* 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.
To the stirred solution of trifluoroacetic acid (TFA) (250.0 mL) added tert-butyl (5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)carbamate 23 (25.0 g, 0.07 mol) and stirred for 2h at 25-30°C. Reaction completion was confirmed by TLC, distilled the TFA and the residue was diluted with ethyl acetate (EtOAc),(250.0 mL). Ethyl acetate layer was washed with saturated NaHCO3 solution (2 X 25.0 mL), water, followed bysaturated NaCl solution (125.0 mL). Ethyl acetate layer was dried over Na2SO4 and concentrated. The residual mass on treatment with methyl tert-butyl ether (250.0) gave 9 (16.2 g, 89percent) [11].IR (KBr, cm-1): 3382.4, 3284.85 (N-H), 1627.02 (C=O), 1644; 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm(J, Hz): 9.63 (s, 1H, thiazole-H), 7.86 (s, 1H), 7.60 (s, 2H, -NH2), 7.38 (dd, 1H, J =7.5, 4.02, Ar-H), 7.20-7.22 (m,2H, J =7.5, Ar-H), 2.20 (s, 3H, Ar-CH3); 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 172.2, 159.6, 143.2,138.9, 133.7, 132.5, 129.0, 128.0, 127.0, 120.7 and 18.3; MS (ESI) m/z 268.0 [M + H] + [11].
85%
With trifluoroacetic acid In dichloromethane at -5 - 20℃; for 10.5 h;
(4) 2 - amino - N - (2 - chloro -6 - methyl phenyl) -5 - thiazole carboxamide preparation The 5m1 dichloromethane and 5m1 trifluoroacetic acid are added 50m1 three flasks, the reaction container is transferred to the low-temperature constant in the responds the bath, adjusting the temperature to the -5 °C; then, the filling funnel into the Cape - 3 (1g), stirring 30min, the reaction container from the low temperature constant temperature responds the bath transferred to under the room temperature condition in the stirring, the reaction 10h; the solvent in the reaction liquid to dryness, adding 15m1 ethyl acetate to dissolve, then 5percent sodium bicarbonate solution to wash two times, saturated salt aqueous solution used for washing a, drying the organic phase, concentrated under reduced pressure off solvent, to obtain a yellow solid Cape - 4 (0.6188g), yield 85percent. The total reaction equation is as follows: Nuclear magnetic with the mass spectrometry data:
78%
at 25 - 30℃;
Into a clean and dry 2 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with 2-tert-butoxy-carbonyl-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide (50 g) and trifluoroacetic acid (500 mL) under stirring. Maintained the reaction mass at 25-30 °C for 3-5 h under stirring and after TLC compliance distilled-off TFA completely under vacuum at the temperature not crossing 50 °C. Charged 2.0 L of ethyl acetate into reaction mass and washed the reaction mass with 5 percent Aq KHCO3(2 × 2 L) solution. Transferred the reaction mass into a separating funnel, separated aqueous and organic layers. Distilled-off the organic layer completely under plant vacuum at the temperature not crossing 50 °C and cooled the reaction mass temperature to 25-30 °C. Charged acetonitrile (150 mL) and isopropyl ether (400 mL) to the reaction mass and stirred for 60 min at 25-30 °C. Transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum and washed the wet cake with 100 mL of isopropyl ether. Dried the wet material in a dryer at 60-65 °C for 4-6 h to furnish 30 gof the title compound with purity above 99 percent. Light brown colour solid; Elemental analysis C11H10N3OSClcalcd (found) percent: C 49.35 (49.63), H 3.76 (3.54), N 15.69 (15.81),O 5.98 (6.12), S 11.98 (12.04). IR (KBr, νmax, cm-1): 3284.01-3378.81, 3110.16, 1627.01, 1612.25, 1538.42-1481.88, 773.58; 1H NMR (400 MHz, DMSO-d6): δ2.206 (s, 3H, -CH3), 7.209-7.272 (m, 2H, ArH), 7.361-7.384 (dd, 1H, ArH), 7.616 (s, 2H, -NH2), 7.865 (s, 1H, ArH), 9.642 (s, 2H, -NH); 13C NMR (100MHz, DMSO-d6): δ172.12, 159.54, 143.10, 138.82, 133.68,132.46, 128.92, 127.98, 126.92, 120.66, 18.27; ESI-MS (m/z):268.12 (M+1), 270.12 (M+3)
30.0 g
at 25 - 30℃;
Into a clean and dry 2.0.L 4-neck RB flask is charged 2-tert-butoxy- carbonyl (0107) amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide(50gm), trifluoroaceticacid(500ml) under stirring., the reaction mass at temperature was (0108) maintained at 25-30°C for 3-5 hrs, after completion of the reaction, distilled off (0109) trifluoroaceticacid completely under vacuum at temperature not crossing 50°C, (0110) ethylacetate(2 ltr) was added into reaction mass and washed the reaction mass (0111) with 5percent Aq KHCO-'-e (2x2.0L) solution. Transferred the reaction mass into a (0112) separating funnel. Transferred the organic layer into a clean and dry conical flask. (0113) Dry with sodium sulphate. Transferred the dry organic layer into a clean and dry (0114) single neck RB flask. Distilld off the solvent completely under plant vacuum at (0115) temperature not crossing 50°C. Cooled the reaction mass temperature to 25-30°C. (0116) Charged acetonitrile (150 ml) and isopropyl ether (400.0 ml) and stirred for 60 (0117) min at 25-30°C.Transferrd the reaction mass into a buchner funnel and flask kept (0118) under plant vacuum. Washed the wet cake with 100.0 ml of ether Suck dried (0119) thoroughly for 30-45 min, transferred the wet material into a petridish. Dried the (0120) above wet material in a drier at temperature 60-65 C for 4-6 hrs. (0121) Weight: 30.0 g
