2-tert-Butoxycarbonylamino- thiazole-5-carboxylic

White solid

To a vigorously stirred suspension of ethyl 2-(tert- butoxycarbonylamino)thiazole-5-carboxylate (4.2 g, 15 mmol) in methanol (11 mL) was added 2 M aqueous solution of NaOH (22 mL, 44.0 mmol). The suspension was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove methanol. The residual aqueous suspension was acidified with 6 N aqueous solution of HCl to pH ~ 1-2. The mixture was stirred and occasionally sonicated for 1 hr. The solid was filtered, washed with water, and dried to give 2-(tert- butoxycarbonylamino)thiazole-5-carboxylic acid (3.7 g, 100percent yield) as a white solid. MS found: (M+H-Boc)+ = 145.To 50m1 of three added in the flask THF (6m1) and ethanol (7m1), then balance for weighing Cape - 1 (1g) to join the three flasks, stir at room temperature 20min to mix uniformly; then the reaction container is transferred to the low-temperature constant in the responds the bath, the temperature dropped to 0 °C, stirring 15min; in a reaction container dropwise fresh preparation of 2 mol/L NaOH aqueous solution of 10m1, canada finishes, room temperature stirring 10h. For evaporating the reaction liquid in the Rotavapor THF; the reaction container is transferred to the low-temperature constant in the responds the bath, the temperature dropped to 0 °C, the instillment matches newly of 10percent solution of hydrochloric acid to adjust the PH to 1, separating white precipitation, filtration, the filter cake is washed with water, dried to obtain white solid product Cape - 2 (0.875g), yield 97.55percent. The total reaction equation is as follows: Nuclear magnetic with the mass spectrometry data:Into a clean and dry 2 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with 600 mL of 6N NaOH solution and slowly add 25 g of ethyl 2-tert-butoxycarbonylaminothiazole-5-carboxylate (2) to the 6N NaOH solution at 25-30 °C within 30-60 min period. Maintained the reaction mass at 25-30 °Cfor 24 h and after TLC compliance added 6N HCl solution (600 mL) to the reaction mass at 25-30 °C within 60-90 min period (pH test limit should be 0.5-1.5). Maintained the reaction mass at 25-30 °C for 60-90 min period and transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 100 mL DM water and dried the above wet material in the dryer at 60-65°C for 6-8 h to furnish 17 g of the title compound with purity above 99 percent. Off white colour solid; Elemental analysis C9H12N2O4Scalcd (found) percent: C 44.25 (44.55), H 4.95 (4.72), N 11.47 (11.31), O 26.20 (26.07), S 13.13 (13.16). IR (KBr, νmax, cm-1): 3434.68, 3167.64, 2980.51, 1727.41, 1672.79, 1576.45, 1522.35; 1H NMR (400 MHz, DMSO-d6): δ1.506 (s, 9H, -3CH3), 7.970 (s, 1H, ArH), 11.937 (s, 2H, -NH & -OH); 13C NMR (100 MHz, DMSO-d6): δ164.34, 163.09, 152.91, 145.39, 122.46, 82.40, 28.04; ESI-MS (m/z): 245.12 (M+1), 246.13 (M+2)A solution of ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (5 g, 18.36 mmol) and KOH (10.3 g, 184 mmol) in EtOH/HInto a clean and dry 2.0.L 4-neck RB flask charged 600 ml of 6N-NaOH (0069) solution. Slowly added ethyl 2-tert-butoxy-carbonylamino-thiazole-5- carboxylate (20gm) to the 6N-NaOH solution at temperature 25-30°C within 30- 60 min period.Maintained the reaction mass temperature at 25-30°C for 24hrs. after completion of the reaction, added 6N-HC1 solution to the reaction mass at temperature 25-30°C within 60-90 min period, maitained the reaction mass at temperature 25-30°C for 60-90 min period, transfered the reaction mass into a buchner funnel and flask kept under lant vacuum. Wash the wet cake with (0070) 100.0ml DM Water, suck dried thoroughly for 30-45 min. Transfered the wet material into a clean and dry petridish. Dried the above wet