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CAS No. : | 6436-59-5 | MDL No. : | MFCD00156148 |
Formula : | C7H9NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QWWPUBQHZFHZSF-UHFFFAOYSA-N |
M.W : | 171.22 | Pubchem ID : | 293353 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.17 |
TPSA : | 67.43 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.99 cm/s |
Log Po/w (iLOGP) : | 1.85 |
Log Po/w (XLOGP3) : | 1.91 |
Log Po/w (WLOGP) : | 1.63 |
Log Po/w (MLOGP) : | 0.37 |
Log Po/w (SILICOS-IT) : | 2.64 |
Consensus Log Po/w : | 1.68 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.24 |
Solubility : | 0.978 mg/ml ; 0.00571 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.95 |
Solubility : | 0.192 mg/ml ; 0.00112 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.16 |
Solubility : | 1.19 mg/ml ; 0.00697 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.65 |
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 |
---|---|---|
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 |
---|---|---|
77% | With ammonia In methanol at 60℃; for 144 h; | Step 1. Syntheis of compound 2A mixture of compound 1 (0.8 g, 4.68 mmol) and NH3/EtOH (10 mL) was stirred at 60 °C for 6 days. Then the mixture was concentrated in vacuo to give the residue, which was purified by chromatography (petroleum: ethyl acetate = 1 : 1) to give compound 2 (0.44 g, 77percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | for 1.5 h; Inductive heating | EtOH, 250 prom, 25 kHz, 2 ml/min, 1.5 h |
86% | at 80℃; for 12 h; | To a stirred solution of thioacetamide 7 (2.12 g, 28.27 mmol) in EtOH (40.00 mL), ethyl bromopyruvate (3.40 mL, 25.70 mmol) was added and the reaction was stirred at 80 °C for 12 h. Solvent was removed under reduced pressure. The crude was purified by means of chromatography on silica gel (20 percent ethyl acetate in petroleum ether) to afford title compound (86 percent yield) as a yellow solid. ESI-MS m/z 172 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 4.41 (q, J = 6.9 Hz, 2H), 2.76 (s, 3H), 1.40 (t, J= 7.1 Hz, 3H). |
83% | With sodium carbonate In neat (no solvent)Milling | General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) An oily mixture of ethyl α-bromopyruvate (9, 2.14 g, 11 mmol) and thioacetamide (10a, 0.75 g, 10 mmol) was ground in presence of Na2CO3 (0.50 g) for 5-6 min. When it becomes solid, the progress of reaction was monitored with TLC. On completion of the reaction, water (20 ml) was added to the reaction followed by extraction with chloroform (20 ml). The organic layer thus separated was dried over anhy. Na2SO4. Excess of solvent was removed by distillation. Filtered the crude product and crystallized from aqueous ethanol (83percent) to give pure solid 12a. Similarly, 12b-12g and 13a-13g were prepared following the above procedure and their formation was confirmed by comparing their melting points with literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 4.5 h; Stage #2: With acetic acid In dichloromethane; toluene at -78 - 25℃; Stage #3: With Rochelle's salt In dichloromethane; water for 0.166667 h; |
A solution of ethyl 2-methylthiazole-4-carboxylate (1.00 g, 5.8 mmol) in toluene (18 mL) at -78° C. was treated dropwise with a diisobutyl aluminum hydride solution in dichloromethane (11.1 mL, 1 M) over 30 minutes, stirred at -78° C. for 4 hours, quenched with acetic acid (0.46 mL), warmed to 25° C. and concentrated. The concentrate was treated with dichloromethane and Rochelle's salt, stirred vigorously until a clear, two-phase solution formed (approximately 10 minutes). The layers were separated and organic layer was washed with 10percent NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 14percent ethyl acetate in hexanes to give the title compound (0.28 g, 38percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With selenium(IV) oxide In acetic acid at 100℃; for 24 h; | To a stirred solution of compound 8 (3.50 g, 20.44 mmol) in glacial acetic acid (50.00 mL), selenium oxide (11.32 