Reference：
[1] Synthetic Communications, 2017, vol. 47, # 17, p. 1610 - 1621
[2] Patent: CN106674150, 2017, A, . Location in patent: Paragraph 0032-0036
[3] Asian Journal of Chemistry, 2018, vol. 30, # 7, p. 1621 - 1628
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 4007 - 4010
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6061 - 6066
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 23, p. 6819 - 6832
[7] Arkivoc, 2010, vol. 2010, # 6, p. 32 - 38
[8] Patent: WO2017/100703, 2017, A1, . Location in patent: Paragraph 00105; 00106
[9] Patent: WO2018/100585, 2018, A1, . Location in patent: Page/Page column 9-10
2
[ 863127-76-8 ]
[ 17356-08-0 ]
[ 302964-24-5 ]
Yield
Reaction Conditions
Operation in experiment
98.8%
Stage #1: With iodine(I) bromide; 1-n-butyl-3-methylimidazolim bromide In tetrahydrofuran at 40℃; Stage #2: for 1.5 h;
23.9 g (100 mmol) of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide was mixed with 7.2 g (35 mmol) of iodine monobromide at room temperature,And 10.9 g (50 mmol) of 1-butyl-3-methylimidazolium bromide were added to a flask and stirred in 120 ml of THFAnd the temperature was raised to 40 ° C. 22.8 g (300 mmol) of thiourea was added to the mixture obtained by the above-mentioned mixingThe reaction was stirred for 1.5 hours, cooled to room temperature, poured into ice water, extracted with methylene chloride, the organic phase was concentrated, washed with water and then ethanolAnd then dried to obtain 26.4 g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide in a yield of 98.8percentpurity99.61percent.
90%
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at -10 - 22℃; for 3 h; Stage #2: at 100℃; for 2 h; Stage #3: With ammonia In 1,4-dioxane; water at 20 - 22℃;
Example 2; [0164] To a mixture of compound 1 (5.30 g, 22.1 1 mmol) in 1 ,4-dioxane (100 mL) and water (70 mL) was added NBS (4,40 g, 24,72 mmol) at -10 to 0°C. The slurry v/as warmed and stirred <n="55"/>at 20-22°C, for 3 h. Thiourea (1 ,85 g, 26, 16 mmol) was added and the mixture heated to 100°C. After 2 h, the resulting solution was cooled to 20-22°C and cone, ammonium hydroxide (6 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5 "C. The solid was collected by vacuum filtration, washed with cold water, and dried to give 5.4 g (90percent yield) of compound 2 as deep-yellow solids, 1H NMR (500 MHz1 DMSOd6) δ 2, 19 (s, 3H), 7.09-7.29 (m, 2H, J=7,5), 7.29-7,43 (d, IH, J=7,5), 7.61 (s, 2H)1 7,85 (s, IH)1 9.63 (s, IH); ESI-MS: calcd for (Cl 1H10C1N3OS) 267, found 268 MH+),
90%
Stage #1: With N-Bromosuccinimide In 1,4-dioxane at -10 - 22℃; for 3 h; Stage #2: at 100℃; for 2 h; Stage #3: With ammonium hydroxide In 1,4-dioxane; water at 20 - 22℃;
Example 2[0157] To a mixture of compound 1 (5.30 g, 22.11 mmol) in 1,4-dioxane (100 mL) and water (70 mL) was added NBS (4.40 g, 24.72 mmol) at -10 to 0° C. The slurry was warmed and stirred at 20-22° C for 3 h. Thiourea (1.85 g, 26.16 mmol) was added and the mixture heated to 100° C. After 2 h, the resulting solution was cooled to 20-22° C and cone, ammonium hydroxide (6 mL) was added drop wise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water, and dried to give 5.4 g (90percent yield) of compound 2 as deep-yellow solids. 1H NMR (500 MHz, DMSO-d6) δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, IH, J=7.5), 7.61 (s, 2H), 7.85 (s, IH), 9.63 (s, IH); ESI-MS: calcd for (CπHioClN3OS) 267, found 268 MH+).
213 g
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at 25 - 30℃; for 3 h; Stage #2: at 25 - 70℃; for 2 h;
E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide compound of formula-8 (240 gm) was added to a mixture of N-bromosuccinimide (267.1 gm), water (960 ml) and 1,4-dioxane (480 ml) at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Thiourea (76.8 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 15-20°C. The reaction mixture was added slowly to a pre-cooled (15-20°C) aqueous ammonia solution (600 ml of ammonia in 960 ml of water) at 15-20°C and stirred the reaction mixture for 2 hours at same temperature. Filtered the precipitated solid and washed with water. Water was added to the obtained compound and stirred for 40 minutes at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 213 gm; MR.: 195-200°C; HPLC Purity: 98.77percent.
