* 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.
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
[2] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
2
[ 107106-62-7 ]
[ 754-10-9 ]
[ 630-22-8 ]
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
[2] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
3
[ 754-10-9 ]
[ 630-22-8 ]
Yield
Reaction Conditions
Operation in experiment
65%
With Lawessons reagent In tetrahydrofuran at 80℃; for 4 h; Inert atmosphere
To a round bottom flask (250 mL) was added trimethyl amine (5.0 g, 0.049 mol) and Lawesson's reagent (8.0g, 0.020 mol), dissolved in THF (100 mL), nitrogen, 80° C oil The reaction bath for 4 hours.The reaction progress monitored by TLC.After completion of the reaction, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography (petroleum ether: 1: ethyl acetate = 10) to give a white solid (3.7 g, 65percent yield).
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 29, p. 9655 - 9662
[2] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
[3] Patent: CN103936728, 2016, B, . Location in patent: Paragraph 0211; 0213; 0214; 0215
[4] Canadian Journal of Chemistry, 1977, vol. 55, p. 2331 - 2335
[5] Journal of the Chemical Society [Section] C: Organic, 1966, p. 686 - 691
[6] Patent: WO2016/82930, 2016, A1, . Location in patent: Page/Page column 21-22
[7] Patent: WO2009/144494, 2009, A1, . Location in patent: Page/Page column 93
4
[ 630-18-2 ]
[ 630-22-8 ]
Reference：
[1] Synlett, 2009, # 14, p. 2338 - 2340
[2] Synthetic Communications, 2006, vol. 36, # 3, p. 295 - 298
[3] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 410 - 418
5
[ 107106-62-7 ]
[ 754-10-9 ]
[ 630-22-8 ]
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
[2] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 169 - 184
6
[ 630-22-8 ]
[ 1166227-08-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3569 - 3574
7
[ 630-22-8 ]
[ 1195768-20-7 ]
[ 1195768-23-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With N-Bromosuccinimide In dichloromethane at 10 - 20℃; Stage #2: at 10 - 75℃; for 2.5 h;
Step C: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide To a reactor vessel was charged /V-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2,2- Dimethylpropanethioamide (1 .3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1 .75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonannide (28.8 g, 80percent).
80%
Stage #1: With N-Bromosuccinimide In dichloromethane at 10 - 20℃; Stage #2: at 10 - 75℃; for 2.5 h;
To a reactor vessel was charged N- {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80percent).
80%
Stage #1: With N-Bromosuccinimide In dichloromethane at 10 - 20℃; Stage #2: at 20 - 75℃; for 3.16667 h;
Step C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3-thiazol-4-yl]- 2-fluorophenyl}-2,6-difluorobenzenesulfonamide To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80percent).
80%
Stage #1: With N-Bromosuccinimide In dichloromethane at 0.2 - 10℃; Stage #2: at 10 - 75℃; for 2.5 h;
Ste C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide: To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2,2- Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours. The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25 °C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50 °C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0 °C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N- {3-[5-(2-chloro-4-pyrimidinyl)- 2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80percent).
64%
Stage #1: With N-Bromosuccinimide In N,N-dimethyl acetamide at 20℃; for 0.25 h; Stage #2: at 20 - 80℃;
Intermediate 18: N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) was added and the solution was allowed to stir 15 min at rt. 2,2-dimethylpropanethioamide (0.531 g, 4.53 mmol) was then added at rt. The reaction was heated to 60° C. for 2 hours. The reaction was not complete by LC-MS. The reaction mixture was then heated to 80° C. for an additional hour. The reaction mixture was diluted with water and extracted.x.2 with EtOAc. The combined EtOAc washings were washed with water.x.3 to remove DMA, dried over MgSO4, filtered and concentrated onto silica gel. The crude material was chromatographed in 10-80percent EtOAc in Hexanes to give the desired product, 1.6 g (64percent). MS (ESI): 539.1 [M+H]+.
55%
Stage #1: With N-Bromosuccinimide In N,N-dimethyl acetamide at 20℃; for 1 h; Stage #2: at 20 - 60℃;
N-Bromosuccinimide (80mg, 0.45mmol) was added to a solution of /V-(3-(2-(2- chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0253) (200. Omg, 0.45mmol) in dimethylacetamide (2mL). The reaction mixture was stirred at room temperature for lh then 2,2,2-Trimethylthioacetamide (58mg, 0.49mmol) was added. After stirring at room temperature for lh, the medium was stirred at 60°C. Once the reaction was complete, the medium was partitioned between water and EtOAC. The aqueous layer was extracted with EtOAc. Combined organics were washed with water and brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography on silica gel (cHex/EtOAc, 1/0 to 0/1) afforded the title compound (135mg, 55percent). LC/MS (ES+): 539.2-541.2 (M+l).