material in drier at temperature 60-65 C for 6-8 hrs. (0071) Weight: 17.0To a vigorously stirred suspension of ethyl 2-(tert- butoxycarbonylamino)thiazole-5-carboxylate (4.2 g, 15 mmol) in methanol (11 mL) was added 2 M aqueous solution of NaOH (22 mL, 44.0 mmol). The suspension was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove methanol. The residual aqueous suspension was acidified with 6 N aqueous solution of HCl to pH ~ 1-2. The mixture was stirred and occasionally sonicated for 1 hr. The solid was filtered, washed with water, and dried to give 2-(tert- butoxycarbonylamino)thiazole-5-carboxylic acid (3.7 g, 100% yield) as a white solid. MS found: (M+H-Boc)+ = 145.To 50m1 of three added in the flask THF (6m1) and ethanol (7m1), then balance for weighing Cape - 1 (1g) to join the three flasks, stir at room temperature 20min to mix uniformly; then the reaction container is transferred to the low-temperature constant in the responds the bath, the temperature dropped to 0 C, stirring 15min; in a reaction container dropwise fresh preparation of 2 mol/L NaOH aqueous solution of 10m1, canada finishes, room temperature stirring 10h. For evaporating the reaction liquid in the Rotavapor THF; the reaction container is transferred to the low-temperature constant in the responds the bath, the temperature dropped to 0 C, the instillment matches newly of 10% solution of hydrochloric acid to adjust the PH to 1, separating white precipitation, filtration, the filter cake is washed with water, dried to obtain white solid product Cape - 2 (0.875g), yield 97.55%. The total reaction equation is as follows: Nuclear magnetic with the mass spectrometry data:Into a clean and dry 2 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with 600 mL of 6N NaOH solution and slowly add 25 g of ethyl 2-tert-butoxycarbonylaminothiazole-5-carboxylate (2) to the 6N NaOH solution at 25-30 C within 30-60 min period. Maintained the reaction mass at 25-30 Cfor 24 h and after TLC compliance added 6N HCl solution (600 mL) to the reaction mass at 25-30 C within 60-90 min period (pH test limit should be 0.5-1.5). Maintained the reaction mass at 25-30 C for 60-90 min period and transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 100 mL DM water and dried the above wet material in the dryer at 60-65C for 6-8 h to furnish 17 g of the title compound with purity above 99 %. Off white colour solid; Elemental analysis C9H12N2O4Scalcd (found) %: C 44.25 (44.55), H 4.95 (4.72), N 11.47 (11.31), O 26.20 (26.07), S 13.13 (13.16). IR (KBr, numax, cm-1): 3434.68, 3167.64, 2980.51, 1727.41, 1672.79, 1576.45, 1522.35; 1H NMR (400 MHz, DMSO-d6): delta1.506 (s, 9H, -3CH3), 7.970 (s, 1H, ArH), 11.937 (s, 2H, -NH & -OH); 13C NMR (100 MHz, DMSO-d6): delta164.34, 163.09, 152.91, 145.39, 122.46, 82.40, 28.04; ESI-MS (m/z): 245.12 (M+1), 246.13 (M+2)A solution of ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (5 g, 18.36 mmol) and KOH (10.3 g, 184 mmol) in EtOH/H2O (1 :1) (60 mL) was stirred at RT for 12 hrs. The solution was acidified with IN HCl and the precipitate was filtered and dried, yielding 2-(tert- butoxycarbonylamino)thiazole-5-carboxylic acid (3.84 g, 86%) as a white solid. 1H-NMR (400 MHz, DMSOd6): delta(ppm): 12.0 (bs, IH), 7.94 (s, IH), 1.5 (s, 9H). 