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CAS No. : | 35272-15-2 | MDL No. : | MFCD03407332 |
Formula : | C5H5NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZHDRDZMTEOIWSX-UHFFFAOYSA-N |
M.W : | 143.16 | Pubchem ID : | 284728 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 34.04 |
TPSA : | 78.43 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 1.02 |
Log Po/w (XLOGP3) : | 1.21 |
Log Po/w (WLOGP) : | 1.15 |
Log Po/w (MLOGP) : | -0.36 |
Log Po/w (SILICOS-IT) : | 1.9 |
Consensus Log Po/w : | 0.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.84 |
Solubility : | 2.09 mg/ml ; 0.0146 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.45 |
Solubility : | 0.503 mg/ml ; 0.00352 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.03 |
Solubility : | 13.3 mg/ml ; 0.0931 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.32 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With water; potassium hydroxide In tetrahydrofuran at 20℃; for 2 h; | General procedure: An aqueous KOH (10percent w/v) solution was added to an ester solution in THF. The reaction mixture was stirred at room temperature until reagent disappearance was confirmed by TLC. HCl 1 M was added until pH 4 and the solution was extracted with EtOAc.The organic layer was dried over MgSO4 and concentrated in vacuoto afford the acid. |
91% | Stage #1: at 20℃; for 2 h; Stage #2: With hydrogenchloride; water In methanol |
Step 1: 2-Methyl-thiazole-4-carboxylic acid Ethyl 2-methylthiazole-4-carboxylate (17.0 g, 99.3 mmol) was dissolved in 150 ml of methanol and 2N NaOH (150 ml, 300 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. Methanol was evaporated and the residue was acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (13.0 g, 91percent) was used without any further purification for the next step. |
87% | Stage #1: at 20℃; for 0.75 h; Stage #2: With hydrogenchloride In n-heptane |
EXAMPLE 115; 2-Methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (2-methyl-pyrimidin-4-yl)-amide; The title compound was prepared as illustrated in schemes 4 and 5. A) A solution of 2-methyl-thiazole-4-carboxylic acid ethyl ester (3.14 g, 20.00mmol) in methanol (50.00 ml) was treated with 2N NaOH (30.00 ml) and stirred at room temperature for 45 min. Methanol was removed in vacuo and the resulting slurry was neutralized with HCl 2N (30.00 ml). The aqueous phase was then extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulphate and evaporated. 2-Methyl-thiazole-4-carboxylic acid (2.48 g, 87percent) was obtained as a yellow solid, MS (ISP): m/e=142.1 (M-H), which was used crude. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride; In dichloromethane; benzene; | (a) Phosphorus pentachloride (13.35 g) was added in small portions to a suspension of <strong>[35272-15-2]2-methyl-4-thiazolecarboxylic acid</strong> (7.65 g) in dry dichloromethane over a period of 10 minutes. The resulting mixture was vigorously stirred for 1.5 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in dry benzene (40 ml) and the mixture was concentrated under reduced pressure to give yellow powders of 2-methyl-4-thiazolecarbonyl chloride (9.0 g). | |
With sulfuryl dichloride; N,N-dimethyl-formamide; In chloroform; for 2h;Heating / reflux; | To <strong>[35272-15-2]2-methyl-thiazole-4-carboxylic acid</strong> (CAS No. 35272-15-2, 600 mg, 4.2 mmol) in chloroform (4 mL) was added excess sulfuryl chloride (600 mul_) and dimethylformamide (100 mul_) and the reaction heated to reflux. After 2 hours, the reaction was hot filtered and the solvent removed under reduced pressure to provide 2-methyl-thiazole-4-carbonyl chloride as a gummy solid which was used directly in the next reaction. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.416667h; | 2-Methyl-1,3-thiazole-4-carboxylic acid [e.g. available from Acros Organics] (1 25 mg) was dried overnight under vacuum over phosphorus pentoxide and was then suspended in dry dichloromethane (2 ml) and treated at 20° C. with oxalyl chloride (0.077 ml) and DMF (1 drop). The mixture was stirred at room temperature for 25 mins and was then added dropwise to a solution of Intermediate 16 (240 mg) in anhydrous acetonitrile (5 ml). DIPEA (0.155 ml) was added and the solution stirred at room temperature for 3 h. The solution was blown down to dryness and purified by mass directed autoprep HPLC to give a pale orange gum. The gum was further purified using an SPE cartridge (5 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 309 as a pale orange gum (287 mg). LCMS showed MH+=429; TRET=2.37 min. |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.416667h; | Example 309 /V-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H- pyrazolo[3,4-/j]pyridin-5-yl]methyl}-2-methyl-1,3-thiazoIe-4-carboxamide2-Methyl-1 ,3-thiazole-4-carboxylic acid [e.g. available from Acros Organics] (125mg) was dried overnight under vacuum over phosphorus pentoxide and was then suspended in dry dichloromethane (2ml) and treated at 2O0C with oxalyl chloride (0.077ml) and DMF (1 drop). The mixture was stirred at room temperature for 25mins and was then added dropwise to a solution of Intermediate 16 (240mg) in anhydrous acetonitrile (5ml). DIPEA (0.155ml) was added and the solution stirred at room temperature for 3h. The solution was blown down to dryness and purified by mass directed autoprep HPLC to give a pale orange gum. The gum was further purified using an SPE cartridge (5g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 309 as a pale orange gum (287mg). LCMS showed MH+ = 429; TRET = 2.37min. | |
With thionyl chloride; at 80℃; for 12h; | To 2-methyl-1 ,3-thiazole-4-carboxylic acid (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80 °C for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80 °C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound, 1 .12 g.1 H NMR (DSMO) delta 8.34 (s, 1 H), 2.80 (s, 3H). | |
With thionyl chloride; at 80℃; for 12h; | To 2-methyl-1 ,3-thiazole-4-carboxylic acid (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80 °C for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80 °C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound, 1 .12 g.1H NMR (DSMO) delta 8.34 (s, 1 H), 2.80 (s, 3H) | |
1.12 g | With thionyl chloride; at 80℃; for 12h; | 2-Methyl-1,3-thiazole-4-carbonyl chloride To <strong>[35272-15-2]2-methyl-1,3-thiazole-4-carboxylic acid</strong> (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80° C. for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80° C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound, 1.12 g. 1H NMR (DSMO) delta 8.34 (s, 1H), 2.80 (s, 3H). |
With thionyl chloride; at 80℃; | Intermediate 482-Methyl-1 ,3-thiazole-4-carbonyl chloride To 2-methyl-1 ,3-thiazole-4-carboxylic acid (1g) was added thionyl chloride (5ml). The mixture was heated at 800C for 8h. Thionyl chloride (5ml) was added and the mixture heated for 2h at 8O0C. Further thionyl chloride (5ml) was added and the mixture heated for 2h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound (1.12g) as a brown solid1H NMR (DSMO) delta 8.34 (s, 1 H), 2.80 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | Preparation of nitrile intermediates (Method B); The desired carboxylic acid (1.0 g, 1 eq), t-butylamine (1 eq), EDCI (1.2 eq), NEt3 (2 eq) and HOBT (20 mg) were dissolved in 15ml of dichloromethane. The solution was stirred at room temperature over night, a further 15 ml dichloromethane added, and the solution washed with 1 N NaOH and brine, dried and concentrated to afford the amide. This was refluxed in POCl3 overnight, evaporated under reduced pressure, and the crude product purified by column chromatography. EDCI = l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide HOBT = 1 -hydroxybenzotriazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | 2-METHYLTHIAZOLE-4-CARBOXYLIC acid (2 g, 13.9 mmol) was combined with N, N- (methoxy) methylamine HCL (1.78 g, 18.18 mmol), N-hydroxybenzotriazole (2.83 g, 20.98 mmol), diluted into CH2C12 (30 mL), treated with diisopropylethylamine (6.1 ML, 34.97 mmol) and then treated with solid BOP reagent (6.80 g, 15.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained under TLC control (SI02, 20percent acetone-hexanes). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and CH2CL2, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified (Biotage 40M SIO2, 20-25percent acetone-hexanes) to provide the N-methoxy-N- methyl amide as a pale yellow oil (2.04 g, 78percent). |
78% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Thioacetamide (75 g, 1 mol) was suspended in CC14 (250 mL), and a solution of ethyl bromopyruvate (205 g, 1.05 mol) in CC14 (250 mL) was added by portions with intensive stirring. An exothermic reaction was observed, resulting in formation of a layer of heavy orange- red oil, that was separated, washed with ether (3X250 mL) and heated in a boiling water bath for 1 hour. Then water was added (1 L), followed by solid sodium bicarbonate addition to alkaline pH. The ethyl ester was extracted with ether (5X250 mL), the extracts dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was distilled under vacuum. Ethyl 2-methylthiazole-4-carboxylate (100 g, 0.58 mol) was dissolved in a minimum amount of cold methanol, and a solution of potassium hydroxide (36 g, 0.64 mol) in a minimum amount of cold methanol was added. The hydrolysis of the ester was rapid, and the potassium salt of the target acid precipitated from the mixture. Water was added to homogeneity, and the methanol was evaporated. The aqueous was acidified carefully with concentrated hydrochloric acid, the preciptant acid filtered off, washed with cold water, and recrystallized with water to provide 55 g of <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong>. 2-Methylthiazole-4-carboxylic acid (2 g, 13.9 mmol) was combined with N, N- (methoxy) methylamine HC1 (1.78 g, 18.18 mmol), N-hydroxybenzotriazole (2.83 g, 20.98 mmol), diluted into methylene chloride (30 mL), treated with diisopropylethylamine (6.1 ML, 34.97 mmol) and then treated with solid BOP reagent (6.80 g, 15.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained under TLC control (SI02, 20percent acetone-hexanes). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified (Biotage 40M SI02, 20-25percent acetone- hexanes) to provide the N-methoxy-N-methyl amide as a pale yellow oil (2.04 g, 78percent). 2-Methylthiazole-4-N-methoxy-N-methyl amide (2.05 g, 11.02 mmol) was diluted into dry toluene (30 mL), chilled TO-78 °C, and treated with fresh DIBAL-H (8.4 ML, 1.5 M toluene) under nitrogen. The reaction mixture was maintained 10 minutes under TLC control (SI02, 20percent acetone-hexanes), quenched at-78 °C with saturated aqueous Rochelle salt, warmed to room temperature, partitioned between water and chloroform, and the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and dried under vacuum to provide the aldehyde as a yellow oil which was used directly in the next reaction without purification. 2-Methylthiazole-4-carboxaldehyde (1.4 g, 11.02 mmol) was diluted into dry toluene (30 mL), treated with the solid stabilized ylide (Ph3P=CHC (O) N (CH3) (OCH3), 4.6 g, 12.67 mmol) at 23 °C, and the reaction mixture heated at 60 °C overnight under nitrogen. The reaction mixture was concentrated in vacuo and purified (Biotage 40M SI02, 15-20percent acetone- hexanes) to provide the N-methoxy-N-methyl acrylamide as a white solid (1.43 g, 61percent). |
Analogous to the general method described in J. Med. Chem., (2005), 48(6), 2134-2153. To a flask containing <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (1.10 g, 7.68 mmol) was added DCM (30 mL) and the homogeneous solution was stirred at room temperature as carbonyldiimidazole (1.30 g, 8.02 mmol) was added. A white opaque suspension resulted. After the mixture was stirred at room temperature for 2.25 hours a colorless homogeneous solution resulted and then N,O-dimethylhydroxylamine hydrochloride (820 mg, 8.41 mmol) was added which caused an opaque solution to result once again. The mixture was stirred at room temperature for 18 hours, then diluted with water and 1 N NaOH (to pH 9) and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a colorless oil, which was passed through a plug of silica gel eluting with (20percent THF-DCM) to provide the title compound as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With water; potassium hydroxide; In tetrahydrofuran; at 20℃; for 2h; | General procedure: An aqueous KOH (10percent w/v) solution was added to an ester solution in THF. The reaction mixture was stirred at room temperature until reagent disappearance was confirmed by TLC. HCl 1 M was added until pH 4 and the solution was extracted with EtOAc.The organic layer was dried over MgSO4 and concentrated in vacuoto afford the acid. |
91% | Step 1: 2-Methyl-thiazole-4-carboxylic acid Ethyl 2-methylthiazole-4-carboxylate (17.0 g, 99.3 mmol) was dissolved in 150 ml of methanol and 2N NaOH (150 ml, 300 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. Methanol was evaporated and the residue was acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (13.0 g, 91percent) was used without any further purification for the next step. | |
87% | EXAMPLE 115; 2-Methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (2-methyl-pyrimidin-4-yl)-amide; The title compound was prepared as illustrated in schemes 4 and 5. A) A solution of 2-methyl-thiazole-4-carboxylic acid ethyl ester (3.14 g, 20.00mmol) in methanol (50.00 ml) was treated with 2N NaOH (30.00 ml) and stirred at room temperature for 45 min. Methanol was removed in vacuo and the resulting slurry was neutralized with HCl 2N (30.00 ml). The aqueous phase was then extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulphate and evaporated. 2-Methyl-thiazole-4-carboxylic acid (2.48 g, 87percent) was obtained as a yellow solid, MS (ISP): m/e=142.1 (M-H), which was used crude. |
Ethyl 2-methylthiazole-4-carboxylate (100 g, 0.58 mol) was dissolved in a minimum amount of cold methanol, and a solution of potassium hydroxide (36 g, 0.64 mol) in a minimum amount of cold methanol was added. The hydrolysis of the ester was rapid, and the potassium salt of the target acid precipitated from the mixture. Water was added to homogeneity, and the methanol was evaporated. The aqueous was acidified carefully with concentrated hydrochloric acid, the preciptant acid filtered off, washed with cold water, and recrystallized with water to provide 55 g of 2-methylthiazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; | Thioacetamide (75 g, 1 mol) was suspended in CC14 (250 mL), and a solution of ethyl bromopyruvate (205 g, 1.05 mol) in CC14 (250 mL) was added by portions with intensive stirring. An exothermic reaction was observed, resulting in formation of a layer of heavy orange- red oil, that was separated, washed with ether (3X250 mL) and heated in a boiling water bath for 1 hour. Then water was added (1 L), followed by solid sodium bicarbonate addition to alkaline pH. The ethyl ester was extracted with ether (5X250 mL), the extracts dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was distilled under vacuum. Ethyl 2-methylthiazole-4-carboxylate (100 g, 0.58 mol) was dissolved in a minimum amount of cold methanol, and a solution of potassium hydroxide (36 g, 0.64 mol) in a minimum amount of cold methanol was added. The hydrolysis of the ester was rapid, and the potassium salt of the target acid precipitated from the mixture. Water was added to homogeneity, and the methanol was evaporated. The aqueous was acidified carefully with concentrated hydrochloric acid, the preciptant acid filtered off, washed with cold water, and recrystallized with water to provide 55 g of 2-methylthiazole-4-carboxylic acid. 2-Methylthiazole-4-carboxylic acid (2 g, 13.9 mmol) was combined with N, N- (methoxy) methylamine HC1 (1.78 g, 18.18 mmol), N-hydroxybenzotriazole (2.83 g, 20.98 mmol), diluted into methylene chloride (30 mL), treated with diisopropylethylamine (6.1 ML, 34.97 mmol) and then treated with solid BOP reagent (6.80 g, 15.38 mmol) at 0 °C. The reaction mixture was warmed to room temperature and maintained under TLC control (SI02, 20percent acetone-hexanes). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified (Biotage 40M SI02, 20-25percent acetone- hexanes) to provide the N-methoxy-N-methyl amide as a pale yellow oil (2.04 g, 78percent). 2-Methylthiazole-4-N-methoxy-N-methyl amide (2.05 g, 11.02 mmol) was diluted into dry toluene (30 mL), chilled TO-78 °C, and treated with fresh DIBAL-H (8.4 ML, 1.5 M toluene) under nitrogen. The reaction mixture was maintained 10 minutes under TLC control (SI02, 20percent acetone-hexanes), quenched at-78 °C with saturated aqueous Rochelle salt, warmed to room temperature, partitioned between water and chloroform, and the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and dried under vacuum to provide the aldehyde as a yellow oil which was used directly in the next reaction without purification. 2-Methylthiazole-4-carboxaldehyde (1.4 g, 11.02 mmol) was diluted into dry toluene (30 mL), treated with the solid stabilized ylide (Ph3P=CHC (O) N (CH3) (OCH3), 4.6 g, 12.67 mmol) at 23 °C, and the reaction mixture heated at 60 °C overnight under nitrogen. The reaction mixture was concentrated in vacuo and purified (Biotage 40M SI02, 15-20percent acetone- hexanes) to provide the N-methoxy-N-methyl acrylamide as a white solid (1.43 g, 61percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃;Molecular sieves 4A; | A mixture of I(1mmol), thiazol-2-ylamine (120 mg,1.2 mmol), HOBT(162 mg, 1.2 mmol), EDC (230 mg, 1.2 mmol) and little 4AMS in dry DMF (10mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with H2O for three times in order to remove DMF, then washed with saturated aqueous NaCl and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure and chromatography afforded products 55-59.Compound 55: 1H NMR (CDCl3, 300 MHz): delta (ppm) 11.08 (br, 1H), 8.12 (s, 1H), 7.53(d, J = 3.6Hz, 1H), 7.00 (d, J = 3.6Hz, 1H), 2.70 (s, 3H); 13C NMR (CDCl3, 300MHz): delta (ppm) 166.87 (1C), 158.54 (1C), 158.04 (1C), 147.70 (1C), 138.30 (1CH), 125.59 (1CH), 113.79 (1CH), 19.25 (1CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | B) A solution of <strong>[35272-15-2]2-methyl-thiazole-4-carboxylic acid</strong> (2.48 g, 17.32 mmol) in tetrahydrofurane (200.00 ml) was cooled to -78° C. under argon and treated with a 1.6N solution of buthyllithium in hexanes (22.74 ml, 36.38 mmol). The reaction mixture was left to warm to room temperature over 15 min, then cooled again to -78° C. A solution of elemental bromine (3.04 g, 19.05 mmol) in hexane (2.00 ml) was added. The reaction mixture was left to warm to room temperature, then quenched by addition of 1N HCl. The mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulphate and evaporated. 5-Bromo-<strong>[35272-15-2]2-methyl-thiazole-4-carboxylic acid</strong> (3.79 g, 99percent) was obtained as a yellow solid, MS (ISP): m/e=220.0, 222.1 (M-H), which was used crude. | |
81% | Step 2: 5-Bromo-<strong>[35272-15-2]2-methyl-thiazole-4-carboxylic acid</strong> 2-Methyl-thiazole-4-carboxylic acid (13.0 g, 90.8 mmol) was dissolved in 750 ml THF and cooled to -75° C. n-BuLi (1.6M in THF; 120 ml, 190.7 mmol) was added dropwise in 30 minutes. The red suspension was stirred for 15 min. at -75° C. and 30 min. at 0° C. A solution of bromine (5.1 ml, 100 mmol) in 20 ml cyclohexane was added dropwise at -75° C. and stirring was continued at room temperature for 2 hrs. The reaction mixture was quenched with 20 ml water, evaporated and acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (16.4 g, 81percent) [MS: m/e=223.0 (M+H+)] was used without any further purification for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | General Procedure: To a 100 mL round bottom flask equipped with a stir bar were added 2- methyl-l,3-thiazole-4-carboxylic acid (1.0 g, 6.98 mmol), potassium carbonate (3.86 g, 27.9 mmol), N,N-dimethylformamide (20 mL) and iodomethane (0.52 mL 8.38 mmol). The reaction mixture was stirred at room temperature over the weekend, diluted with ethyl acetate (100 mL) and washed with water (100 mL). The aqueous layer was then extracted with ethyl acetate (3x75 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel using hexanes:ethyl acetate = 80:20 to 50:50 in a gradient fashion, to give the desired product as an off-white solid (1.06 g, 97 percent). 1H NMR (300 MHz, CDCl3): delta 8.06 (s, IH), 3.95 (s, 3H), 2.78 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-methyl-1 ,3-thiazole-4-carboxylic acid (81 mg) in DMF (6 ml.) was addedDIPEA (129 mg), followed by HATU (209 mg). The reaction was stirred at room temperature for 15 mins. Intermediate 9 (200 mg) was added and the reaction mixture was stirred at <n="46"/>room temperature overnight. The crude material was purified by ISCO Companion.(TM). silica chromatography, eluting with a gradient 5-100percent EtOAc in cyclohexane to give the title compound.MS calcd for (C28H33N3O4S2 + H)+: 540 MS found (electrospray): (M+H)+ = 540 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 60℃; for 0.333333h; | To a suspension of (5-((4-fluorophenylamino)-methyl)-pyridin-2-yl)-diethyl-amine (150 mg, 0.43 mmol, Example 1 ) in tetrahydrofuran (4 mL) was added 2-methyl-thiazole-4- carbonyl chloride (210 mg, 0.8 mmol) and triethylamine (600 mul_) and the reaction heated to 600C. After 20 minutes the reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (10 mL). The aqueous phase was extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to afford a yellow oil. Purification by chromatography (silica gel; 50-75percent ethyl acetate in hexane) provided <strong>[35272-15-2]2-methyl-thiazole-4-carboxylic acid</strong> (6- diethylamino-pyridin-3-yl-methyl)-(4-fluorophenyl)-amide as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; at 180℃; for 0.5h; | General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1percent by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99percent).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wtpercent of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 3A Method A Preparation of compound 1002Step 1aTo a mixture of 2-methyl-4-thiotaazolecarboxyliotac acid 3a1 (27 mg, 0 17 mmol) and anhydrous DCE (1 mL) is added triphosgene (22 mg, 0 08 mmol) and 2,4,6-colliotadiotane (100 muL) and /-Pr-aniline 2a3 (35 mg, 0 10 mmol) The mixture is agitated on a J- Kem.(R). orbital shaker (300 rpm) at 8O0C overnight The mixture is concentrated under reduced pressure using a Savant.(TM). speed-vac The residue is taken up in EtOAc and washed with saturated aqueous NaHCO3 (x 2) and brine The solvent is <n="55"/>removed under reduced pressure The residue is taken up in DMSO then aqueous NaOH (10 N, 50 muL, O 5 mmol) and water (180 mul_) are added and the mixture is agitated on a J-Kem.(R). orbital shaker (300 rpm) at RT overnight The mixture is acidified with AcOH (200 muL) then injected onto a preparative HPLC to isolate compound 1002 |
Yield | Reaction Conditions | Operation in experiment |
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With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; for 16h; | 1-Propanephosphonic acid cyclic anhydride (1.57M solution in THF, 4.18 mL) was added to a solution of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.92 g), <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (0.94 g) and triethylamine (5.48 mL) in DMF (70 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic solutions <n="54"/>were washed with water (2 x 100 mL) and brine (100 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate to give the subtitled compound as a clear oil. Yield 2.30 g.1H NMR (400 MHz, D6-DMSO, 900C) delta 7.95 (s, IH), 3.80-3.45 (m, 8H), 3.18-2.96 (m, 2H), 2.67(s, 3H), 1.77-1.62 (m, 2H), 1.43-1.31 (m, HH) |
Yield | Reaction Conditions | Operation in experiment |
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68% | With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 1h; | 00456] Step A: A mixture of 5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (311 mg, 2.17 mmol), and triethylamine (606 muL, 4.35 mmol) in CH2CL (10 mL) at room temperature was treated withBOP-Cl (203 mg, 2.17 mmol). After 1 hour the solid formed was filtered and washed with CH2Cl2 (3 X 4 mL) to provide N-(5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)-2- methylthiazole-4-carboxamide (210 mg, 68percent yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) delta 12.14 (s, IH), 9.83 (s, IH), 8.38 (d, IH), 8.26 (s, IH), 7.74 (d, IH), 2.77 (s, 3H); LCMS (APCI+) m/z 354.9, 356.9 (M+H)+, Retention time = 3.39 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 23N-((ls,4s)-4-(2-(2'-(azepan-l-ylmethyl)-4'-hydroxybiphenyl-3-yloxy)-5- fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide Step (a) N-((l s,4s)-4-(5-fluoro-2-(3-iodophenoxy)nicotinamido)cyclohexyl)-2- methylthiazole-4-carboxamideTriethylamine (4 mL, 28.78 mmol) was added to a stirred suspension of N-((ls,4s)-4- aminocyc Io hexyl)-5-fluoro-2-(3-iodophenoxy Nicotinamide (1.655 g, 3.64 mmol) and 2- methylthiazole-4-carboxylic acid (0.625 g, 4.36 mmol), whereupon the reaction mixture became homogeneous. It was stirred for 40 min, during which time a precipitate formed, then <n="72"/>1-propanephosphonic acid cyclic anhydride (T3P, 1.57M in THF) (3.01 rnL, 4.73 mmol) was added slowly. The reaction mixture became homogeneous once more and the mixture was stirred overnight. The reaction mixture was evaporated to dryness and redissolved in EtOAc, then washed with saturated sodium hydrogen carbonate, 2M hydrochloric acid, water and saturated brine. The organic was dried over sodium sulfate, filtered and evaporated to afford the sub-title compound as a white foam. Yield: 2.16 g1H NMR (400 MHz, CDCl3) delta 8.36 (dd, J = 8.2, 3.1 Hz, IH), 8.07 (d, J = 3.1 Hz, IH), 7.93 (s, IH), 7.90 (d, J = 6.9 Hz, IH), 7.63 (dt, J = 7.2, 1.7 Hz, IH), 7.55 (t, J = 1.9 Hz, IH), 7.24 - 7.15 (m, 3H), 4.25 - 4.20 (m, IH), 4.12 - 4.06 (m, IH), 2.71 (s, 3H), 1.96 - 1.77 (m, 6H), 1.67 - 1.61 (m, 2H). MS: [M+H]+=581 (MultiMode+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 98N-((ls,4s)-4-(2-(4'-(((3S,5R)-3,5-dimethylpiperazin-l-yl)methyl)-31-hydroxybiphenyl-3- yloxy)-5-fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide To a solution of <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (27.2 mg, 0.19 mmol) in acetonitrile (3.00 niL) was added DIPEA (0.066 niL, 0.38 mmol). To this mixture was then added HATU (72.3 mg, 0.19 mmol). The mixture was stirred at RT for 10 min before it was added to a solution of N-((ls,4s)-4-aminocyclohexyl)-2-(4'-(((3S,5R)-3,5-dimethylpiperazin-l- yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fluoronicotinamide, hydrochloride (125 mg, 0.19 mmol) and DIPEA (0.066 mL, 0.38 mmol) in acetonitrile (3 mL) . The mixture was stirred at RT overnight. 1 mL of 7N NH3 in methanol was added to the reaction and then left to stir for 2 h. 1 mL water and 1 mL acetic acid was then added to the mixutre and this was then purified using reverse phas prep HPLC (eluent = TFA(aq)/MeCN), the appropriate fractions were combined and evaporated to give a residue. This was triturated with ether to afford the title compound as a solid which was isolated by filtration and dried overnight under vacuum at 400C. Yield: 84 mg1H NMR (400 MHz, CD3OD) delta 8.47 (d, J= 7.2 Hz, IH), 8.11 (d, J= 3.1 Hz, IH), 8.05 (dd, J= 7.9, 3.1 Hz, IH), 7.96 (s, IH), 7.80 (d, J= 9.0 Hz, IH), 7.51 - 7.43 (m, 2H), 7.37 (t, J= 1.8 Hz, IH), 7.28 (d, J= 7.7 Hz, IH), 7.18 (dt, J= 7.9, 1.8 Hz, IH), 7.11 - 7.08 (m, 2H), 4.14 - 4.11 (m, IH), 4.09 (s, 2H), 4.00 - 3.94 (m, IH), 3.58 - 3.51 (m, 2H), 3.43 (d, J= 13.3 Hz, 2H), 2.67 - 2.60 (m, 5H), 1.88 - 1.67 (m, 8H), 1.32 (d, J= 6.7 Hz, 6H). MS: [M+H]+=673.2 (calc=673.2972) (MultiMode+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 2h;Inert atmosphere; | Step (f) N-((ls,4s)-4-(2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3- yloxy)-5-fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamideHATU (116 mg, 0.30 mmol) was added in one portion to N-((ls,4s)-4-aminocyclohexyl)-2- (4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoronicotinamide (170 mg, 0.25 mmol), <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (39.9 mg, 0.28 mmol) and DIPEA (0.221 mL, 1.27 mmol) in DMF (2 mL) at 250C under nitrogen. The resulting solution was stirred at 25 0C for 2 h. The reaction was diluted with methanol (2mL) and acidified with HCl. The crude reaction was then purified on reverse phase HPLC 95/05 MeOH/TFA. The title compound was obtained as a white solid after freeze drying. Yield: 90 mg 1H NMR (300 MHz, DMSO) delta 8.37 (d, J = 6.9 Hz, IH), 8.28 (d, J = 2.9 Hz, IH), 8.09 (s, IH), 8.05 (dd, J = 7.9, 2.9 Hz, IH), 7.78 (s, IH), 7.66 - 7.52 (m, 3H), 7.46 (d, J = 7.9 Hz, IH), 7.30 <n="195"/>(d, J = 7.7 Hz, IH), 7.22 (m, 2H), 4.33 (s, 6H), 3.99 (s, IH), 3.88 (s, IH), 3.65 (s, 4H), 2.79 (s,8H), 2.68 (s, 3H), 1.69 (m, 8H).MS: [M+H]+=687 (calc=687) (MultiMode+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 34N-((ls,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3- yloxy)nicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide HATU (0.064 g, 0.17 mmol) and DIPEA (0.06 mL, 0.34 mmol) were added to a solution of 2- methylthiazole-4-carboxylic acid (0.024 g, 0.17 mmol) in acetonitrile (4 mL). The mixture was stirred for 10 min then a solution of N-((ls,4s)-4-aminocyclohexyl)-5-fluoro-2-(4'- hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0.100 g, 0.17 mmol) and DIPEA (0.09 mL, 0.52 mmol) in acetonitrile (4 mL) was added and the reaction stirred at RT for 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Waters X-Bridge column using a 95-5percent gradient of aqueous 0.2percent TFA in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound as a white solid. Yield: 87 mg.1H NMR (500 MHz, DMSO) delta 9.92 (br s, IH), 9.67 (br s, IH), 8.35 (d, J= 7.2 Hz, IH), 8.26 (d, J= 3.0 Hz, IH), 8.08 (s, IH), 8.04 (dd, J= 3.0, 7.9 Hz, IH), 7.61 (d, J= 8.0 Hz, IH), 7.50 (t, J= 7.9 Hz, IH), 7.22 (d, J= 7.9 Hz, IH), 7.19 - 7.09 (m, 3H), 7.05 (s, IH), 6.91 (d, J= 6.7 Hz, IH), 4.32 - 4.18 (m, 2H), 4.01 - 3.96 (m, IH), 3.91 - 3.84 (m, IH), 3.78 - 3.66 (m, 2H), 3.62 - 3.51 (m, 2H), 3.20 - 3.07 (m, 2H), 2.77 - 2.62 (m, 5H), 1.78 - 1.63 (m, 8H). MS: [M+H]+=646.2 (calc=646.2499) (MultiMode+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step (e) N-((ls,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5- fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide trifluoroacetateTo a solution of 2-methyl-l,3-thiazole-4-carboxylic acid (38.9 mg, 0.27 mmol) in acetonitrile (5 mL) was added DIPEA (0.095 mL, 0.54 mmol) and HATU (103 mg, 0.27 mmol). The mixture was allowed to stir at RT for 10 min before a solution of N-((ls,4s)-4- aminocyclohexyl)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5- fluoronicotinamide, 2HCl (150 mg, 0.27 mmol) in MeCN (5mL) with 2eq of DIPEA was added and the mixture stirred at RT overnight. The mixture was purified using reverse phase prep HPLC (eluent = TFA (aq)/MeCN), the appropriate fractions were combined and evaporated to give an oil. On trituration with ether the oil gave the title compound as a colourless solid which was dried. Yield: 105 mg1H NMR (400 MHz, CDCl3) delta 8.36 (dd, J= 8.2, 3.1 Hz, IH), 8.02 (d, J= 3.3 Hz, IH), 7.97 (d, J= 7.2 Hz, IH), 7.92 (s, IH), 7.54 (t, J= 7.9 Hz, IH), 7.33 (s, IH), 7.25 - 7.19 (m, 3H), 7.13 (d, J= 7.7 Hz, IH), 7.07 (t, J= 1.9 Hz, IH), 6.95 (d, J= 8.5 Hz, IH), 4.27 - 4.21 (m, 3H), 4.08 - 4.01 (m, IH), 2.66 (s, 3H), 2.58 (s, 6H), 1.97 - 1.83 (m, 6H), 1.71 - 1.62 (m, 2H). MS: [M+H]+=604.2 (calc=604.2394) (MultiMode+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 15N-((ls,4s)-4-(2-(2'-((l,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5- fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide HATU (0.089 g, 0.23 mmol) and DIPEA (0.081 niL, 0.47 mmol) were added to a solution of <strong>[35272-15-2]2-methylthiazole-4-carboxylic acid</strong> (0.033 g, 0.23 mmol) in acetonitrile (4 mL). The mixture was stirred for 10 min then a solution of 2-(2'-((l,4-oxazepan-4-yl)methyl)-4'- hydroxybiphenyl-3-yloxy)-N-((ls,4s)-4-aminocyclohexyl)-5-fluoronicotinamide (0.125 g, 0.23 mmol) in acetonitrile (4 mL) was added and the reaction stirred at RT for 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Waters X-Bridge column using a 95-5percent gradient of aqueous 0.2percent TFA in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound as an off-white solid. Yield: 0.134g 1H NMR (400 MHz, DMSO) delta 9.94 (br s, IH), 8.35 (d, J= 7.2 Hz, IH), 8.25 (d, J= 2.8 Hz, IH), 8.08 (s, IH), 8.04 (dd, J= 7.9, 3.1 Hz, IH), 7.60 (d, J= 7.7 Hz, IH), 7.51 (t, J= 7.8 Hz, IH), 7.24 - 7.22 (m, IH), 7.18 - 7.10 (m, 4H), 6.92 (d, J= 8.3 Hz, IH), 4.33 - 4.28 (m, 2H), 4.02 - 3.97 (m, IH), 3.90 - 3.85 (m, IH), 3.64 - 3.53 (m, 4H), 3.02 - 2.80 (m, 2H), 2.68 (s, 3H), 1.96 - 1.64 (m, 10H). Remaining protons obscured by water peak. MS: [M+H]+=660.2 (calc=660.2656) (MultiMode+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-Methyl-1 ,3-thiazole-4-carboxylic acid (4.59 g), HATU (13.4 g) and DIPEA (16.8 ml) were stirred in DMF (140 ml) for 30 min at 20 °C. 6-Bromo-1 H-indazol-4-amine (3.40 g) was added and the reaction stirred at 20 °C for 2 days. The solvent was reduced to -40 ml and the reaction mixture applied to 5 x 70 g aminopropyl SPE cartridges and left to stand for 3 h. The cartridges were eluted with DCM:MeOH (1 :1 , v/v) and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 0 - 15 percent methanol (containing 1 percent Et3N) in DCM. Appropriate fractions were evaporated to give the title compound, 1 .02 g.LC/MS (Method D) Rt = 0.96 min, MH+ = 339. | ||
Intermediate 32lambda/-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide 2-Methyl-1 ,3-thiazole-4-carboxylic acid (4.59g) (available from Maybridge), HATU (13.41g) and DIPEA (16.80ml) were stirred in DMF (140ml) for 30min at 2O0C. 6-Bromo- 1 H-indazol-4-amine (3.4g) (available from Sinova) was added and the reaction stirred at 2O0C for 2 days. The solvent was reduced to ~40ml and the reaction mixture was applied across 5x70 g aminopropyl SPE cartridges and left to stand for 3h. The cartridges were eluted with DCM:methanol (1 :1 ) and the combined solvent was evaporated in vacuo. The <n="103"/>residue was suspended in DCM:methanol, adsorbed onto Florisil.(R). and purified by chromatography on silica gel (10Og cartridge) eluting with 0 - 15percent gradient of methanol (containing 1percent triethylamine) in DCM over 60min to give title compound (1.02g). LC/MS Rt 0.95min m/z 337 [MH+]. Method B | ||
Intermediate 7lambda/-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide <n="103"/> 2-Methyl-1 ,3-thiazole-4-carboxylic acid (4.59 g, 32.1 mmol), HATU (13.4 g, 35.3 mmol) and DIPEA (16.8 ml, 96 mmol) were stirred in DMF (140 ml) for 30 mins at 20 0C. 6- Bromo-1 H-indazol-4-amine (3.40 g, 16.03 mmol) was added and the reaction stirred at 20 0C for 2 days. The solvent was reduced to -40 ml and the reaction mixture applied to 5 x 70 g aminopropyl SPE cartridges and left to stand for 3 h. The cartridges were eluted with DCM:MeOH (1 :1 , v/v) and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 0 - 15percent MeOH (containing 1percent Et3N) in DCM. Appropriate fractions were evaporated to give the title compound 1.02 g. LC/MS (Method B) Rt = 0.96 mins, MH+ = 339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 86lambda/-[3-Fluoro-6-(1 H-indol-4-yl)-1 H-indazol-4-yl]-2-methyl-1 ,3-thiazole-4-carboxamide <n="184"/> To 2-methyl-1 ,3-thiazole-4-carboxylic acid (24mg) in DMF (0.375ml) was added HATU (69mg) followed by DIPEA (0.043ml), and the solution stirred for 10min at 2O0C. To this was then added a solution of 3-fluoro-6-(1 H-indol-4-yl)-1 H-indazol-4-amine (67mg) in DMF (0.375ml) and the top was placed on the vial which had been pierced with a needle. The solution was stirred at 2O0C for 73h, heated at 5O0C for 3h, then left to stand for 3.5 days. A further portion of 2-methyl-1 ,3-thiazole-4-carboxylic acid (0.024g) in DMF (0.375ml) was treated with HATU (0.069g) followed by DIPEA (0.043ml). This solution was stirred for 15min at 2O0C then added to the original reaction mixture. This was then stirred at 2O0C for a further 72h then loaded onto a dried aminopropyl SPE cartridge (1g) which had been preconditioned with chloroform. The material was left on the cartridge for 2h, then the cartridge was eluted with methanol (3 column volumes) and the solvent blown off. This was purified directly by mass directed preparative HPLC (Method A). The residue was azeotroped with methanol (5ml) to give the title compound (7mg) as a beige solid. LC/MS R1 3.68min m/z 392 [MH+]. Method A |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 142lambda/-[3-Fluoro-6-(6-fluoro-1H-indol-4-yl)-1H-indazol-4-yl]-2-methyl-1,3-thiazole-4- carboxamide <n="211"/> 2-Methyl-1 ,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2- methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 30 mins. 3-fluoro-6-{6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1 H- indol-4-yl}-1-(phenylsulfonyl)-1 H-indazol-4-amine (0.1 mmol) was dissolved in THF (0.4 ml) and added to the reaction mixture, followed by pyridine (0.016 ml, 0.2 mmol). The reaction mixture was shaken and then left to stand for 1 hour. A further portion of 2- methyl-1 ,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2- methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 20 mins before being added to the ongoing reaction mixture above, along with further pyridine (0.097 ml, 1.2mmol). The mixture was shaken and left to stand for 30 mins. A further portion of 2-methyl-1 ,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 20 mins before being added to the ongoing reaction mixture above, along with further pyridine (0.097 ml, 1.2mmol). The mixture was shaken and left to stand for 30 mins, then evaporated by blow down under a stream of nitrogen. The crude reaction mixture was dissolved in isopropanol (0.3 ml) and NaOH (2M aqueous, 0.3 ml) was added. The mixture was stood for 60 h at room temperature. Further NaOH (2M aqueous, 0.3 ml) was added and the mixture was heated to 8O0C for 1 hour. The reaction mixture was neutralised with HCI (2 M, aq.) and blown down under a stream of nitrogen. The crude material was dissolved in DMSO (0.5 ml), filtered and purified by Mass Directed Auto Prep on an Xbridge column using Acetonitrile/Water with a formic acid modifier (Method F). The solvent was evaporated in vacuo using the Genevac. The residue was dissolved in DMSO (0.5 ml) and further purified by formic acid MDAP (as above), over an extended run time. The product-containing fractions were blown down under a stream of nitrogen to give the title compound (11 mg). LCMS (Method D) R1 = 1.16 min, MH+ = 410. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 163lambda/-[6-(6-Fluoro-1 H-indol-4-yl)-1 H-indazol-4-yl]-2-methyl-1 ,3-thiazole-4-carboxamide HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 ml) and added to 2-methyl-1 ,3-thiazole-4-carboxylic acid (0.1 mmol) also in DMF (0.2 ml). DIPEA (0.05 ml 0.3 mmol) was added and the mixture was left to stand for 5 mins. 3-Fluoro-6-{6-fluoro-1- [(4-nitrophenyl)sulfonyl]-1 H-indol-4-yl}-1-(phenylsulfonyl)-1 H-indazol-4-amine (0.1 mmol) was dissolved in DMF (0.2 ml) and to this was added the acid containing mixture. The solution was shaken for 5 minutes and left to stand at room temperature overnight. A further portion of HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 mL) and added to further 2-methyl-1 ,3-thiazole-4-carboxylic acid (0.1 mmol), also in N, N- Dimethylformamide (DMF) (0.2 mL). DIPEA (0.3 mmol) was added and the mixture left to stand for 5 mins, then the resultant solution was added to the vessel containing the reaction mixture. Solutions were shaken for 5 minutes and then placed in the oven at 4O0C for 1 hour. DMF was removed by vacuum centrifugation (not to dryness) and the residue was dissolved in chloroform (0.3 ml). The solution was loaded onto aminopropyl SPE cartridge (500mg) that had been preconditioned with MeOH followed by chloroform (2 ml each). The column was eluted with 10percent MeOH in EtOAc (5 ml) and the fractions <n="219"/>obtained were blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water as eluent with an ammonium carbonate modifier. The solvent was evaporated in vacuo using the Genevac. The residue was dissolved in isopropanol (0.3 ml) and NaOH (2M, aqueous, 0.3 ml) was added. The solution was left for 32 hours at room temperature, then heated at 4O0C overnight. The reaction mixture was neutralised using 2 M, aqueous HCI and then blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water with a formic acid modifier. The solvent was evaporated by vacuum centrifugation to give the title compound (4 mg). LCMS (Method D) R1 = 0.97 min, MH+ = 392. |
Tags: 35272-15-2 synthesis path| 35272-15-2 SDS| 35272-15-2 COA| 35272-15-2 purity| 35272-15-2 application| 35272-15-2 NMR| 35272-15-2 COA| 35272-15-2 structure
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P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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