g, 102.00 mmol) was added and the reaction was stirred at 100 °C for 24 h. The mixture was cooled down to 25 °C, filtered and volatiles were removed under reduced pressure. Water was added and the aqueous phase was extracted with DCM (3 x 20.00 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude was purified by means of chromatography on silica gel (15 percent ethyl acetate in petroleum ether) to afford title compound (60percent yield) as a pale yellow oil. ESI-MS m/z 186 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 8.50 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: With N-Bromosuccinimide In tetrachloromethane at 76℃; for 1 h; Stage #2: With 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 76℃; for 4 h; |
Ethyl 2-methyl-l,3-thiazole-4-carboxylate (500 mg, 2.92 mmol) was dissolved in CCU (10 rnL) and NBS (624 mg, 3.50 mmol) was added and the reaction heated at 76 0C for 60 min. AIBN (36 mg, 0.21 mmol) was added and heating continued at 76 0C for 4 h. The reaction mixture was allowed to cool to ambient temperature and filtered through Celite. The filter cake was washed with DCM. The combined organic layers were concentrated in vacuo with silica and purified using FCC, eluting with 50 percent EtOAc in heptanes, to afford the title compound. Yield: 274 mg, 38 percent. |
31% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneHeating / reflux | 2-Bromomethyl-thiazole-4-carboxylic acid ethyl ester was prepared according to N. Kindon et al. (U.S. Pat. No. 6,162,808): A mixture of 2-methyl-thiazole-4-carboxylic acid (available from Maybridge pic, Tintagel, UK; 9.8 g, 57.2 mmol), benzoyl peroxide (40 mg, 0.165 mmol) and NBS (10.6 g, 60.0 mmol) in carbon tetrachloride (250 mL) was heated at reflux over the weekend. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The crude material was partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulfate), filtered, evaporated, and purified by chromatography on flash silica gel, eluting with 20percent ethyl acetate/hexane to give 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (4.4 g, 31percent) as an orange oil. 1HNMR (CDCl3): δ 9.23 (s, 1H), 4.77 (s, 2H), 4.44 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H). MS (APCl+): 252 (100), 250 (90). |
31% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneHeating / reflux | 2-Bromomethyl-thiazole-4-carboxylic acid ethyl ester was prepared according to Kindon, N et al. (U.S. Pat. No. 6,162,808): A mixture of 2-methyl-thiazole-4-carboxylic acid (available from Maybridge plc, Tintagel, UK; 9.8 g, 57.2 mmol), benzoyl peroxide (40 mg, 0.165 mmol) and NBS (10.6 g, 60.0 mmol) in carbon tetrachloride (250 mL) was heated at reflux over the weekend. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The crude material was partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulfate), filtered, evaporated, and purified by chromatography on flash silica gel, eluting with 20percent ethyl acetate/hexane to give 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (4.4 g, 31percent) as an orange oil. 1HNMR (CDCl3): δ 9.23 (s, 1H), 4.77 (s, 2H), 4.44 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H). MS (APCI+): 252 (100), 250 (90). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-Bromosuccinimide In tetrachloromethane | Preparation of the starting material: A solution of ethyl 2-methyl-4-thiazolecarboxylate [JCS 1946, 87, E. R. H. Jones, F. A. Robinson, M. N. Strachan] (5.0 g, 29.2 mmol) in CCl4 (30 ml) was treated with N-bromosuccinimide (5.2 g, 29.2 mmol) and benzoylperoxide (0.03 g). The reaction was heated to reflux while irradiating with a strong lamp for 21/2 hours. The reaction mixture was allowed to cool to ambient temperature, filtered and evaporated. The residue was purified by chromatography (eluant: CH2 Cl2) to obtain ethyl 2-bromomethyl-4-thiazolecarboxylate (2.27 g, 31percent). NMR (250 MH, DMSO-d6): δ8.55 (s, 1H), 5.04 (s, 2H), 4.30 (g, 2H), 1.32 (t, 3H). |
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