10. MS (ESI): m/z (%): 245.35 [MH+].Into a clean and dry 2.0.L 4-neck RB flask charged 600 ml of 6N-NaOH (0069) solution. Slowly added ethyl 2-tert-butoxy-carbonylamino-thiazole-5- carboxylate (20gm) to the 6N-NaOH solution at temperature 25-30C within 30- 60 min period.Maintained the reaction mass temperature at 25-30C for 24hrs. after completion of the reaction, added 6N-HC1 solution to the reaction mass at temperature 25-30C within 60-90 min period, maitained the reaction mass at temperature 25-30C for 60-90 min period, transfered the reaction mass into a buchner funnel and flask kept under lant vacuum. Wash the wet cake with (0070) 100.0ml DM Water, suck dried thoroughly for 30-45 min. Transfered the wet material into a clean and dry petridish. Dried the above wet material in drier at temperature 60-65 C for 6-8 hrs. (0071) Weight: 17.0[0405] A stirred solution of ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (1.1 g, 4.2 mmol) in tetrahydrofuran-methanol (80 mL, 1:1) was treated with a 6N aq. NaOH solution (20 mL, 120 mmol). The mixture was stirred at rt for 24 h. Most of THF and methanol were removed by distillation under reduced pressure and the aq. Solution was acidified with 6 N aq. HCl solution (22 mL). The precipitated solid was filtered, washed with water and ether, air dried followed by drying in vacuo to obtain the title acid (940 mg, 96%) as an off-white solid.To an cooled (0 C) dichloromethane (4 mL) solution of 2-[(tert- butoxycarbonyl)amino]-l, 3-thiazole-5-carboxylic acid (0.30 g) was added a solution of oxalyl chloride (0.13 mL) in dichloromethane (1 mL). One drop of N, N- dimethylformamide was added and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue dissolved in acetonitrile (5 mL). To the cooled (0 C) acetonitrile solution, a 2 M solution of (trimethylsilyl)diazomethane in tiexanes (1.23 mL) was added and the mixture stirred at 0 C for 1 hour. To the reaction mixture, a solution of 33 wt. % hydrogen bromide in acetic acid (0.20 mL) was added and the mixture stirred at 0 C for a further 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate ( 0 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the crude title compound having the following physical properties (0.37 g). LC MS fR 1.92 minutes; MS (ES+) m/z 265 and 267 (M-C(CH3)3+H) a.[00106] Compound 8 was made using by adapfing the synthesisdsdosed n J.Med.Chem. 2006, 6819. Synthesis of amde 5 was accomphshedn two steps, starting from compound 1. Compound I was converted to acidchorde 2 using oxay chorde n dchoromethane (DCM). Formafion of theacd chorde was confirmed by quenching an aquot n methano (MeOH);LCMS anayss ndcated the presence of the corresponding methy' ester 3 n>90%. Add Won of 2 to a mixture of excess anWne 4 and dsopropy ethyamne(DPEA) gave good conversion to amine 5. After fHtehng the sohds off thisafforded 1.15 g (40%) amde 5 n high purIty. Remova of the Boc-group using tr[fluoroacefic acid (TFA) gave good conversion to amine 6. Amine 6 was converted to compound 8 n the presence of compound 7 and sodium t-butoxde (NaOBu-t).Into a clean and dry 1 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with 2-tert-butoxy-carbonylaminothiazole-5-carboxylic acid (3) (25.0 g), THF (1 L) and DMF (1 mL) at 25-30 C under stirring. Charged thionyl chloride (22.5 mL of thionyl chloride dissolved in 125 mL of dichloromethane) to the mass at 25-30 C. Maintained the reaction mass at 25-30 C for 4-6 h and after TLC compliance, distilled-off solvent completely under plant vacuum at the temperature not crossing 50 C. Charged THF (125 mL) to the reaction mass, stirring the mass for 10-15 min and distilled-off solvent completely under plant vacuum at the temperature not crossing 40 C. Charged 125 mL of dichloromethane to the reaction mass, stirring the mass for 10-15 min and distilled-off solvent completely under plant vacuum at the temperature not crossing 40 C to furnish 27-28 g of crude compound.Into a clean and dry 1.0. L 4-neck RB charged 2- tert-butoxycarbonylamino- thiazole-5-carboxylic acid(25gm), and THF(lltr, Lot-I) and DMF(10 ml) at (0075) temperature 25-30C under stirring. Charged thionyl chloride (22.5 ml, dissolved (0076) in 125ml