzaldehyde</strong> (LXXIX) (2.03 g, 10.01 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.01 mmol) and TEA (2.79 mL, 20.02 mmol). NaBH(OAc)3 (3.00 g, 14.13 mmol) was added and stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer separated and washed with water, brine, dried over MgSO4 and evaporated under vacuum to produce N-(3-bromo-5-fluorobenzyl)methanesulfonamide (LXXX) as a colorless oil (2.653 g, 9.40 mmol, 93.9% yield). ESIMS found C8H9BrFNO2S m/z 282.0 (M+H).
With 1,10-Phenanthroline; palladium(II) trifluoroacetate; oxygen; In toluene; at 140℃; for 40h;
General procedure: 2.2 General procedure: 4-methyl-N-phenylbenzenesulfonamide (3a) A 25 mL oven-dried reaction vessel was charged with Pd(TFA)2 (2.3 mg, 0.01 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol), p-toluene sulfonamide (1a, 34.2 mg, 0.2 mmol), cyclohexanone (2a, 32 muL, 0.3 mmol). The reaction vessel was flushed with oxygen three times and then sealed. Toluene (0.7 mL) was added by syringe and the resulting solution was stirred at 140 C for 40 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give the corresponding product 3a (39.9 mg) as white solid in 81% yield.
With copper(II) acetate monohydrate; potassium carbonate; In water; for 4h;Reflux; Green chemistry;
General procedure: To a mixture of copper salt (0.2 mmol) and arylboronic acid (1.0 mmol) in H2O (6 mL), base (1.3 mmol), sulfonamide (1.0 mmol), and H2O (12 mL) were added, and the mixture was vigorously stirred for the appropriate times under reflux conditions. After completion (as monitored by TLC), the reaction mixture was cooled to r.t. The resulting product was filtered and purified by recrystallization using EtOAc and n-hexane to afford the N-arylated product. All anlytical data are consistent with those reported in the literature.
4-bromo-2,5-difluoro-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.8%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;
STEP 1 : 4-BROMO-2,5-DIFLUOPvO-N-(METHYLSULFONYL)BENZAMIDE_: [00212] A round bottom flask was charged with <strong>[28314-82-1]4-bromo-2,5-difluorobenzoic acid</strong> (10.00 g, 42.2 mmol, Aces Pharma), methanesulfonamide (4.82 g, 50.6 mmol), N,N- dimethylpyridin-4-amine (11.34 g, 93 mmol), and N^^ethylimino^ethylene^N^N3- dimethylpropane-l,3-diamine hydrochloride (16.18 g, 84 mmol) and DCM (150 mL) was added. After stirring for 2 d at RT, the mixture was concentrated under reduced pressure to afford the crude material which was dissolved in 500 mL DCM and 10 mL methanol and filtered over 25 micron filter paper. The crude solution was injected onto a 1500 g silica gel cartridge (40-63 micron) and eluted at 300 mL/min with a gradient over ten column volumes (15 L total volume) from 2/98/0.1 methanol/DCM/HCOOH to 20/80/1methanol/DCM/HCOOH to afford 4-bromo-2,5-difluoro-N-(methylsulfonyl)benzamide (Intermediate A) (9.78 g, 73.8%).
38.5%
STEP 2: SYNTHESIS OF 4-BROMO-2,5-DIFLUORO-N-(METHYLSULFONYL)[00317] A solution of <strong>[28314-82-1]4-bromo-2,5-difluorobenzoic acid</strong> (15.3 g, 64.6 mmol) in thionyl chloride (150 mL) and DMF (2 drops) was heated at 85 C for 4 h. Reaction mixture was concentrated under reduced pressure and the crude was taken in DCM (50 mL). This solution was added dropwise to a pre-cooled solution of methane sulfonamide (6.13 g, 64.6 mmol) and TEA (22.5 mL, 161.4 mmol) in DCM (200 mL) at 0 C. The reaction mixture was allowed to stir at ambient temperature for 12h. Reaction mixture was concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography (silica gel 100- 200 mesh and 0-1% MeOH in DCM as eluent) to obtain 4-bromo-2,5-difluoro-N- (methylsulfonyl)benzamide (7.8 g, 38.5%) as white solid. TLC solvent system: 10%> MeOH in DCM. Product's Rf: 0.3. MS (ESI, negative ion) m/z; 312.0 (M-l). 1H NMR (400 MHz, DMSO) delta 12.46 (s, 1H), 7.94 (dd, J= 9.2, 5.5 Hz, 1H), 7.75 (dd, J= 8.3, 6.0 Hz, 1H), 3.37 (s, 3H).