70 g
Stage #1: With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 3 h; Stage #2: With β-cyclodextrin In dichloromethane; N,N-dimethyl acetamide; ethyl acetate at 0 - 80℃; for 3 h;
N-{3-[(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} -2, 6-difluorobenzenesulfonamide (100 g) was added to dichloromethane (1000 ml) and the reaction mixture was cooled to 0-10 °C. To this, N-bromosuccinimide (40.3 g) was added in 3 equal portions. After the addition of N-bromosuccinimide, the reaction mixture was heated to 20 °C and stirred for 1-3 hours. Water was added to the reaction mixture and the organic and aqueous layers were separated. Dichloromethane was added to the aqueous and the layers were again separated. The combined organic layer was concentrated to a volume of 400 ml. To this, ethyl acetate (700 ml) was added and the reaction mixture was concentrated to a volume of 400 ml. Dimethylacetamide (900 ml) and β-cyclodextrin (100 g) were added to the reaction mixture and cooled to 0-10 °C. To this, 2, 2-dimethylpropanethioamide (26.6 g) was added in 3 equal portions. The reaction mixture was warmed to 20-30 °C and stirred. The reaction was further heated to 70-80 °C and stirred for 1-3 hours. The reaction mixture was cooled to 0-10 °C and water (900 ml) was slowly added at 0- 10 °C. To this, ethyl acetate (400 ml) was added and the pH of reaction mass was adjusted to 6.0-8.0 with aqueous ammonia solution. The reaction mixture was stirred and the layers were separated. Ethyl acetate was added to the aqueous layer and the layers were again separated. The combined organic layers were washed with twice with water. The organic layer was treated with activated charcoal (10 g), filtered, and washed with ethyl acetate (100 ml). The filtrate was then concentrated under vacuum at 30-50 °C. To this, ethyl acetate (400 ml) was added and the reaction mass was heated to 50-60 °C. Heptanes (400 ml) were slowly added to the reaction mixture at 50-60 °C. After addition of heptanes, the reaction mass was heated to reflux then cooled to 0-10 °C and maintained for 2-4 hours at same temperature. The solid was filtered and washed with heptanes (200 ml) and dried under vacuum at 30-60 °C to get formula-Ill (N-{3-[5- (2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide) (70 g).
To a reactor vessel was charged A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 ml_). The reaction slurry was cooled to ~10°C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 ml_. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 ml_. Dimethylacetamide (270 ml_) was then added to the reaction mixture and cooled to ~10°C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 ml_. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 ,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80percent).
With Lawessons reagent; In tetrahydrofuran; at 80℃; for 4h;Inert atmosphere;
To a round bottom flask (250 mL) was added trimethyl amine (5.0 g, 0.049 mol) and Lawesson's reagent (8.0g, 0.020 mol), dissolved in THF (100 mL), nitrogen, 80 C oil The reaction bath for 4 hours.The reaction progress monitored by TLC.After completion of the reaction, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography (petroleum ether: 1: ethyl acetate = 10) to give a white solid (3.7 g, 65% yield).