of dichloromethane-Lot-I) to the mass at temperature 25-30C, (0077) maintained the mass at temperature 25-30C for 4-6hrs., after completion of the (0078) reaction, distilled-off solvent completely under plant vacuum at temperature not (0079) crossing 50C, charged THF (125ml, Lot-II) to reaction mass.Stirr the mass for (0080) 10-15 min. Distilled-off solvent completely under plant vacuum at temperature not crossing 40C, charged dichloromethane (125ml, Lot-II) to reaction mass. (0081) Stirred the mass for 10-15 min.Distilled-off solvent completely under plant (0082) vacuum at temperature not crossing 40C. Distilled-off solvent completely under (0083) plant vacuum at temperature not crossing 60C. Crude acid chloride is directly (0084) taken to next stage in-situ. (0085) Weight: 27 gmCompound 11 (0.394 g, 1.83 mmol, 1.1 eq) was dissolved in anhydrous DMF (20 mL), and the reaction mixture was cooled to 0 C. Triethylamine (0.81 mL, 5.81 mmol, 3.5 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HCl salt (EDC; 0.48 g, 2.49 mmol, 1.5 eq) were added. The reaction mixture was removed from the ice bath and stirred under argon for 20 h at room temperature. The solvents were evaporated under reduced pressure, and the crude product was purified by flash column chromatography using hexane/ethyl acetate/methanol (5:4:1) as the eluent to afford the Boc-protected compound. The latter (0.71 g, 1.75 mmol, 1 eq)was dissolved in dichloromethane (15 mL), and CF3COOH was added (5 mL). The reaction mixture was stirred under argon for 1 h at room temperature. Solvents were evaporated under reduced pressure to afford compound 5b.Preparation Example 204 To a mixture of 2-[(tert-butoxycarybonyl)amino]-1, 3-thiazole-5-carboxylic acid (500 mg), N-[3-(diethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (589 mg), 1H-benzotriazol-1-ol (415 mg), and N, N-dimethylformamide (10 mL), 1-methylpiperazine (451 muL) was added followed by stirring at room temperature for 3 days. To the reaction mixture, water was added followed by extraction with ethyl acetate. An organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give tert-butyl {5-[(4-methylpiperazin-1-yl)carbonyl]-1, 3-thiazol-2-yl}carbamate (560 mg).EXAMPLE 14: 2-(tert-Butoxycarbonylamino)thiazole-5-carboxylic acid BocHN [0111] A mixture of 2-aminothiazole-5-carboxylic acid (2.2 kg, 15.33 mol), aqueous 2 M NaOH (0.674 kg in 8.39 L of DI water), DI water (17.68 L), and THF (17.68 L) was cooled to about 0C. A solution of Boc-anhydride (4.02 kg, 1.20 equiv) in THF (2.21 L) was added to the mixture while maintaining an internal temperature below 5C. When the addition was complete, the reaction mixture was warmed to an internal temperature of 25C and was stirred for 24 hours. The reaction mixture was cooled to about 0C and diluted with DI water (22.1 L). While maintaining an internal temperature below 5C, the pH of the mixture was adjusted to 4.9 by slowly adding acetic acid (5.30 L). After 1 hour a precipitate formed, which was collected by filtration, and rinsed successively with DI water (6.63 L) and MTBE (4.42 L). The filter cake was held under nitrogen for 1 hour and then dried under reduced pressure at 25C to afford the title compound (5.14 kg).2-tert-Butoxycarbonylamino-thiazole-5-carboxylic acid methyl ester (6.5 g, 25.28 mmol) was dissolved in THF (150 mL) and Methanol (200 mL) and placed in a 60C oil bath, while stirring vigorously. Sodium hydroxide (5.1 g, 127.5 mmol) was dissolved in water (40 mL) and slowly added to the reaction vessel. The reaction was stirred for 16 hours at 60C. After this time, the reaction mixture was concentrated in vacuo to about 1/3 the original volume. Water (60 mL) was added to the reaction mixture and the