4-bromo-2-fluoro-5-methyl-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
STEP 1 : 4-BROMO-2-FLUORO-5-METHYL-N-(METHYLSULFONYL)BENZAMIDE[00236] To a flask charged with <strong>[415965-24-1]4-bromo-2-fluoro-5-methylbenzoic acid</strong> (Ark Pharm) (9.93 g, 42.6 mmol) was added N,N-dimethylpyridin-4-amine (7.81 g, 63.9 mmol),methanesulfonamide (4.86 g, 51.1 mmol), DCM (170 ml) and N1-((ethylimino)methylene)- N3,N3-dimethylpropane-l,3-diamine hydrochloride (12.25 g, 63.9 mmol). The mixture was stirred overnight at room temp overnight affording the desired product cleanly as the main species according to LCMS. The mixture was cooled in an ice water bath prior to the addition of 2N HCl (about 150 ml) and the resulting mixture was stirred for 10 mins. The mixture was transferred to a sep funnel, the DCM layer collected and the aqueous layer washed again with DCM. The combined organics were collected, dried with Na2S04, filtered, and dried under reduced pressure affording 4-bromo-2-fluoro-5-methyl-N-(methylsulfonyl)benzamide (13.02 g, 42.0 mmol, 99 % yield) as an off-white foamy solid. MS m/z: [M+l]+= 309.9
4-bromo-3-methoxy-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
STEP-2: 4-BROMO-3-METHOXY-N-(METHYLSULFONYL)BENZAMIDE[00242] To a solution of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (50.0 g, 216 mmol, F- Chemicals) and methane sulfonamide (24.6 g, 259 mmol, Apollo) in DCM (1.0 L) was added DMAP (79.0 g, 648 mmol) and EDC.HC1 (82.5, 432 mmol, Spectrochem). The reaction mixture was stirred at room temperature for 12h. The reaction mass was washed with 1.5 N aqueous HC1 (200 mL) and the organic layers were separated. The aqueous layer was washed with DCM (2 x 200 mL). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was dissolved in minimum DCM (100 mL) and added hexanes (about 200 mL) dropwise. The precipitates thus obtained were filtered and dried to get pure 4-bromo-3- methoxy-N-(methylsulfonyl)benzamide (51 g, 77%). TLC solvent system: 10% MeOH in EtOAc. Product's Rf: 0.1. MS (ESI +ve ion) m/z: [M+l] = 307.9. 1H NMR (300 MHz, Chloroform-;/) delta 9.05 (s, 1H), 7.67 (d, J= 8.2 Hz, 1H), 7.43 (d, J= 1.9 Hz, 1H), 7.30 (d, J= 2.0 Hz, 1H), 3.98 (s, 3H), 3.45 (s, 3H).
4-bromo-3-chloro-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.8%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
STEP-1 : 4-BROMO-3-CHLORO-N-(METHYLSULFONYL)BENZAMIDE[00300] To a solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (20 g, 84.94 mmol, Combi blocks) and methane sulfonamide (9.69 g, 101.93 mmol, Apollo) in DCM (150 mL) was added DMAP (31.26 g, 254.82 mmol) followed by EDC.HCl (32.56 g, 169.88 mmol). The reaction mixture was stirred at RT for 12 h. The crude reaction mixture was diluted with DCM (100 mL) and washed with 1.5 N aqueous HC1 (50 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was dissolved in DCM (25 mL) and hexane (50 mL) was added drop-wise with stirring. The precipitate thus obtained was filtered and dried to afford 4-bromo- 3-chloro-N-(methylsulfonyl)benzamide (22 g, 82.8%). MS (ESI -ve ion) m/z: [M-l] = 310.12. 1H NMR (400 MHz, DMSO-d6) delta 12.42 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.80 (dd, J= 8.4, 2.0 Hz, 1H), 3.43 (s, 3H).
3-bromo-4-iodo-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
STEP 1 : 3-BROMO-4-IODO-N-(METHYLSULFONYL)BENZAMIDE (INTERMEDIATE D)[00338] A suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.586 g, 3.06 mmol), 4-(dimethylamino) pyridine (0.561 g, 4.59 mmol), methanesulfonamide (0.128 ml, 1.835 mmol) and <strong>[249647-25-4]3-bromo-4-iodobenzoic acid</strong> (0.5 g, 1.529 mmol, HDH Pharma) was shaken at ambient temperature for 16 h. The reaction mixture was purified by reverse phase HPLC using water and acetonitrile and TFA as modifier to obtain Intermediate D (0.268 g, 0.663 mmol, 43.4 % yield) as a white sticky, solid. MS (ESI, positive ion) m/z 405.0.
(3R,4S,5S,8S,9S,10S,11R,13R,14S,16S,Z)-3,11-dihydroxy-4,8,10,14-tetramethyl-17-(6-methyl-1-(methylsulfonamido)-1-oxohept-5-en-2-ylidene)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate[ No CAS ]
(S)-tert-butyl (3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With dmap; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 100h;
[0010141 Prepared using General Procedure 7. To a stirring solution of (S)-3-(4- bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 g, 2.91 mmoi) in DCM (20 rnL) was added methanesulfonamide (2.76 g, 29.1 rnmol), DIEA (2.53 ml, 14.53 mmol) and DMAP (0.710 g. 5.81 rnmol) followed by EDC (0.780 g, 4.07 mrnol). After 100 h, the mixture was filtered, diluted with DCIVI (30 mL) and washed with saturated aqueous NH4QI (50 mL). The organics were dried over MgSO4 and solvents evaporated to afford 1.154 g (94percent) of (S)-tert-butyl (3-(4-bromophenyl)-1-(methylsulfonamido)-1- oxopropan-2-yl)carbamate. LCMS-E SI (in/z) calculated for C15H21 BrN2O5S: 420.0; found 443.1 [M+Na], tp. = 2.19 mm (Method 11).
In the reaction vessel was added 1,4-butanediol (2) 0.15mol, triethylamine 170ml, the temperature of the solution is reduced to 5 , controlling the stirring speed 160rpm, methanesulfonic acid was slowly added to the amine (3) 0.38mol, dropwise Upon completion, the solution temperature rises to 40 , stirred for 4h, the temperature of the solution is reduced to 20 , the precipitated solid was filtered, washed with sodium nitrite solution, dried over anhydrous magnesium sulfate, recrystallized from cyclohexane to 95% (mass fraction), as a white solid of 1,4-bis-methyl sulfonate polybutyleneterephthalate 33.58g, yield 91%.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 25℃;Inert atmosphere;
To a solution of compound 1-a-2 (26 g, 0.112 mmol)Methanesulfonamide (16.34 g, 0.172 mol), EDCI (32.93 g, 0.172 mol)DMAP (21 g, 0.172 mol) was added dichloromethane (270 ml)N2 protection,Room temperature overnight,Water (100ml) quenched,HCl (1 M) adjusted to pH 1 to 2, DCM (3 x 150 ml),Saturated brine (100 ml)Sodium sulfate,filter,The filtrate was spin-dried to give the white solid compound 1-a-3 (22.5 g, 65% yield). ESI-MS: 310.7 (M + H) +.
With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); 3-cyano-1-methylquinolinium cation; In acetonitrile; at 20℃; for 5h;Inert atmosphere; Irradiation; Green chemistry;
In order to 1 - methyl -3 - cyano quinoline salt as a photosensitizer, to cobalt wo complex 2 makes the cobalt catalyst, 5 ml acetonitrile is added in 2.69 mg (1 × 10-2Mmol) photosensitizer and 2.80 mg (6 × 10-3Mmol) of the cobalt catalyst, the air thickness of cylinder Ar atmosphere, then adding 0.2 mmol benzene (R1, R2, R3, R4For independent of H) and 0.4 mmol a sulfonamide (CH R is3). At room temperature, high-pressure mercury lamp irradiation 5 h. After the reaction, GC (TCD) for detecting H2The output, GC (FID) for the conversion of the examination benzene, then column separation. Nuclear magnetic hydrogen and mass spectrometry identification of product is N - phenyl a sulfonamide. The conversion of benzene is 39%, N - phenyl methanesulfonamide yield is 29%, H2The yield is 24%.
N-(methylsulfonyl)phenazine-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
General procedure: To a stirred solution of 17 (0.05g, 0.21mmol) in DMF (5mL) and CH2Cl2 (5mL) added 1,1?-carbonyldiimidazole (0.07g, 0.41mmol) and 4-dimethylaminopyridine (2.0mg, 0.02mmol) under an N2 atmosphere. The mixture was stirred at 70C for 2h, and cooled to room temperature. Triethylamine (0.06mL, 0.41mmol) and methanesulfonamide (0.04g, 0.41mmol) were added, the mixture was stirred at 70C for 48h, and the solvents were evaporated in vacuo. The residue was acidified using hydrochloric acid (1N) and the yellow precipitated was filtered and dried under vacuum. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (50:1) as eluent to afford the title compound as a yellow solid (28mg, 22%).
4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
General procedure: To a solution of 15 6 (60mg, 0.2mmol) in 57 CH2Cl2 (4mL) were added EDCI (58mg, 0.3mmol) and 16 DMAP (4 mg, 0.03mmol). The solution was stirred at room temperature for 0.5h and compound 715 (97mg, 0.18mmol) was added. The resulting mixture was stirred for another 8h and 58 water was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under vacuo. The residue was prified by chromatography (CH2Cl2/CH3OH 40:1) to provide 17 8 as white solid (108mg, 73%).
With hydrogenchloride; formaldehyd;Zinc chloride; In 1,4-dioxane;
Preparation JJ1 [5-(Methanesulfonylamino-methyl)-thiophen-2-yl]-acetic acid methyl ester To a solution of thiophen-2-yl-acetic acid methyl ester (2 mL, 12.8 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL, 4.8 mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) was added and the reaction was lowered into a pre-heated water bath at 45 C. and was stirred for 15 minutes. HCl (g) was bubbled into the solution for 2-3 minutes. The temperature of the reaction rose to about 60 C. Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was added dropwise and the temperature rose to 70 C. The reaction was cooled to room temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added in portions. The reaction was stirred for 3 h and was poured into EtOAc (60 mL). The organic solution was washed with water and the aqueous solution was washed with EtOAc (60 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3) provided the title compound (69%) as a gold oil. 1H NMR (400 MHz, CDCl3) delta6.85 (d, 1H), 6.70 (d, 1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s, 3H).
With dichloro bis(acetonitrile) palladium(II); silver(I) acetate; In 1,4-dioxane; dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: Under the argon atmosphere, a Schlenk tube (15 mL) equipped with a magnetic bar was loaded with the sulfonamide 1 (0.5 mmol), sodium arylsulfinates 2 (0.6 mmol, 1.2 equiv.), Pd(MeCN)2Cl2 (6.5 mg, 5 mol%) and AgOAc (166.9 mg, 1.0 mmol) in one portion. Then, the mixture of 1,4-dioxane/DMSO (3.5 mL in a 9:1 ratio) was added to obtain a clear solution and the reaction mixture was allowed to stir at 120 C for 24 h. After cooling to room temperature, the mixture was filtered through a short celite pad and washed with dichloromethane (15 mL 3). The filtrate was concentrated and the oily crude product was purified by column chromatography using silica gel (200-300 mesh) as stationary phase and a petroleum ether and ethyl acetate (3/1) as eluent to give the N-aryl sulfonamides 3 in noted yields.
tert-butyl (S)-3-((methylsulfonyl)carbamoyl)morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
(S)-N-Boc-3-morpholinecarboxylic acid (2g, 8.65mmol), CDI (2.1g, 12.98mmol) and anhydrous THF (40mL) were added to the reaction flask, and the reaction was carried out at 70 C for 5 hours under nitrogen atmosphere. The temperature was lowered to 5 C, and methanesulfonamide (1 g, 10.38 mmol) and DBU (1.98 g, 12.98 mmol) were added in that order, and the reaction was carried out at 25 C for 12 hours. The reaction mixture was concentrated and DCM (200 mL) was dissolved. The mixture was washed with EtOAc(30 mL), filtered to give a white solid (1.98g, 74%).
benzyl 3-(methylsulfonylcarbamoyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of <strong>[97628-92-7]1-benzyloxycarbonylazetidine-3-carboxylic acid</strong> (500 mg, 2.13 mmol) and CDI (414 mg, 2.55 mmol) in DMF (5 mL) was heated at 65 °C with stirring for 1 hr. The resulting mixture was cooled to 0 °C, then to the cooled mixture was added a mixture of NaH (510 mg, 12.7 mmol) and methanesulfonamide (607 mg, 6.38 mmol) in DMF (5 mL). The resulting mixture was warmed to rt and stirred for 1 hr, then neutralized with formic acid and extracted with EA (200 mL). The organic layer was washed with brine, dried over anhydrous Na2SC"4 and concentrated in vacuo to afford benzyl 3-(methylsulfonylcarbamoyl)azetidine-1-carboxylate (900 mg, crude) as a colorless oil, which was used in the next step without any further purification.
benzyl 3-(methylsulfonylcarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.2 g
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h;
To a solution of <strong>[188527-21-1]1-benzyloxycarbonylpyrrolidine-3-carboxylic acid</strong> (2.0 g, 8.02 mmol) in DCM (20 mL) was added a solution of N,N'-dicyclohexylcarbodiimide (2.48 g, 12.03 mmol) in DCM (5 mL), followed by addition of methanesulfonamide (763 mg, 8.02 mmol) and 4- dimethylaminopyridine (980 mg, 8.02 mmol). The mixture was stirred at rt for 16 hrs, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by columnchromatography (eluting with DCM/MeOH=40/l, v:v) to give benzyl 3- (methylsulfonylcarbamoyl)pyrrolidine-1-carboxylate (2.2 g) as a white solid.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
To a solution of <strong>[183062-96-6]2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid</strong> (2.0 g, 9.3 mmol) in DCM (20 mL) was added methanesulfonamide (1.06 g, 11.1 mmol), TBTU (4.47 g, 13.95 mmol) and DIPEA (2.4 g, 18.6 mmol). The mixture reaction was stirred at r.t. overnight. The mixture was extracted with 0.1N HC1, then the acidic water was extracted with DCM and the dichloromethane solution was dried over Na2S04, filtered and concentratedto give crude product, which was purified by flash chromatography (silica gel, 0 to ~2% MeOH in DCM) to give tert-butyl 3-formylazetidine-1-carboxylate as yellow oil (1.3 g). LC-MS (ESI) found: 237 [M+l-56]+.
With potassium phosphate; copper(l) iodide; dimethylaminoacetic acid; In N,N-dimethyl acetamide; at 100℃; for 2h;Inert atmosphere;
A flask was charged with <strong>[182056-39-9]2-bromo-4-iodoanisole</strong> (1.0 g, 3.0 mmol), methanesulfonamide (1.4 g, 15 mmol), cuprous iodide (590 mg, 3.03 mmol), NN- dimethylglycine (319 mg, 3.03 mmol) and potassium phosphate tribasic (1.3 g, 6.1 mmol) and the flask was purged with nitrogen. X.X- Di methyl acetami de (10 mL) was then added and the reaction was stirred at 100 C for 2 hours. The reaction mixture was diluted with water (10 mL) and 10% aqueous glycine (10 mL) and acidified to pH = 1 with 1N HC1, extracted with z-PrOAc (3 x 10 mL), dried with anhydrous MgSCf. concentrated and purified by silica gel column chromatography (0% to 100% z-PrOAc in heptane) to give the title compound as a white solid (598 mg, 70% yield). LCMS (ESI+) m/z 280 (M+H)+
N-(methanesulfonyl)-1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; triethylamine; In ethyl acetate; toluene; at 60℃; for 1.5h;
15. To a solution of alkylsulfonamide or arylsulfonamide (Compound 2 in Scheme 8a, 0.69 mmol) in ethyl acetate (1 mL) were added triethylamine (175.4 mg, 1.734 mmol), DMAP (4.28 mg, 0.035 mmol) and a solution of 1,3-dihydro-1,3-dioxoisobenzofuran-5-carbonylchloride (Compound 1 in Scheme 8a, 160 mg, 0.7627 mmol) in toluene (6 mL). The reaction mixture was stirred at 60C for 1.5h. The solvent was evaporated and dried under vacuum to give crude 5-(sulfonylaminocarbonyl)-1,3-dioxo-1,3-dihydro-2-benzofuran (Compound 3 in Scheme 8a).
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