Stage #1: With 1-butyl-3-methylimidazolium Tetrafluoroborate; copper(I) bromide In tetrahydrofuran for 0.5 h; Stage #2: at 40℃; for 1.5 h;
A process for the preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide of dasatinib, which comprises: 23.9 g (100 mmol) of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide and 11.5 g (80 mmol) of cuprous bromide and 1-butyl- (30 mmol) of tetrafluoroborate was added to a flask and stirred and mixed in 120 ml of THF for 30 minutes. Then, the temperature was raised to 40 ° C,5.2 g (200 mmol) of thiourea was added to the mixture obtained above and the reaction was allowed to proceed for 1.5 hours. The reaction mixture was cooled to room temperature, poured into ice water, Dichloromethane extraction, organic phase concentration, washing,Then recrystallized from ethanol and dried to obtain 26.5 g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide. The yield was 98.9percent and the purity was 99.66percent.
85 g
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at 0 - 10℃; Stage #2: at 20 - 80℃;
To a stirred solution of N-(2-chloro-6-methylphenyl)-3 -ethoxyprop-2-enamide (100.0 gm) in dioxane:water(400 ml: 400 ml), was added N-bromosuccinimide(8 1.67 gm) under cooling and allowed to stir at 0-10°C.Thiourea(31.75 gm) was added to the above reaction mixture and heated the reaction mixture at 20-30°C. The reaction mixture was heated for 1-2h at 60-80°C.Cooled the reaction mixture to 20-30°C and ammonium hydroxide (84.0 ml) was added. Distilled off the reaction mixture to a half volume and cooled it. Separated solid was filtered off and washed with water (200 ml) and dried to obtain 2-Amino-N-(2-chloro-6-methylphenyl)- 1, 3 -thiazole-5 -carboxamide (85 gm).
Reference：
[1] Patent: CN106008392, 2016, A, . Location in patent: Paragraph 0024; 0029; 0030
[2] Patent: WO2015/49645, 2015, A2, . Location in patent: Page/Page column 20
[3] Patent: CN106749223, 2017, A, . Location in patent: Paragraph 0102; 0106; 0109
4
[ 17356-08-0 ]
[ 302964-24-5 ]
Yield
Reaction Conditions
Operation in experiment
94.9%
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at -10 - 22℃; for 3 h; Stage #2: at 80℃; for 2 h;
To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at-10 to 0°C. The slurry was warmed and stirred at 20-22°C for 3h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80°C. After 2h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5°C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9 percent yield) of 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) 8 8 2.19 (s, 3H), 7.09-7. 29 (m, 2H, J=7.5), 7.29-7. 43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125MHz, DMSO-d6) b : 18. 18,120. 63,126. 84,127. 90,128. 86,132. 41,133. 63,138. 76,142. 88,159. 45, 172.02.
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at 0 - 10℃; Stage #2: at 20 - 80℃;
To a stirred solution of N-(2-chloro-6-methylphenyl)-3 -ethoxyprop-2-enamide (100.0 gm) in dioxane:water(400 ml: 400 ml), was added N-bromosuccinimide(8 1.67 gm) under cooling and allowed to stir at 0-10°C. 1 -trityl thiourea(3 1.75 gm) was added to the above reaction mixture and heated the reaction mixture at 20-30°C. The reaction mixture was heated for 1-2h at 60-80°C.Cooled the reaction mixture to 20-30°C and ammonium hydroxide (84.0 ml) was added. Distilled off the reaction mixture to a half volume and cooled it. Separated solid was filtered off and washed with water (200 ml) and dried to obtain 2-Amino-N-(2-chloro-6-methylphenyl)- 1, 3 -thiazole-5 -carboxamide (85 gm).