solution was acidified to pH=l-2 with 3M HC1 (aq) to afford the product, 2-tert-Butoxycarbonylamino- thiazole-5-carboxylic acid, as a white precipitate. The product was washed with water and taken on to the next reaction as is. LCMS [M+H] 244.9.Example 2nthesis of tert-butyl 5-fluorothiazol-2-ylcarbamate2-(tert-Butoxycarbonylamino)thiazole-5-carboxylic acid, 0.50 g, 2.0 mmol, and F-TEDA, N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate), 1.16 g, 1.6 eq., were combined with 6 mL of methyl tetrahydrofuran in a 50 mL, 3-necked round-bottomed flask fitted with a mechanical agitator. Potassium phosphate, tribasic monohydrate, 1.30 g, 2.8 eq., was dissolved in 4 mL of water and this solution was added dropwise to the reaction over about 15 minutes while maintaining the reaction contents at 2-5 C. The ice bath was removed and the mixture was stirred vigorously at ambient temperature for three hours. Solids were removed, rinsed with methyl tetrahydrofuran, and discarded. The phases were separated and the aqueous layer was extracted with 10 mL of methyl tetrahydrofuran and the combined organic layers were washed with 15 mL of dilute brine. Evaporation of the solvent at ambient temperature provided 0.29 g, 66%, of a tan solid of tert-butyl 5- fluorothiazol-2-ylcarbamate, LC/MS: 219.3; NMR: 11.50 (broad s, IH), 7.17 (d, J=2.2, IH), 1.47 (s, 3H); HPLC: RT 9.60 min, 96.8%.EXAMPLE 15: tert-Butyl 5-fluorothiazol-2-ylcarbamate BocHN [0113] 2-(tert-Butoxycarbonylamino)thiazole-5-carboxylic acid (2.06 kg, 8.43 mol) and 2-methyl THF (16.5 L) were combined and cooled to -5C. Selectfiuor (5.975 kg, 2.0 equiv) was added in portions while maintaining an internal temperature below 5C. Next, a solution of potassium phosphate (5.192 kg, 2.90 equiv) in DI water (16.5 L), which was cooled to a temperature of 0 to 5C, was slowly added to the mixture while maintaining an internal temperature below 5C. When the addition of the potassium phosphate solution was complete, the reaction mixture was filtered through a pad of Celite, which was rinsed with 2-methyl THF (6.18 L). The organic and aqueous phases of the filtrate were separated. The aqueous layer was extracted with 2-methyl THF (2 x 6.18 L), and the organic layers were combined and washed successively with aqueous sodium bicarbonate (0.964 kg in 12.36 L DI water) (2 x 6.0 L), aqueous HC1 (0.516 L), and brine (1.607 kg in 4, 57 L DI water). The organic phase was concentrated to dryness at 45C and then dried under vacuum at 25C for approximately 2 days to give the title compound (3.756 kg).To a suspension of 23 (46.8 g, 191.7 mmol) and N, N-dimethylformamide (0.8 mL) in CH2Cl2 (1.1 L) at 0 C. was added dropwise oxalyl chloride (24.3 mL, 287.6 mmol). The resulting reaction mixture was stirred 2 h at rt, evaporated to dryness, dissolved in CH2Cl2 (1.1 L), then cooled to 0 C. To this reaction mixture was added 41-d3 (69.3 g, 479.2 mmol). After 20 minutes (min) of stirring at 0 C., diisopropylethylamine (120.0 mL, 690.1 mmol) was added and the reaction mixture was stirred 4 h at 0 C. Volatile components were removed in vacuo, and the resulting solid was dispersed in saturated sodium bicarbonate (500 mL) then was allowed to stand for 2 h. The precipitate was filtered, washed sequentially with water (300 mL) and MTBE (400 mL), and dried under vacuum at 50 C. to give 25-d3 as a yellow solid (22.6 g, 32%). Synthesis of 2-amino-N-(2-chloro-6-(methyl-d3)phenyl)thiazole-5-carboxamide (43-d3).

Molecular Weight:244.27
XLogP3:1.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:4
Exact Mass:244.05177804
Monoisotopic Mass:244.05177804
Topological Polar Surface Area:117
Heavy Atom Count:16
Complexity:290
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes