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CAS No. : | 40004-69-1 | MDL No. : | MFCD01760300 |
Formula : | C5H5NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QCXCIYPOMMIBHO-UHFFFAOYSA-N |
M.W : | 143.16 | Pubchem ID : | 98845 |
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) : | 1.11 |
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 : | 1.0 |
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 : | 2.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
70% | Stage #1: With water; sodium hydroxide In 1,4-dioxane at 20℃; for 1 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water |
b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of 2-methyl-thiazole-5-carboxylic acid ethyl ester (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]". |
41% | With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 16 h; | To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): δ 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+. |
14 g | With water; sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16 h; | To a 0° C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g). |
14 g | With water; sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 2.16667 h; | To a 0°C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g). |
14 g | With water; sodium hydroxide In tetrahydrofuran at 0℃; for 2.16667 h; | To a 0° C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of <strong>[79836-78-5]2-methyl-thiazole-5-carboxylic acid ethyl ester</strong> (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]". | |
41% | With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h; | To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): delta 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+. |
Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min. |
Synthesis of (E) To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g). | ||
Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ = | ||
14 g | With water; sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2.16h; | To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g). |
14 g | With water; sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2.16667h; | To a 0°C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g). |
14 g | With water; sodium hydroxide; In tetrahydrofuran; at 0℃; for 2.16667h; | To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | (194-2) To a solution of the compound of Example 194-1 (5.74 g) in THF (100 mL)-MeOH (100 mL) was added a 6N NaOH solution (27 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and thereto was added a 6N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-methyl-1,3-thiazole-5-carboxylic acid (4.02 g, 86percent). 1H NMR (DMSO-d6, 400 MHz) delta 13.31 (brs, 1H), 8.17 (s, 1H), 2.70 (s, 3H). | |
86% | (194-2) To a solution of the compound of Example 194-1 (5.74 g) in THF (100 mL)-MeOH (100 mL) was added a 6N NaOH solution (27 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and thereto was added a 6N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-methyl-1,3-thiazole-5-carboxylic acid (4.02 g, 86 percent). 1H NMR (DMSO-d6, 400MHz) delta 13.31 (brs, 1H), 8.17 (s, 1H), 2.70 (s, 3H). | |
EXAMPLE 93 1-(2-Methylthiazole-5-carbonyl)-2-cyanoaziridine. 1.6 g. 2-Methylthiazole-5-carboxylic acid (m.p. 209° C.) and 0.76 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.0% and 92.8% | In 5,5-dimethyl-1,3-cyclohexadiene; | EXAMPLE 14 In a similar apparatus to Example 1, 10.0 g (0.07 mole) of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> were suspended in 100 ml of xylene, followed by the addition of 0.03 g of triethylenediamine. Under heating and reflux, phosgene was blown at a rate of 930 ml/hr for 6 hours (0.25 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.5 g of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> chloride. Its purity and yield were 96.0percent and 92.8percent, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.0% and 95.0% | In toluene; | EXAMPLE 5 In a similar apparatus to Example 1,5.7 g (0.04 mole) of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 390 ml/hr for 10 hours (0.17 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 5.7 g of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> chloride. Its purity and yield were 95.0percent and 95.0percent, respectively. NMR (deltaCDCl 3/TMS, ppm): 2.79(3H,s). |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h;Product distribution / selectivity; | Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min. | |
With oxalyl dichloride;N-formyldiethylamine; In dichloromethane; for 0.25h;Product distribution / selectivity; | 2-Methyl-1,3-thiazole-5-carboxylic acid (0.133 g, 0.93 mmol) (e.g. which can optionally be prepared as in Example 311) was suspended in dichloromethane (3 ml) and treated at 20° C. under nitrogen with oxalyl chloride (0.24 ml, 2.75 mmol) and diethylformamide (1 drop). A vigorous reaction occurred. After 15 min, the reaction mixture was evaporated to dryness to give a dark yellow oil which was presumed to be 2-methyl-1,3-thiazole-5-carbonyl chloride. |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h; | Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ = |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; dimethyl sulfoxide; | EXAMPLE 30 3.15 g (22.0 millimoles) of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> are dissolved in 500 ml of absolute tetrahydrofuran and 50 ml of absolute dimethylsulfoxide, 3.6 g (22.2 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is stirred overnight at room temperature. The solvents are stripped off under reduced pressure on a rotary evaporator and the residue is stirred thoroughly with 100 ml of 0.5 percent strength sodium bicarbonate solution, whereupon crystallization occurs. The crystals are filtered off, washed with water and dried under reduced pressure, over a phosphorus pentoxide desiccant. 5.6 g of crude 1-(2-methylthiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained and are recrystallized from isopropanol, giving 2.7 g of pure product, of melting point 183°-185° C. The following compounds were also obtained by the method described in Example 30: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5; | Synthesis of (F); To a 0° C. solution of Compound (D) (41 mmol) and <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOBT (7.9 g, 50 mmol) and HBTU (18.0 g, 50 mmol) in tetrahydrofuran (800 mL) was added a solution of N,N-diethylisopropylamine (50 g) in tetrahydrofuran (200 mL) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mL), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3.x.400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 436.15). | |
17.1 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5; | To a 0° C. solution of Compound (D) (41 mmol) and <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOBT (7.9 g, 50 mmol) and HBTU (18.0 g, 50 mmol) in tetrahydrofuran (800 mL) was added a solution of N,N-diethylisopropylamine (50 g) in tetrahydrofuran (200 mL) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mL), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 436.15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | ) 2- [2-(5-Methyl-3 -phenyl- isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acidTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (100 mg, 0.7 mmol) in THF (5 mL) at -72°C and under argon was added LDA (0.7 mL of a 2M solution in THF, 1.40 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3 -phenyl- isoxazo Ie (145 mg, 0.7 mmol) in THF (5 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (IN, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated then triturated with diisopropyl ether to give the title compound (135 mg, 61percent) as a light brown solid which was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1242-[(E)-2-(3-Butyl-5-methyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid isoprop- ylamidea) 2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (215 mg, 1.50 mmol) in THF (10 mL) at -78°C and under argon was added n-butyllithium (1.88 mL of a 1.60M solution in hexane, 3.0 mmol) dropwise. After 1 h, a solution of 3 -butyl-5 -methyl- isoxazole-4-carbaldehyde (251 mg, 1.50 mmol) in THF (10 mL) was added dropwise. After 2 h the reaction mixture was quenched with 10percent aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and the residue redissolved in ethyl acetate and washed with NaOH (2 N). The organic phase was dried, filtered and concentrated then purified by chromatography (silica, 0 to 4percent methanol in dichloromethane) to give the title compound (49 mg, 10percent) as a brown oil. MS: m/e = 307.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 572-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid isopropylamidea) 2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (286 mg, 2.0 mmol) in THF (14 mL) at -72°C and under argon was added n-butyllithium (2.50 mL of a 1.6M solution in hexane, 4.0 mmol) dropwise. After 2 h, a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (375 mg, 2.0 mmol) in THF (6 mL) was added dropwise. After 2.5 h the reaction mixture was quenched with 10 percent aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was dissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added. After 15 h, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and purified by chromatography (silica, 0 to 75percent ethyl acetate in heptane) to give the title compound (360 mg, 58 percent) was a light brown oil. MS: m/e = 309.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 402-{2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl)-amidea) 2- {2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl} -thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.37 g, 9.58 mmol) in THF (80 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 12 mL, 19.15 mmol) dropwise. After 2 h at -75°C a solution of 2-(4-chloromethyl-5-methyl-isoxazol-3-yl)-5-fluoro- pyridine (2.17 g, 9.58 mmol) in THF (30 mL) was added dropwise. After 4 h the reaction mixture was quenched with citric acid solution (5percent, 60 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound (4.12 g) as a yellow solid. To a solution of intermediate acid (4.12 g) in MeOH (72 mL) and diethylether (40 mL) was added trimethylsilyldiazo methane (2M in diethylether, 3 x 9.6 mL, 57.48 mmol) under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (cone, 0.7 mL), evaporated and extracted with with ethyl acetate. The combined extracts were washed with NaOH (1 N, 100 mL), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate 1 :0 to 0:1) afforded the title compound (1.37 g, 41percent) as a yellow solid. MS: m/e = 348.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Example 772-{(E)-2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5- carboxylic acid (tetrahydro-pyran-4-yl)-amidea) 2- {2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-2-hydroxy-ethyl} -thiazole-5- carboxylic acidTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.15 g, 8.05 mmol) in THF(67 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 10.06 mL, 16.1 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde(1.66 g, 8.05 mmol) in THF (24 mL) was added dropwise. After 3h the reaction mixture was quenched with citric acid solution (5percent, 50 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by trituration (ethyl acetate) afforded the title compound (1.85 g, 66percent) as a light yellow solid. MS: m/e = 348.2 [M-H]". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 212- [2-(5-Methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl] -thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.03 g, 7.0 mmol) in THF (61 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 8.99 mL, 14.0 mmol) dropwise. After 2 h a solution of 2-(4-chloromethyl-5 -methyl- isoxazo 1-3 -yl)-pyridine (1.5 g, 7.0 mmol) in THF (26 mL) was added dropwise. After 3h the reaction mixture was quenched with citric acid solution (5percent, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound (2.43 g) as a light brown solid. To a solution of intermediate acid (2.43 g) in MeOH (54 mL) and diethylether (30 mL) was added trimethylsilyldiazomethane (2M in diethylether, 21.6 mL, 4.3 mmol) in two portions under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (cone, 0.7 mL), evaporated and extracted with with ethyl acetate. The combined extracts were washed with NaOH (IN), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 2:3) afforded the title compound (915 mg, 39percent) as an orange solid. MS: m/e = 330.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 3h; | CS)-Benzyl 3-methoxy-2-((S)-3-methoxy-2-(2-methyl-N-((5-methyl-2-oxo-l, 3- dioxol-4-yl)methyl)thiazole-5-carboxamido)propanamido)propanoate Referring to FIG. 38, phosphorous oxychloride (323 mu, 3.46 mmol) was added dropwise to (S)-benzyl 3-methoxy-2-((S)-3-methoxy-2-(((5-methyl-2-oxo-l,3-dioxol-4- yl)methyl)amino)propanamido)propanoate (1.46 g, 3.46 mmol), 2-methylthiazole-5- carboxylic acid (248 mg, 3.46 mmol) and pyridine (1.07 mL, 10 mmol) in DCM (20ml) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours, diluted with IN HCl, and extracted with DCM. The organic layer was separated, dried (Na2S04) and evaporated. The residue was purified by flash column chromatography to give the product as a white solid (346 mg, 22percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.1 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5; | To a 0°C. solution of Compound (D) (41 mmol) and<strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOST (7.9 g, 50 mmol) and HH11J (18.0 g, 50 mmol) in tetrahydroffiran (800 mE) was added a solution of N,N-diethylisopropylamine (.?50 g) in tetrahydroffiran (200 mE) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mE), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3x400 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mE) and brine (100 ml), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH)m/z: 436.15). |
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃; for 4h; | P) To a -5 °C mixture of TFA salt (17), 2-methylthiazole-5- carboxylic acid, HOBt, and HBTU in THF is added DIEA slowly. The reaction is kept at the same temperature for 4 h and then diluted with EtOAc and brine. The layers are separated, and the aqueous layer is extracted with EtOAc. The organic layers are combined and dried over Na2S04- The Na2S04 is removed by filtration, and the volatiles are removed under reduced pressure. The resulting residue is purified by flash chromatography using a mixture of hexane and ethyl acetate to provide benzyl ester (18) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; at 160℃; for 0.5h;Microwave irradiation; | <strong>[4316-98-7]6-chloropyrimidine-4,5-diamine</strong> (200mgs, 1.3mmol) and 2-methylthiazole-5-carboxylic acid (218 mgs, 1 .5 mmol) were dissolved in phosphoryl chloride (4 mL) in a 10 mL microwave vial. The reaction mixture was stirred at 160°C for 30 min in a microwave reactor. After cooling down to room temperature reaction mixture was diluted with diethyl-ether and solids filtered out. Solids were re-dissolved in dichloromethane and extracted with aqueous saturated solution of sodium bicarbonate. Organic layer was dried over Mg2SO4 and evaporated under reduced pressure. Solids were suspended in ACN and stirred over 1 hr. Solids were filtered out to yield 5-(6-chloro-9H-purin-8-yl)-2- methylthiazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The title compound was prepared as described in Intermediate 3, by substituting 2- methylthiazole-5-carboxylic acid for 5-methylisoxazole-3-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | To a solution of the compound of Formula XV(a), (S)-2-amino-N?{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethyl}-3-difluoromethoxy-propionamide TFA salt (2.2 g, 3.70 mmol), <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (0.635 g, 4.44 mmol), HOBt (0.649 g, 4.81 mmol) and HBTU (1.82 g, 4.81 mmol) in THF (70 mL) was added DIPEA (1.29 mL, 7.4 mmol) dropwise at 0° C. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was then quenched with ice water, washed with NaHCO3 and brine and extracted with 2×100 mL of ethyl acetate. The organic layer was dried over magnesium sulphate and concentrated. The crude product was purified by column chromatography, eluting with 70percent to 80percent ethyl acetate in hexanes, to give the compound of Formula I of Example 1. (2.11 g, 94.6percent) as a pale-yellowish solid. 1H NMR (300 MHz, CDCl3): delta (ppm) 8.10 (s, 1H), 7.28-7.25 (m, 3H), 7.20 (dd, 2H), 6.82 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 6.18 (wt, 1H), 6.14 (wt, 1H), 4.90-4.65 (m, 2H), 4.60 (td, 1H), 4.35 (dd, 1H), 4.25 (dd, 1H), 4.05 (td, 1H), 3.95 (dd, 1H), 3.30 (d, 1H), 3.28 (dd, 1H), 3.16 (d, 1H), 2.90 (dd, 1H), 2.85 (dd, 1H), 2.75 (s, 3H), 1.41 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 12h; | Dissolve (2S)-2-ammo-l~[4~[2-(4-ammo-6-ehloro-2-methyl-pyrimidin-5- yl)ethyl]-l-piperidyl]propan-l-one (600 mg, 1.84 mmol) and 2-methylthiazole-5- carboxylic acid (290 mg, 2,03 mmol) in THF (12.3 mL). Add 1 -hydroxy-?- azabenzotriazole (281 mg, 2.03 mmol), l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (430 mg, 2.21 mmol) and TEA (0.77 mL, 5,52 mmol). Stir the mixture at room temperature for 12 hours. Dilute the mixture with EtOAc, filter through a SPE cartridge (ISOLUTE® HM-N) washing with EtOAc and remove the solvent under reduced pressiffe. Purify the crude mixture by mass-guided SFC (Waters ZQ MS; 4- nitrobenzene-sulfon amide column, eluting with 0,14 mM ammonia in MeOH/C02) to obtain the title compound as a yellow tar (626 mg, 75percent). LC-ES/MS m/z. (35C1/37C1) 451/453 (M-f-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.8 g | With propylphosphonic anhydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 5 - 20℃; | Dissolve (25)-2-amino- 1 -[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5- yl)ethyl]-l -piperidyl]propan-l-one dihydrochloride (21.0 g, 52.66 mmol), 2-methyl-5- thiazolecarboxylic acid (11.31 g, 78,99 mmol) and DIPEA (36.7 mL, 210.65 mmol) in DCM (210 mL). Stir until complete dissolution and then cool in an ice bath (internal temperature 5 °C). Add dropwise a solution of 1 -propanephosphonic anhydride (50percent solution in EtOAc, 50.27 g, 78.99 mmol) over 5 min to maintain the internal temperature between 5-10 °C. Stir in ice bath for 1 hour, allow to warm to room temperature and stir overnight. Dilute with DCM (200 mL) and wash with saturated aqueous sodium bicarbonate (300 mL). Extract the aqueous layer with DCM (3 * 100 mL) and wash the combined organic layers with saturated ammonium chloride (300 mL), water (300 mL) and brine (500 mL). Dry over MgS04, filter and remove solvent in vacuum. Purify the crude mixture by chromatography (330 g silica gel column) eluting with 15-60percent THF in EtOAc to give the title compound as a pale yellow solid (12.8 g, 54percent). LC-ES/MS m/z' (35C1/37C3) 451/453 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 8h; | To a solution of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> (215 mg, 1.5 mmol), 5-methyl-2-(2- pyridyl)-5,6,7,8-tetrahydropyrido[4,3 d]pyrimidine trifluoroacetic acid salt (227 mg, 1.0 mmol, the product of step 2 in Example 34) in anhydrous DMF (10 mL) was added DIPEA (258 mg,2.0 mmol) and HATU (762 mg, 2.0 mmol). The mixture was stirred at rt for 8 hrs. The mixture was poured into water (50 mL) and the aqueous solution was extracted with EA (100 mL) twice. The organic layer was combined and washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluting with DCM/MeOH=20/ 1, v:v) to provide [5-methyl-2- (2-pyridyl)-7 ,8-dihydro-5H-pyrido [4,3 -d]pyrimidin-6-yl]-(2-methylthiazol-5-yl)methanone (40 mg) as a yellow solid. ?H NMR (400 MHz, CDC13) oe: 8.76 (d, 1H), 8.61 (br s, 1H), 8.43 (d, 1H), 7.78-7.84 (m, 2H), 7.34 (m, 1H), 5.64 (br s, 1H), 4.47 (br s, 1H), 3.50 (br s, 1H), 3.05-3.23 (m, 2H), 2.69 (s, 3H), 1.60 (d, 3H). MS obsd. (ESI)[(M+H)]: 352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.1 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH Ca. 8.5; | To a 0°C. solution of Compound (D) (41 mmol) and <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOST (7.9 g, 50 mmol) and HH11J (18.0 g, 50 mmol) in tetrahydrofuran (800 mE) was added a solution of N,N-diethylisopropylamine (.-50 g) in tetrahydroffiran (200 mL) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mE), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3x400 mE). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 ml), dried over sodium sulfate and filtered through Celite-545®. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH) m/z:436.15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere; | To a stirred solution compound 98 (19 g, 132.86 mmol) in DMF (300 mL) under inert atmosphere were added EDCI.HCl (38.06 g, 199.26 mmol), HOBt (26.9 g, 199.25 mmol) N, O-dimethylhydroxylamine hydrochloride (15.3 g, 158.54 mmol) and diisopropylethylamine (69.48 mL, 398.44 mmol) at 0 oC, followed by warming to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 50percent EtOAc/ hexanes to afford compound 99 (13 g, 53percent) as thick syrup. TLC: 10percent MeOH/ CH2Cl2 (Rf: 0.7); 1H NMR (500 MHz, DMSO-d6): delta 8.26 (s, 1H), 3.75 (s, 3H), 3.27 (s, 3H), 2.68 (s, 3H); LCMS Calculated for C7H10N2O2S: 186.05; Observed: 187.1 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | To the stirred solution of 2-methylthiazole-5-carboxylic acid (1, 1.0 g, 6.99 mmol) in THF (10 mL) at -10 C, was added triethylamine (1.02 mL, 7.34 mmol) followed by ethyl chloro format (0.66 mL, 6.99 mmol) in THF (2 mL) drop wise at -10 C and stirred at same temperature for 1 h. The reaction mixture was filtered through celite and the filtrate was cooled to -10 C. To the filtrate, suspension of NaBH4(0.68 g, 17.4 mmol) in water (2 mL) was added and allowed to attain rt and stirred for 2h. The reaction mixture was diluted with 2N NaOH (5 mL) and extracted with EtOAc (2 X 25 mL). Organic layer was washed with brine (5mL) solution, dried over anhydrous Na2S04and evaporated. The crude residue was purified by gradient column chromatography using 40-60% EtOAc in Hexane to afford the product as yellow oil (2) (0.2 g, 25%, Yield). MS (ESI): Mass calcd. for C5H7NOS, 129.02; m/z found 130.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium phosphate; carbon dioxide; CrH6Mo6O24(3-)*3H3N*3H(1+) In dimethyl sulfoxide at 80℃; for 24h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride at 0℃; for 16h; Reflux; | 12.1 Step 1: preparation of methyl 2-methylthiazole-5-carboxylate. To a 1 L round bottom flask was added 2-methyl-l,3-thiazole-5-carboxylic acid (10.0 g, 70 mmol) and MeOH (100 mL). The reaction mixture was then cooled to 0 °C, and thionyl chloride (13 mL, 180 mmol) was added in a dropwise fashion. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was partially concentrated then diluted with EtOAc. The organic layer was washed with water, brine, dried over MgSCL, then concentrated to afford the title compound as a white solid, which was used without further purification (11.0 g, 100%). |
91.8% | With sulfuric acid In water Reflux; | 1.1-3.1 Step 1: Add Compound A (100g, 0.70mol, 1eq) to 1000ml of methanol, then add concentrated sulfuric acid (100g, 1mol, 1.4eq), heat reflux overnight, TLC detection, reaction complete, pour into ice water, ethyl acetate extraction, sodium bicarbonate solution backwashed and dried to give a brown liquid 106g compound B, yield 91.8%, purity 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: thionyl chloride / 16 h / 0 °C / Reflux 2: ammonium hydroxide / water / 3 h 3: pyridine / 3 h / 50 °C |
Tags: 40004-69-1 synthesis path| 40004-69-1 SDS| 40004-69-1 COA| 40004-69-1 purity| 40004-69-1 application| 40004-69-1 NMR| 40004-69-1 COA| 40004-69-1 structure
[ 1286734-84-6 ]
2-(Trifluoromethyl)thiazole-5-carboxylic acid
Similarity: 0.85
[ 61291-21-2 ]
5-Methylthiazole-2-carboxylic acid
Similarity: 0.81
[ 53137-27-2 ]
2,4-Dimethylthiazole-5-carboxylic acid
Similarity: 0.81
[ 40283-46-3 ]
2-Aminothiazole-5-carboxylic acid
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[ 79836-78-5 ]
Ethyl 2-methylthiazole-5-carboxylate
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[ 1286734-84-6 ]
2-(Trifluoromethyl)thiazole-5-carboxylic acid
Similarity: 0.85
[ 1003-60-7 ]
2-Methylthiazole-5-carbaldehyde
Similarity: 0.83
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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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