Reference：
[1] Archiv der Pharmazie, 2011, vol. 344, # 7, p. 451 - 458
12
[ 1416737-47-7 ]
[ 17356-08-0 ]
[ 302964-24-5 ]
Reference：
[1] Archiv der Pharmazie, 2011, vol. 344, # 7, p. 451 - 458
13
[ 1780-26-3 ]
[ 302964-24-5 ]
[ 302964-08-5 ]
Yield
Reaction Conditions
Operation in experiment
98.7%
With potassium hydride In tetrahydrofuran at -25 - -10℃; for 4 h;
To 80 ml of tetrahydrofuran cooled to -25 ° C, 8.73 g of potassium hydride (30percent by weight, 65.38 mmol) was added; stirred and stirred for 10 min; slowly added to 5.00 g of 2-amino-N- (2-chloro- Phenyl) thiazole-5-carboxamide was added at a temperature of -25 ° C and a solution of 3.65 g of tetrahydrofuran (7 ml) containing 2-methyl-4,6-dichloropyrimidine was added in advance to a solution of In the reaction system, the temperature was stabilized and the reaction was stirred at -10 ° C for 4 hours. Then, ImoVL hydrochloric acid quenched reaction was slowly added. The pH was adjusted to 6, controlled at 0-5 ° C, crystallized for 2 h, centrifuged, washed with THF, The crude product was 7.27g. The yield was 98.7percent, the purity was 99.95percent (HPLC), and the maximum single hetero content was 0.03percent
94%
Stage #1: With sodium t-butanolate In tetrahydrofuran at 10 - 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 5℃; for 2 h;
To the stirred solution of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5- carboxamide 9 (15.0 g, 0.06 mol) and 4,6-dichloro-2-methylpyrimidine (10.9 g, 0.07 mol) in tetrahydrofuran (THF) (150.0 mL) was added a 29percent wt.solution of NaOtBu in THF (64.9 g, 0.2 mol) at 10-20°C, over 15-20 minutes. The mixture was stirred at room temperature for 1h and cooled to 0-5°C. 1N Hydrochloric acid (~90.0 mL) was added slowly to pH 2-3 followedby the added water 90.0 mL) and stirred for 2h at 0-5°C, product was filtered and washed the wet cake with water (60.0 mL) followed by acetone (30.0 mL) gave 5 (20.7 g, 94percent).UV (Methanol): max, 319.6 & 203.2 nm; IR (KBr, cm-1): 3420.3 (N-H), 3016.6 (Ar C-H), 1638.6 (C=O); 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 12.23 (s, 1H, thiazole-NH), 10.02 (s, 1H, amide-NH), 8.32 (s,1H, thiazole-H), 7.42-7.40 (m, 1H, Ar-H), 7.31-7.25 (m, 2H, J =7.5, Ar-H), 6.95 (s, 1H, pyrimidine-H), 2.59 (s,3H, Ar-CH3), 2.25 (s, 3H, pyrimidine-CH3); 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 167.4(pyrimidine-C), 161.2 (pyrimidine-C), 159.5 (pyrimidine-C), 158.5 (amide-C), 157.6 (thiazole-C), 140.8 (Ar-C),138.8 (thiazole-C), 133.3 (Ar-C), 132.4 (Ar-C), 129.0 (Ar-C), 128.3 (Ar-C), 127.2 (thiazole-C), 103.4 (pyrimidine-C), 67.0 (pyrimidine-C), 25.2 (Ar-CH3), 18.3 (pyrimidine-CH3); MS (ESI) m/z 391.9 [M - H] - [5].
86.4%
Stage #1: With sodium t-butanolate In tetrahydrofuran at 10 - 20℃; for 1.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 5℃; for 1.75 h;
To a stirring solution of compound 5C (5. ou g, 18.67 mmol) and 4,6-dichloro- 2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30percent-wt. solution of sodium t-butoxid in THF (21. 1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20°C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5°C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5°C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4 percent yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) 8 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7. 18-7. 34, (m, 2H, J=7.5), 7.34-7. 46 (d, 1H, , J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).
86.4%
With alkali metal tret-butoxide In tetrahydrofuran at 10 - 20℃; for 1.5 h;
2-Amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (3) (5 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (4) (3.65 g, 22.4 mmol), tetrahydrofuran (65 mL) were charged into a 250 mL four necked round bottomed flask. Stirred the mass for 15 min. To this a 30 percent w/w solution of sodium t-butoxide in tetrahydrofuran (21 g, 65.36 mmol) was added slowly with cooling to keep the temperature at 10-20 °C. The mixture was stirred for 1.5 h and cooled to 0-5 °C. Then 21.5 mL of 2 N HCl was added slowly and the compound was collected by vacuum filtration. Then the compound was washed with water (15 mL) and drying of the filtered wet compound to give 6.63 g (86.4 percent) of a cream coloured solid.
74.06%
With sodium t-butanolate In tetrahydrofuran at -5 - 30℃; Inert atmosphere; Large scale
At room temperature,1.50 kg of 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazolamide,1.11kg of 4,6-dichloro-2-methylpyrimidine was added to a 50L reactor.Add 13.35kg of tetrahydrofuran,Nitrogen protection, stirring and cooling to -5 °C ~ 10 °C,The temperature of the reaction solution is maintained at -5°C to 10°C, and sodium tert-butoxide solids are added to the reaction solution in several portions.The total amount of tert-butoxide sodium solids is 2.13kg, and the addition method is to feed once every 20-30min.Each time no more than 10percent of the total and no more than 200g,After the addition, the reaction liquid is allowed to react at -5°C to 10°C for 1 to 2 hours.After warming the reaction solution to 10 °C ~ 30 °C,Stir the reaction solution,To HPLC detection of 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazoleamide/N-(2-chloro-6-methylphenyl)-2-[(6-chloro- The amount of 2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide is less than 1.5percent.Cool the reaction solution to -10°C to 10°C.Dropping hydrochloric acid at a concentration of 4 mol/L,Adjust the system pH to 6 to 7,After dropping, continue stirring at -10°C10°C for 12h,filter,The filter cake is washed with an appropriate amount of water and methanol.The filter cake is vacuum dried at 50-60°C.N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide 1.364kg, yield 74.06percent;
69%
With sodium t-butanolate In tetrahydrofuran at 10 - 30℃; Inert atmosphere
Into aclean and dry 5 L 4 N round bottom flask connected to a mechanical stirrer and equipped with a condenser and thermometer socket is charged under stirring, 200 g of 2-amino-thiazole-N-(2-chloro-6-methylphenyl)-5-carboxamide, 146 g of 4,6-dichloro-2-methylpyrimidine and 2 L of THF under a nitrogen atmosphere. After clear solution, cooled the mass temperature to 10-20 °C. Added 30 percent sodium-t-butoxide solution to the reaction mass over a period of 60-75 min at 10-20 °C and brown coloured solution formation is observed. Raised the reaction mass temperature to 25-30 °C and maintained the mass temperature to 25-30 °C for 90-120 min. After HPLC compliance cooled the mass temperature to 0-5 °C and added 2 N HCl solution to the reaction mass over a period of 60-90 min at 0-5 °C. Maintained the mass temperature at 0-5 °C for 105-120 min and transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 600.0 mL of water and dried the wet material in a drier at 60-65 °C for 8-10 h gave 210.0 g of the title compound with purity above 99 percent. Off white colour solid; Elemental analysis C16H13N5OSCl2calcd (found) percent: C 48.74 (48.91), H 3.32 (3.45), N 17.76 (15.97),O 4.06 (4.24), S 8.13 (8.29). IR (KBr, νmax, cm-1): 3424.28,3241.22, 2876.23-2789.82, 1638.82, 770.36; 1H NMR (400MHz, DMSO-d6): δ2.247 (s, 3H, -CH3), 2.594 (s, 3H, -CH3),6.952 (s, 1H, ArH), 7.252-7.314 (m, 2H, ArH), 7.403-7.422(dd, 1H, ArH), 8.320 (s, 1H, ArH), 10.030 (s, 1H, -NH), 12.251(s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6): δ167.38, 161.23,159.52, 158.48, 157.51, 140.76, 138.74, 133.28, 132.35, 129.02,128.24, 127.18-126.99, 103.40, 66.97, 25.12, 18.23; ESI-MS(m/z): 394.14 (M+1), 396.15 (M+3).
60%
With sodium amide In tetrahydrofuran at 5 - 35℃; Inert atmosphere
Into a RBF 6.6 g of Sodium Amide was added at 30-35° C. under N2 atmosphere and stirring was done for 10-15 minutes. Then the reaction mass was cooled to 5-10° C. and 120.0 mL THF and 7.92 g 4,6-Dichloro-2-methyl pyrimidine were added to the reaction mass. Addition of 10.0 g 2-amino-N-(2-chloro-6-methyl phenyl)-5-thiazole carboxamide was then performed into the reaction mass. The reaction mass was stirred for 40 mins at 30-35° C. to get clear solution which was transferred to an addition dropper. At temperature of 5-10° C., the reaction mass was slowly added over 30 minutes, into another RBF having 40.0 mL THF. At the same temperature, the reaction mass was stirred for 1.0-1.5 hrs. Then the reaction mass temperature was increased to 30-35° C., where stirring was performed for 3 to 4 hrs. On completion of the reaction as verified by TLC, the reaction mass was cooled slowly to a temperature of 0-5° C. Then the reaction mass pH was adjusted to 3-4 by addition of 22.4 mL HCl and 240 mL water over 10-15 mins. The reaction mass was then stirred for 2.0-2.5 hrs at 0-5° C. [0069] After the completion of stirring the reaction mass was filtered and washed with 20 mL water. The compound was then suck dried at RT for 10-15 mins. The wet compound was then unloaded and added to a RBF containing 12.0 mL DMF. The reaction mass was then heated to 65-70° C. for 45 mins. Then the reaction mass was slowly cooled to a temperature of 30-35° C. and stirring was performed for 45 mins. The reaction mass was then filtered and washed with 1 mL DMF. The material obtained was suck dried for 10-15 mins at RT, unloaded and air dried for 30 mins. Then the material was further dried under vacuum: for 1 h at 30-35° C., followed by 8 h drying at temperature of 65° C. After this, the solid material was cooled to 30-35° C. and the vacuum was released to obtain the dry 2-((6-chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide material. (HPLC Purity 97.0percent, Yield: 60percent)
90 g
With hydrogenchloride; sodium t-butanolate In tetrahydrofuran; water at 0 - 25℃;
To a cooled solution of 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5- carboxamide( 100 gm) and 4,6-Dichloro-2-methylpyrimidine(66. 96 gm) in THF(5 00 ml), was added sodium tert-butoxide(125.62 gm). The reaction mixture was allowed to cooled at 0-10°C. Concentrated HC1 (80 ml) was added. The reaction mixture was heated to 25±5°C for 1-2h and was cooled to 0-10°C. The precipitated solid was filtered, washed with water (200 ml) and dried to obtain N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2- methylpyrimidin-4-yl) amino] -1, 3 -thiazole-5 -carboxamide (90gm).
190 g
With sodium t-butanolate In tetrahydrofuran at 5 - 30℃; for 8 h;
A mixture of 2-Amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (200 gm), tetrahydrofuran compound of formula- 10 (1000 ml) & 4,6-dichloro-2-methylpyrimidine compound of formula- 11 (159 gm) was cooled to 5-10°C. Freshly prepared solution of sodium tertiary butoxide (251 gm) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at 5-10°C. Raised the temperature of the reaction to 25-30°C and stirred the reaction mixture for 8 hours at the same temperature. Cooled the reaction mixture to 5-10°C and water was added to it at the same temperature. Acidified the reaction mixture with aqueous HC1 solution at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 190 gm; HPLC Purity: 98.52percent.
210 g
With sodium t-butanolate In tetrahydrofuran at 10 - 30℃; Inert atmosphere
Into clean and dry 5.0 L 4-neck RB flask charged 2-amino-N-(2-chloro-6-methyl (0125) phenyl)-5-thiazole-l-carboxamide (200gm), 4,6-dichloro-2-methyl (0126) pyrimidine(146 g), 2.0 L of THF under nitrogen atmosphere. Clear solution (0127) formation was observed, cooled the reaction mass to temperature 10-20°C, added (0128) 30percent sodium -t-butoxide (845gm) solution to the reaction mass over a period of 60- (0129) 75min at temperature 10-20°C. Brown coloured solution formation was observed. (0130) Reaction mass temperature was raised to 25-30°C and maintained the reaction (0131) mass temperature to 25-30°C for 90-120 min, cooled the mass to temperature 0- (0132) 5°C and added 2N HCl solution to the reaction mass over a period of 60-90min at 0-5°C and maintained for 105-120min. Transferred the reaction mass into a buchner funnel and flask kept under plant vacuum. Washed the wet cake with 600.0mlof water.Suck dried thoroughly for 45-60 mi and dried the wet material in a drier at temperature 60-65 C for 8-10hrs. (0133) Weight: 210 gm
Reference：
[1] Patent: CN104788445, 2017, B, . Location in patent: Paragraph 0016; 0026; 0027; 0029; 0031; 0033; 0035; 0037
[2] Science China Chemistry, 2014, vol. 57, # 6, p. 823 - 832
[3] Synthetic Communications, 2017, vol. 47, # 17, p. 1610 - 1621
[4] Patent: WO2005/77945, 2005, A2, . Location in patent: Page/Page column 51-52
[5] Arkivoc, 2010, vol. 2010, # 6, p. 32 - 38
[6] Asian Journal of Chemistry, 2016, vol. 28, # 6, p. 1275 - 1280
[7] Patent: CN107089976, 2017, A, . Location in patent: Paragraph 0055; 0056; 0057
[8] Asian Journal of Chemistry, 2018, vol. 30, # 7, p. 1621 - 1628
[9] Patent: US2015/57446, 2015, A1, . Location in patent: Paragraph 0067-0069
[10] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6061 - 6066
[11] Patent: US2004/54186, 2004, A1, . Location in patent: Page 115
[12] Patent: US2007/219370, 2007, A1, . Location in patent: Page/Page column 27; 28
[13] Patent: WO2015/49645, 2015, A2, . Location in patent: Page/Page column 20
[14] Patent: WO2017/2131, 2017, A1, . Location in patent: Page/Page column 17; 19
[15] Patent: CN106749223, 2017, A, . Location in patent: Paragraph 0102; 0106; 0110
[16] Patent: WO2017/100703, 2017, A1, . Location in patent: Paragraph 00105; 00106
[17] Patent: WO2018/100585, 2018, A1, . Location in patent: Page/Page column 10-11
14
[ 302964-24-5 ]
[ 302964-08-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6061 - 6066
2-[(Cyclopropylcarbonyl)amino]-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
In 1,4-dioxane; at 93℃;
[0410] A solution of 315D (50.6 mg, 0.19 mmol) and cyclopropanecarboxylic acid anhydride (302 mg, 1.96 mmol) in dioxane (2 mL) was heated to 93 C. overnight. The mixture was concentrated in vacuo, diluted with EtOAc and washed with satd. Aq. KHCO3 solution (2×). The organic extract was dried (Na2SO4), filtered and concentrated. The residue was triturated with ether to obtain the title compound (11 mg, 17%) as a white solid.
2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium hydride; In tetrahydrofuran; at 0℃; for 1h;
[0412] Sodium hydride (19.2 mg, 0.8 mmol) was added to a solution of 315D (48.3 mg, 0.18 mmol) and t-butylisocyanate (41 FL, 0.36 mmol) in THF (5 mL) at 0 C. After 1 h, the mixture was diluted with EtOAc and washed with cold satd. Aq. Ammonium chloride solution. The aqueous layer was separated and extracted with EtOAc. The EtOAc extracts were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by automatic preparative HPLC (conditions: YMC S5 ODS A 20×100 mm Column, 10 min gradient starting from 10% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 100% solvent B, flow rate 20 mL/min, lambda=220 nM to obtain the title compound (18 mg, 28%) as an off-white solid.
[0419] A solution of copper (II) bromide (2.68 g, 12 mmol) in acetonitrile (50 mL) was purged with nitrogen and cooled to 0 C. t-Butyl nitrite (2 mL, 15 mmol) was added, followed by a solution of compound 315D (2.68 g, 10 mmol) in acetonitrile (50 mL), The mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in EtOAc, washed with satd. Aq. NaHCO, solution and the precipitate was removed by filtration. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was crystallized from EtOAc/ether/hexanes mixture to obtain the title compound (1.68 g, 51%) as a yellow solid.
N-(2-chloro-6-methylphenyl)-2-[(1-oxopropyl)amino]-5-thiazolecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[0431] Compounds 336 to 362 were prepared by an analogous method as that of 323-335, except using 315D in place of 144. The crude products were purified by automatic preparative HPLC (conditions: YMC S5 ODS A 20×100 mm Column, 10 min gradient starting from 10% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 100% solvent B, flow rate 20 mL/min, k=220 nM to obtain the title compounds 336-362. [0432] ?HPLC Ret Time? is the HPLC retention time under the following conditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H2O, 0.2% H3PO4) to 100% solvent B (90% MeOH, 10% H2O, 0.2% H3PO4), flow rate 4 mL/min, lambda=220 nM.
To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at-10 to 0C. The slurry was warmed and stirred at 20-22C for 3h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80C. After 2h, the resulting solution was cooled to 20-22 and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9 % yield) of 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) 8 8 2.19 (s, 3H), 7.09-7. 29 (m, 2H, J=7.5), 7.29-7. 43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125MHz, DMSO-d6) b : 18. 18,120. 63,126. 84,127. 90,128. 86,132. 41,133. 63,138. 76,142. 88,159. 45, 172.02.
13.4 g (50 mmol) of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamideMethyl-4-chloro-6- (4-hydroxyethyl-piperidinyl) pyrimidine15.4 g (60 mmol)In 1,4-dioxane at 75 C3 hours,Dumped into the water,The organic phase was concentrated and washed with water, then recrystallized from methanol and dried to obtain 20.3 g of dasatinib. The yield was 83.2% and the purity was 99.71%.
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 100 - 110℃; for 20h;
To a 250 ml of round bottom flask were charged compound 5C (1.9g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO3 (16g, 115.7 mmol), Pd (OAc) 2 (52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110C and stirred at this temperature for 20h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).
2-chloro-N-(2-chloro-6-methyl-phenyl)-3,3-dimethoxy-propionamide[ No CAS ]
[ 17356-08-0 ]
[ 302964-24-5 ]
Yield
Reaction Conditions
Operation in experiment
Preparation of 2-Amino-thiazole-5-carboxylic acid (2-chloro-6-methyl-phenyl)-amide The vessel with the product obtained according to Example 2 was purged with nitrogen and the reaction mixture diluted with 1023 l of acetic acid. Residual methanol was distilled off as a mixture with acetic acid. After 253 l of acetic acid and 109 kg of hydrochloric acid (37% b.w. of HCl) had been added at 50 C. 92 kg of thiourea were charged into the vessel and the reaction mixture heated to 60-65 C. and stirred for eleven hours. About 715 l of acetic acid were distilled off at 100 mbar and 847 l of methanol were added. After about 780 l of a methanol/acetic acid mixture had been distilled off at atmospheric pressure 847 l of methanol and 135 kg of a 30% b.w. solution of sodium methanolate in methanol were added in portions to adjust the pH at pH 8-9. The precipitated salts were filtered off and the filtrate was treated with 125 kg charcoal at 60 C. for several hours. After removal of the charcoal by filtration 1000 l methanol are distilled off at 500 mbar. Then 2000 l water are added and the reaction mixture in cooled down to 0 C. The product is filtered off. The filter cake was dried by purging it with nitrogen at 50 C. In a 4000 l vessel 130 kg of the crude thiazol are dissolved in 870 kg THF at 50 C. and 640 kg hexane are added at 20 C. within 3 h. the suspension is cooled down to 0 C. and the product is filtered off. the filter cake is washed with 380 l hexane and dried in a drying chamber. Overall Yield: 68%.
N-(2-chloro-6-methylphenyl)-2-(tritylamino)thiazole-5-carboxamide[ No CAS ]
[ 302964-24-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
With formic acid; In ethanol;Heating / reflux;
To the reaction solution obtained in the previous step was added 96% formic acid (5 mL). The reaction mixture was refluxed overnight. The reaction mixture was then partitioned between EtOAc and H2O (1:1, 100 mL). The organic phase was separated and concentrated in vacuo. The residue was subjected to column chromatography using EtOAc in hexane (20% to 80%) to give the product 31 (0.94 g, 70% yield). 1H NMR (300 MHz,DMSO-d6) delta 2.21 (s, 3H), 7.20-7.22 (m, 2H), 7.37 (dd, J=7.2 and 2.4 Hz, 1H), 7.57 (s, 2H), 7.86 (s, 1H), 9.60 (s, 1H); LCMS m/z 268.00 (M+H).
With diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 2.5h;
Example 4; (4)[0166] A solution of Compound 3 (560 mg, 3,41 mmole), diisopropylamine (1.00ml, 5.74 mmole) and Compound 2 (700 mg, 2,65 mmole) in THF (40 mL) was stirred at 0 C for 30 min, then at room temperature for 2 hours, Water was added to the reaction mixture, and the aqueous mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried, and evaporated in vacuo. Column chromatography provided Compound 4 as light yellow solids (350 mg, 33%). 1H NMR (500 MHz, DMSO-d6) delta 2, 19 (s, 3H), 2,49 (s, 3H), 7.36-7.58 (m, 3H), <n="56"/>8.23 (br, IH), 9,61 (br, IH), 1 1.63 (br, IH); ESI-MS: calcd for (C15H12C12N6OS) 394, found395 (MH"").
33%
With diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 2.5h;
Example 4[0159] A solution of Compound 3 (560 mg, 3.41 mmole), diisopropylamine (1.00ml, 5.74 mmole) and Compound 2 (700 mg, 2.65 mmole) in THF (40 mL) was stirred at 0 C for 30 min, then at room temperature for 2 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried, and evaporated in vacuo. Column chromatography provided Compound 4 as light yellow solids (350 mg, 33%). 1H NMR (500 MHz, DMSOd6) 5 2.19 (s, 3H), 2.49 (s, 3H), 7.36-7.58 (m, 3H), 8.23 (br, IH), 9.61 (br, IH), 11.63 (br, IH); ESI-MS: calcd for (C15H12Cl2N6OS) 394, found 395 (MH+).
Example 12; [0174] ' To a stirred solution of Compound 2 (100 mg, 0.37 rnrnole), and cyanuric chloride (35 mg, 0, 19 mmole) in THF (5 mL) was added a solution of sodium t-butoxide (125 mg, 1.30 mmol) in THF (ImL) at 0 C and the mixture was stirred at room temperature for 1 ,5 h. Dilute HCl (IN, ImL) was added to the reaction mixture, and the mixture was concentrated, After filtration,, the solids were washed by acetone, water, and dried to give Compound 12 as yellow solids (50 mg, 40%), ESI-MS: calcd for (C25H18C13N9O2S2) 645, found 646 (MH+).
With diisopropylamine; In tetrahydrofuran; at 0℃; for 1h;Product distribution / selectivity;
Example 13; <n="59"/>)[0175] To a stirred solution of Compound 2 (200 mg, 0.75 mmole), diisopropylamine (0.26ml, 1.49 mmole) and cyanuric chloride (134 mg, 0.73 mmole) in THF (10 mL) was stirred at 0 C for 1 h, 2-hydroxyethyl-l -piperazine (l OOmg, 0.77 mmole) was added at 0 C, and the mixture was stirred at room temperature over night, Water was added to the reaction mixture, and concentrated. After filtration, the solids were washed by acetone, water, and dried to give Compound 13 as yellow solids (200 mg, 52%). ESI-MS: calcd for (C20H22C12N8O2S) 508, found 509 (MFf).; Example 14; [0176] To a stirred solution of Compound 3 (170 mg, 0,62 mmole), diisopropylamine (0.20ml, 1 ,08 mmole) and cyanuric chloride (100 mg, 0,54 mmole) in TMF (10 mL) was stirred at 0 C for 1 h, 4-pyridyl-l-piperazine (180mg, 1 , 10 mmole) was added at 0 C, and the mixture was stirred at room temperature over night, Water was added to the reaction mixture, and concentrated, After filtration, the solids were washed by water, THF and dried to give Compound 14 as yellow solids (200 mg, 48%). ESI-MS: calcd for (C32H33C1N12OS) 668, found 669 (MH4"),
With diisopropylamine; In tetrahydrofuran; at 0℃; for 6h;
Example 33[0188] A solution of Compound 2 (1.17 g, 4.38 mmole), diisopropylamine (2.3 ml, 13.20 mmole) and Compound 32 (1.00 g, 4.85 mmole) in THF (30 mL) was stirred at 0 C for 6 hours. 5% NaHCO3 was added and the reaction mixture was extracted by ethyl acetate (3X). The organic layer was washed by saturated ammonium chloride, brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0- 2% methanol in DCM) to give the desired product 33 as light-yellow solids (170 mg, 9%). 1H NMR (500 MHz, DMSO-^6) delta 12.98 (br s, IH), 10.11 (s, IH), 8.35 (s, IH), 7.40 (d, J= 7.5 Hz, IH), 7.28 (m, 2H), 2.67 (br, 2H), 2.29 (m, IH), 2.23 (s, 3H), 0.96 (s, 6H). ESI-MS: calcd for (C18H18Cl2N6OS) 436, found 437 (MH+).
With diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 6h;
Example 30 [0185] A solution of Compound 2 (500 mg, 1.87 mmole), diisopropylamine (0.33 ml, 1.87 mmole) and Compound 9 (630 mg, 2.81 mmole) in THF (30 mL) was stirred at 0 C for 3 hours, then room temperature for additional 3 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried, and concentrated in vacuo until a lot of precipitate formed. After filtration, the solids were washed by ethyl acetate dried to give compound 30 (250 mg, 29%), which was used without purification for the next step reactions.
With diisopropylamine; In tetrahydrofuran; at 0℃; for 8h;
Example 22[0177] A solution of Compound 2 (1.07 g, 4.11 mmole), diisopropylamine (10.78 ml, 4.47 mmole) and Compound 21 (1.10 g, 6.18 mmole) in THF (70 mL) was stirred at 0 0C for 8 hours, then cold 5% NaHCO3 was added to the reaction mixture, and the aqueous mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried, and concentrated in vacuo until a lot of precipitate formed. After filtration, the solids were washed by ethyl acetate dried to give 22 (800 mg, 48%), which was used without purification for the next step reactions.
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