With Lawessons reagent; at 70℃; for 4h;
Synthesis of 2,2-dimethylpropanethioamide (INT-2a) To a stirred solution of pivalamide (INT-1 a, 5.0 g, 49.43 mmol, 1.0 eq) in THF (150 mL) was added Lawesson's reagents (29.9 g, 74.1 mmol, 1.5 eq) and the RM was stirred at 70C for 4 h. The RM was concentrated, diluted with Et20 (30 mL) and washed with NaHC03 solution (30 mL), the organic layer was dried over MgS04 and concentrated under reduced pressure. The crude was washed with hexane (25 mL) to get 2,2-dimethylpropanethioamide (INT-2a, 4.0 g, 70%) which was used without further purification. TLC system: EtOAc/PE (7:3), Rf: 0.6
With tetraphosphorus decasulfide; In tert-butyl methyl ether; at 20℃;
Example 432-tert-butyl-N-((ls,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5- fluoronicotinamido)cyclohexyl)thiazole-4-carboxamide Step (a) 2,2-dimethylpropanethioamidePhosphorus (V) sulfide (1.330 mL, 12.51 mmol) was added to a stirred suspension of pivalamide (5 g, 49.43 mmol) in methyl t-butyl ether (100 mL) and the reaction stirred over the weekend at RT. The mixture was filtered through celite and evaporated in vacuo to give the sub-title compound as a yellow gummy solid. Yield: 9.27 g1U NMR (300 MHz, CDCl3) 5 7.86 (s, IH), 7.16 (s, IH), 1.32 (s, 9H).MS: [M+H]+=118 (MultiMode+)
With Lawessons reagent; In tetrahydrofuran; for 4h;Reflux; Inert atmosphere;
A solution of 2,2-dimethylpropanamide 1a (1 g, 9.8 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (1.98 g, 4.9 mmol) in THF (15 mL)was heated to reflux for 4 h. The reaction mixture was then cooledto room temperature and poured into a saturated aqueous solutionof NaHCO3 (50 mL). The mixture was extracted with ether (35 mL)and the organic layer was dried over anhydrous MgSO4 then evaporated under reduced pressure giving the desired whitepowder 1b that was used without further purification in a yield of78.9%; mp: 117e119 C [39].
Stem 3 Preparation of 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl) thiazole; To a solution of 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole from Step 2 (0.110 g, 0.31 mmol) in methylene chloride (5 mL) at 0 C. was added MCPBA (67 % peroxide content MCPBA) (0.080 g, 0.62 mmol initially) and the reaction was warmed to room temperature. Additional MCPBA was added (0.020 g, 0.15 mmol) later that day, more (0.040 g, 0.31 mmol) on day 4, and more (0.020 g, 0.15 mmol) later on day 4. The crude reaction mixture was diluted with methylene chloride (50 mL) and the resulting solution was washed successively with NaHSO3 solution (0.1M), NaHCO3 saturated solution and brine, dried over Na2 SO4, filtered and concentrated in vacuo. The crude product was recrystallized from methylene chloride and isooctane yielding 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole as a white powder (0.059 g, 49%): mp 144-145 C. 1 H-NMR (CDCl3) 400 mHz delta7.87 (d, J=8.30 Hz, 2H), 7.51-7.45 (m, 4H), 7.00 (t, J=8.79, 2H), 3.08 (s, 3H), 1.50 (s, 9H). MS (EI): m/z 390 (MH+). HRMS Delta=1.9 mmu.
34
(R)-α-(t-butyldimethylsilyloxy)-α-(3-chlorophenyl)acetaldehyde[ No CAS ]
[ 630-22-8 ]
N-[(1E)-2-[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethylidene]-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(II) sulfate; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
To a solution of 3.0 g (10.6 mmol) of [tert-butyl (dimethyl)silyl]oxy}(3-chlorophenyl)acetaldehyde (from Step C) and 1.3 g (10.6 mmol) of (R or S)-2-methyl-2-propanesulfinamide in 50 mL anhydrous dichloromethane was added copper(II) sulfate (3.4 g, 21.2 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Wash reaction with water and extract with dichloromethane. Dry the organics with magnesium sulfate, filter and concentrate under vacuum. The residue was purified by Horizon MPLC, with a 40M+ silica gel column, eluting with a gradient eluent system of 0-25% ethyl acetate in hexane to afford the title compound (3.26 g, 80%). %). m/z (ES) 387, 390 (M, M+2)+.
Intermediate 9: N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide; To a solution of N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.0 g, 2.4 mmol) in 25 mL DMA, NBS (0.420 g, 2.4 mmol) was added and the solution was allowed to stir 15 minutes at rt. 2,2-Dimethylpropanethioamide (0.277 g, 2.359 mmol) was then added and the reaction mixture was heated at 80 C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water×3. The organic layer was dried over MgSO4 and filtered. The organic solution was evaporated onto silica gel and chromatographed. 0-50% EtOAc in DCM to give the title compound (1.01 g, 81% yield). ES-LCMS m/z 521.1 (M+H).
Step C: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide To a reactor vessel was charged /V-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10C. 2,2- Dimethylpropanethioamide (1 .3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1 .75 hours . The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonannide (28.8 g, 80%).
80%
To a reactor vessel was charged N- {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1.75 hours . The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
80%
Step C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3-thiazol-4-yl]- 2-fluorophenyl}-2,6-difluorobenzenesulfonamide To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1.75 hours . The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
80%
Ste C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide: To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10C. 2,2- Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1.75 hours. The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25 C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50 C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0 C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain N- {3-[5-(2-chloro-4-pyrimidinyl)- 2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
80%
To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10C. 2,2- Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1.75 hours. The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain N- {3-[5-(2-chloro-4-pyrimidinyl)- 2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
64%
Intermediate 18: N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) was added and the solution was allowed to stir 15 min at rt. <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (0.531 g, 4.53 mmol) was then added at rt. The reaction was heated to 60 C. for 2 hours. The reaction was not complete by LC-MS. The reaction mixture was then heated to 80 C. for an additional hour. The reaction mixture was diluted with water and extracted×2 with EtOAc. The combined EtOAc washings were washed with water×3 to remove DMA, dried over MgSO4, filtered and concentrated onto silica gel. The crude material was chromatographed in 10-80% EtOAc in Hexanes to give the desired product, 1.6 g (64%). MS (ESI): 539.1 [M+H]+.
55%
N-Bromosuccinimide (80mg, 0.45mmol) was added to a solution of /V-(3-(2-(2- chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0253) (200. Omg, 0.45mmol) in dimethylacetamide (2mL). The reaction mixture was stirred at room temperature for lh then 2,2,2-Trimethylthioacetamide (58mg, 0.49mmol) was added. After stirring at room temperature for lh, the medium was stirred at 60C. Once the reaction was complete, the medium was partitioned between water and EtOAC. The aqueous layer was extracted with EtOAc. Combined organics were washed with water and brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography on silica gel (cHex/EtOAc, 1/0 to 0/1) afforded the title compound (135mg, 55%). LC/MS (ES+): 539.2-541.2 (M+l).
70 g
N-{3-[(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} -2, 6-difluorobenzenesulfonamide (100 g) was added to dichloromethane (1000 ml) and the reaction mixture was cooled to 0-10 C. To this, N-bromosuccinimide (40.3 g) was added in 3 equal portions. After the addition of N-bromosuccinimide, the reaction mixture was heated to 20 C and stirred for 1-3 hours. Water was added to the reaction mixture and the organic and aqueous layers were separated. Dichloromethane was added to the aqueous and the layers were again separated. The combined organic layer was concentrated to a volume of 400 ml. To this, ethyl acetate (700 ml) was added and the reaction mixture was concentrated to a volume of 400 ml. Dimethylacetamide (900 ml) and beta-cyclodextrin (100 g) were added to the reaction mixture and cooled to 0-10 C. To this, 2, 2-dimethylpropanethioamide (26.6 g) was added in 3 equal portions. The reaction mixture was warmed to 20-30 C and stirred. The reaction was further heated to 70-80 C and stirred for 1-3 hours. The reaction mixture was cooled to 0-10 C and water (900 ml) was slowly added at 0- 10 C. To this, ethyl acetate (400 ml) was added and the pH of reaction mass was adjusted to 6.0-8.0 with aqueous ammonia solution. The reaction mixture was stirred and the layers were separated. Ethyl acetate was added to the aqueous layer and the layers were again separated. The combined organic layers were washed with twice with water. The organic layer was treated with activated charcoal (10 g), filtered, and washed with ethyl acetate (100 ml). The filtrate was then concentrated under vacuum at 30-50 C. To this, ethyl acetate (400 ml) was added and the reaction mass was heated to 50-60 C. Heptanes (400 ml) were slowly added to the reaction mixture at 50-60 C. After addition of heptanes, the reaction mass was heated to reflux then cooled to 0-10 C and maintained for 2-4 hours at same temperature. The solid was filtered and washed with heptanes (200 ml) and dried under vacuum at 30-60 C to get formula-Ill (N-{3-[5- (2-chloro-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide) (70 g).
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}carbamate (30 g, 85.9 mmol) in DMA (300 ml_), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (1 1 .0 g, 94.5 mmol) was added at 0 C. The mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc (200 ml_ x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel(DCM etroleum ether 2:1 ) to afford the title compound. 1 1 g (35.4 % yield) 1 H NMR (400 MHz, CDCI3) delta ppm 8.29 (d, J=5.27 Hz, 1 H), 8.12-8.19 (m, 1 H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1 H), 5.20-5.37 (m, 2H), 4.61 -4.67 (m, 2H). MS (ES+): 447 [M+H]+ .
35.4%
Intermediate 23: 2-Propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate; To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (30 g, 85.9 mmol) (Intermediate 20) in DMA (300 mL), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (11.0 g, 94.5 mmol) was added at 0 C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (11 g, 35.4% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.29 (d, J=5.27 Hz, 1H), 8.12-8.19 (m, 1H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1H), 5.20-5.37 (m, 2H), 4.61-4.67 (m, 2H). MS (ES+): 447 [M+H]+.
2.92 g
With N-Bromosuccinimide; In N,N-dimethyl acetamide; at 60℃;
at room temperature, to dimethylacetamide (35mL) in a (3- (2- (t-butyl) -5- (2-chloro-pyrimidin-4-yl) thiazol-4-yl) -2-fluorophenyl ) allyl carbamate (3.21g, 9.18mmol, 1.0eq.) was added N- succinimide (1.64g, 9.21mmol, 1.0eq.).When LCMS showed complete disappearance of the starting material, 2,2,2-trimethoxy thio acetamide (1.3g, 11.1mmol, 1.2eq.) And the reaction was heated overnight at 60 deg.] C.LCMS showed the reaction was complete.The reaction was poured into water (250mL), and extracted with ethyl acetate content.Extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure.With 20% ethyl acetate / heptane, silica gel chromatography (300g, 3 "diameter column) to give the crude product, in the form of an oil to provide (3- (2- (t-butyl) -5- (2- chloro-pyrimidin-4-yl) thiazol-4-yl) - 2-fluorophenyl) allyl carbamate (2.92g, 70% yield)
Intermediate 38: 2-Propen-1-yl {5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate; To a solution of 2-propen-1-yl {5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (35 g, 100.3 mmol in DMA, 500 mL), NBS (17.8 g, 100.3 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (13 g, 111 mmol) was added at 0 C. The mixture was stirred at 80 C. for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (36 g, 80.5% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.24-8.31 (m, 2H), 7.09-7.18 (m, 2H), 7.01 (d, J=5.5 Hz, 1H), 6.92-6.98 (br, 1H), 5.87-5.97 (m, 1H), 5.31-5.37 (m, 1H), 5.24-5.28 (m, 1H), 4.61-4.65 (m, 2H), 1.46 (s, 9H).
Example 23; N-[2-Chloro-3-(2-(1,1-dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,5-difluorobenzenesulfonamide; Step A: N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide; To a solution of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (3.0 g, 6.55 mmol) in DMA (25 mL) was added NBS (1.165 g, 6.55 mmol). After stirring for 1 h at rt, <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (0.767 g, 6.55 mmol) was added and the reaction mixture was stirred at 80 C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and extracted five times with water. The organic layer was dried over anhydrous NaSO4, adsorbed onto silica gel, and purified via column chromatography, eluting with 0-50% EtOAc/DCM. The desired fractions were combined and concentrated to generate 1.31 g (2.36 mmol, 36.0% yield) of the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): delta 10.74 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.41-7.58 (m, 6H), 6.57 (d, J=5.4 Hz, 1H), 1.42 (s, 9H). MS (ESI): 555.0 [M+H]+.
Step (b) ethyl 2-tert-butylthiazole-4-carboxylateEthyl 3-bromo-2-oxopropanoate (6.20 mL, 49.40 mmol) was added very carefully to a stirred solution of <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (5.79 g, 49.40 mmol) in ethanol (60 mL). The solution was then heated under reflux for 16h. After cooling, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate solution and evaporated in vacuo. Purification by silica gel chromatography (Biotage, 10Og) eluting with EtOAc: iso- hexane, 1 :10 gave the sub-title compound as a yellow oil. Yield: 6.56 g1U NMR (300 MHz, CDCl3) delta 8.03 (s, IH), 4.40 (q, J= 7.1 Hz, 2H), 1.48 (s, 9H), 1.39 (t, J =6.3 Hz, 3H).MS: [M+H]+=214 (MultiMode+)
To a solution of Lambda/-{5-[(2-chloro-4-pyriotamiotadiotanyl)acetyl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide (10 00 g, 22 63 mmol) prepared by a procedure analogous to Example 23, Step B in DMF (90 mL) was added NBS (4 23 g, 23 77 mmol) The reaction stirred 30 min at rt and then 2,2-diotamethylpropanethiotaoamiotade (4 64 g, 39 6 mmol) prepared by a procedure analogous to Intermediate 8 was added The reaction stirred 16 h at rt The reaction mixture was then diluted with EtOAc (700 mL) and washed with water (2 x 500 mL) The organic fraction was dried over sodium sulfate, filtered, and concentrated onto silica gel Purification by ISCO chromatography (20 to 100% EtOAc hexanes) afforded Lambda/-{5-[5-(2-chloro-4- pyriotamiotadiotanyl)-2-(1 ,1-diotamethylethyl)-1 ,3-thiotaazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide (4 12 g, 7 26 mmol, 32 1 % yield) as an off-white solid 1H-NMR (400 MHz, DMSO-Cf6) delta 11 01 (s, 1 H), 8 55 (d, J = 5 3 Hz, 1 H), 7 61 - 7 90 (m, 1 H), 7 39 - 7 54 (m, 2 H), 7 19 - 7 39 (m, 3 H), 7 12 (d, J = 5 3 Hz, 1 H), and 1 43 (s, 9 H), MS (ESI) 538 99 [M+H]+
With ammonium molybdophosphate; In methanol; at 25 - 50℃; for 92h;
Stage T.2: N-(7-tert-Butyl-4,5-dihydro-benzo[1,2-d;3,4-d']bisthiazol-2-yl)-acetamideN-(6-Bromo-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage T.3, 473 mg, 1.635 mmol) was dissolved in MeOH (10 mL), 2,2-dimethylthio propionamide (230 mg, 1.962 mmol) and ammonium phosphomolybdate (307 mg, 0.164 mmol) were added, and the RM was stirred at 25 C. for 20 h. The RM was then stood for 2 days before stirring at 50 C. for 24 h. The mixture was extracted with EtOAc/H2O. The organic layers were dried over Na2SO4 and evaporated. The crude material was chromatographed with 30 g of silica gel, eluent DCM/MeOH=99:1. Fractions containing the product were evaporated and lyophilized from dioxane to give 225 mg of the title compound as a white solid (M+H=308; M-H=306; tR 5.525 min (Method F)).
General procedure: A mixture of 3-bromocyclohexane-1,2-dione 3 (50 mg, 0.26 mmol) and pyridine-4-carbothioamide (24.1 mg, 0.17 mmol) in EtOH (0.69 mL) was heated to reflux and stirred for 15 h. The reaction mixture was diluted with DMSO (0.5 mL) to completely dissolve all solids and the resulting mixture was purified by directly injecting the reaction mixture into a preparatory HPLC (C18, water/acetonitrile/ammonium acetate buffer) to give 2-(pyridin-4-yl)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (30.4 mg, 0.13 mmol, 76%) (Table 1, entry 1).
In ISOPROPYLAMIDE; at 20 - 80℃; for 4h;Inert atmosphere;
To a solution of N-(3-(2-bromo-2-(2-(methylthio)pyrimidin-4-yl)acetyl)-2- chloro-5-fluorophenyl)-pivalamide (AT, 489 mg, 1.03 mmol) in DMA (4.7 mL) under Ar at rt was added <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (131 mg, 1.12 mmol). The reaction mixture was stirred at rt for 1 h, and then heated to and maintained at 80 C for 3 h. The reaction was judged complete by LCMS. The reaction mixture was diluted with water and twice extracted with EtOAc. The organic phases were combined, washed with brine, dried (Na2S04), and concentrated. The resulting residue was adsorbed onto silica gel and purified by flash chromatography on silica gel using an EtOAc :heptanes (0-15%) elution gradient to furnish N-(3 -(2 -tert-butyl-5 -(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-chloro-5 - fluorophenyl)pivalamide (175 mg, 0.36 mmol, 38 %) as a white foam: LCMS (m/z): 493.1 (MH+), tR = 1.42 min.
2,2-Dimethyl-thiopropionamide (1.17 g, 10.0 mmol, prepared as described on page 297, in BOYS, M, et. al., ?Preparation of Primary Thioamides From Nitriles Using Sodium Hydrogen Sulfide and Diethylamine Hydrochloride?, Synth. Commun., 200, pp 295-298) and bromomalonaldehyde (1.51 g, 10.0 mmol) in EtOH (7.0 mL) was stirred at 60 C. for 3 h. The resulting mixture was concentrated and chromatographed on an 80-g silica gel column eluting with a gradient of 0-30% EtOAc-hexane, then held at 30% EtOAc-hexane yield a residue. 1H-NMR (400 MHz, CDCl3) delta (ppm): 10.00 (s, 1H), 8.30 (s, 1H), 1.48 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C8H11NOS: 170.1 (M+H), Found 170.1.
Step 2: 2-bromo-l-(2-chloropyrimidin-4-yl)ethanone (1 eq) is dissolved inEtOH (5 mL/mmol) and <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (1.1 eq) is added and the mixture is stirred at 60 C for 2 hours. The solvent is removed under reduced pressure; the crude material is dissolved in DCM. The organic phase is washed with aq NaOH (1 N), brine, dried (MgS04) and the solvent is removed. Purification by flash silica gel chromatography using a gradient of 10-40% EtOAc/hexane affords 2-tert-butyl-4-(2-chloropyrimidin-4- yl)thiazole.
To a solution of 2-propen-1 -yl {2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}carbamate (1 .4 g, 3.82 mmol) in N,N- dimethylacetamide (DMA) (10 ml) was added NBS (0.714 g, 4.01 mmol). After 30min at room temperture; the reaction mixture was charged with 2,2- dimethylpropanethioamide (0.672 g, 5.73 mmol) and stiired at roomtemperature overnight. The reaction was then heated to 60 C for 2 h. The reaction mixture was charged with EtOAc and H2O. The EtOAc layer was washed with water, brine, and concentrated. The residue waschromatographed on a silica gel column and eluted with EtOAc/hexanes to obtain 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (1 .17 g, 59.4 % yield).
To a solution of 2-propen-1 -yl [2-fluoro-3-(4-pyridinylacetyl)phenyl]carbamate (2.2 g, 7.00 mmol) in Lambda/,/V-dimethylacetamide (DMA) (25 ml_) was added N- bromosuccinimide (NBS) (1 .495 g, 8.40 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 h. 2,2-Dimethylpropanethioamide (0.985 g, 8.40 mmol) was added at room temperature and the mixture was stirred at 60 C for 1 .5 h. The reaction mixture was quenched with water and ethyl acetate. The organic layer was separated, washed with water, dried over MgSO4, filtered and evaporated. The red oil was purified by flash column chromatography on silica gel (100 % EtOAc). 2-Propen-1 -yl {3-[2- (1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (200 mg, 0.486 mmol, 6.94 % yield) was isolated as white foam. 1 H NMR (400 MHz, DMSO-c/e) ppm 1 .46 (s, 9 H) 4.58 (dt, J=5.31 , 1 .39 Hz, 2 H) 5.22 (dd, J=10.48, 1 .64 Hz, 1 H) 5.34 (dd, J=17.18, 1 .77 Hz, 1 H) 5.84 - 6.04 (m, 1 H) 7.13 - 7.29 (m, 4 H) 7.66 - 7.84 (m, 1 H) 8.40 - 8.57 (m, 2 H) 9.46 (s, 1 H); HPLC Rt= 2.95 min, MS (ESI): 412.1 [M+H]+.
General procedure: A mixture of 60 (5.4g, 35.0mmol), pyridine (11.4ml, 140mmol), and diethyl bromomalonate (3) (8.84ml, 52.5mmol) in EtOH (15ml) was heated under reflux for 16h. The mixture was concentrated under reduced pressure and H2O was added to the residue. The resulting precipitate was removed by filtration and washed with Et2O to deliver ethyl 2-(2-aminopyrimidin-4-yl)-4-hydroxythiazole-5-carboxylate (5.30g, 19.9mmol, 57% yield) as a tan solid.
N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide[ No CAS ]
[ 1195768-23-0 ]
Yield
Reaction Conditions
Operation in experiment
28.8 g
In N,N-dimethyl acetamide; ethyl acetate; at 10 - 75℃;
To a reactor vessel was charged A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 ml_). The reaction slurry was cooled to ~10C and N-bromosuccinimide ("NBS") (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20C and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 ml_. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 ml_. Dimethylacetamide (270 ml_) was then added to the reaction mixture and cooled to ~10C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 C. After 45 min, the vessel contents were heated to 75C and held for 1.75 hours . The reaction mixture was then cooled to 5C and water (270 ml) was slowly charged keeping the temperature below 30C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25C. The organic layers were then concentrated under heat and vacuum to 120 ml_. The vessel contents were then heated to 50C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30C to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 ,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
To a suspension of <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (35, 3.52 g, 30.0 mmol, 1.00 equiv) in toluene (30 mL) was added ethyl glyoxalate solution (50 wt% in toluene, 11.9 mL, 60.0 mmol, 2.00 equiv). The mixture was heated to 60 C, held for 1 h, then cooled to 25 C and concentrated in vacuo. The resulting crude hemiaminal intermediate was dissolved in CH3CN (40 mL), and pyridine (12.15 mL, 150 mmol, 5.00 equiv) was added. The solution was cooled to 0 C and acetyl chloride (4.26 mL, 60.0 mmol, 2.00 equiv) was added over 30 min while maintaining the temperature below 10 C. The mixture was warmed to 25 C over 30 min, and the resulting solution of crude imine intermediate was transferred over 5 min to a 50 C solution of sodium cyanide (7.34 g, 150 mmol, 5.00 equiv) in H2O (40 mL). The mixture was stirred for 30 min at 50 C, then cooled to 25 C and isopropyl acetate (50 mL) was added, followed by H2O (40 mL). The layers were separated and the organic extract was washed with H2O (40 mL) and NH4Cl (sat, aq, 40 mL). The latter aqueous extracts were combined and washed with isopropyl acetate (30 mL). The combined organic extracts were washed with NaCl (sat, aq, 30 mL), dried over MgSO4 (anh), and filtered. The filtrate was concentrated in vacuo and then purified by flash chromatography (heptane/isopropyl acetate 100:0 ? 80:20 ? 50:50) to provide the title compound as a brown solid. The crude product was dissolved in EtOH (15 mL) at 70 C, cooled to 25 C over 2 h, and then held for 30 min. The resulting crystals were filtered, washed with EtOH (5 mL) and heptane (5 mL), and dried in vacuo under N2 purge at 70 C to furnish 36 as white crystals. Yield: 3.54 g (52%).
methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)propanoate[ No CAS ]
methyl 2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
In methanol;Reflux;
Synthesis of methyl 2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii) To a stirred solution of methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy) (INT-6, 1.0 g, 2.6 mmol, 1.0 eq) in MeOH (10 mL) was <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (INT-2a, 0.367 g, 3.1 mmol, 1.2 eq) and the RM was heated to reflux for 16 h. The RM was concentrated under reduced pressure and the crude was purified by silica gel (100-200 mesh) column chromatography using EtOAc/PE (1 :9) as eluent to get methyl 2- (tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii, 0.450 g, 55 %). TLC system: PE (2:3), Rf: 0.55
2-(tert-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.6 g
In N,N-dimethyl acetamide; at 20 - 60℃; for 3.5h;
By mechanical stirring (33.9g, 152mmol, 1.9equiv) was suspended / dissolved bromide, copper (II) in ethyl acetate (75mL) in.Was then added in CHCl3Form (75mL) solution of 1- (2-fluoro-3-nitrophenyl) ethanone (14.4g, 80.0mmol, 1equiv), and the reaction was heated to reflux for 24 hours.The reaction was cooled to room temperature and filtered through a silica gel short blocks, washed with ethyl acetate.The filtrate was evaporated, leaving crude 2-bromo-1- (2-fluoro-3-nitrophenyl) ethanone, it is dissolved in dimethyl acetamide (150 mL) and 2,2-dimethyl thioamide propane (10.3g, 88.0mmol, 1 equiv) in.The reaction was stirred at room temperature for 1.5 hours.The reaction was heated to 60 2 hours, cooled to room temperature, and washed with water (300mL) was diluted.(2x200mL) and the mixture extracted with 15% MTBE in heptane.The combined organic layers were washed with brine, in Na2SO4Dried, filtered and evaporated.Using 0-15% ethyl acetate in heptane eluting crude material was purified by silica gel column chromatography.The component containing the product was evaporated to give an off-white solid of 2- (t-butyl) -4- (2-fluoro-3-nitrophenyl) thiazole (15.6g, 70% yield in two steps )
N-(3-(2-bromo-2-(pyridazin-4-yl)acetyl)-2-fluorophenyl)-2,6-fluorobenzenesulfonamide[ No CAS ]
N-(3-(2-tert-butyl-5-(pyridazin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.1%
at 50℃; for 2h;
To the above reaction solution was added <strong>[630-22-8]2,2-dimethyl-thiopropionamide</strong> (1.8 g, 0.015 mol), was heated to 50 deg.] C oil bath for 2 hours.After completion of the reaction, the solution was added water (150 mL) and ethyl acetate (200 mL) and extracted liquid separation.The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 1) was isolated as the product (0.15 g, yield 2.1% ).
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