Structure of 2-Amino-4-(4-pyridyl)-thiazole
CAS No.: 30235-28-0
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CAS No. : | 30235-28-0 |
Formula : | C8H7N3S |
M.W : | 177.23 |
SMILES Code : | NC1=NC(C2=CC=NC=C2)=CS1 |
MDL No. : | MFCD00490009 |
InChI Key : | CUSJGENRTWNHPV-UHFFFAOYSA-N |
Pubchem ID : | 930237 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 11 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 49.75 |
TPSA ? Topological Polar Surface Area: Calculated from |
80.04 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.37 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.2 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.8 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.13 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.31 |
Solubility | 0.874 mg/ml ; 0.00493 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.48 |
Solubility | 0.591 mg/ml ; 0.00333 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.08 |
Solubility | 0.148 mg/ml ; 0.000838 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.53 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.08 |
* 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 |
---|---|---|
General procedure: To a solution of 2 (11.2 mmol) in 25 ml of ethanol at room temperature was added thiourea (13.4 mmol).The reaction mixture was stirred at room temperature for 1 hour, quenched with water and washed with dichloromethane. The aqueous phase was concentrated in vacuo to give a yellow solid HBr salt. The salt was then dissolved in minimal amount of water and 10% NaOH added drop wise until a white precipitate 3 formed (approximately at pH 8).The precipitate was then filtered and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; for 2h;Inert atmosphere; Reflux; | General procedure: A mixture of the substrate (i.e. appropriate bromoketone) (1 eq) and thiourea (1.5 eq) in EtOH (3 mL per 1 mmol of bromoketone, unless stated otherwise) was refluxed for 2 h (unless stated otherwise). |
With potassium carbonate; In ethanol; for 5h;Reflux; | General procedure: Preparation of 4-pyridin-3-yl-thiazol-2-ylamine l-b To a solution of 2-bromo-l-pyridin-3-yl-ethanone Hydrobromide l-a (10 g, 35.58 mmol) in ethanol (100 mL) was added thiourea (2.98 g, 39.21 mmol), K2C03 (9.83 g, 71 .16 mmol) and the reaction mixture was refluxed for 5h. After cooling to room temperature and evaporation of solvent, 150 mL of a saturated solution of NaHC03 was added and reaction mixture was stirred for 1 h. The precipitate was collected by filtration, washed by water and dried under vacuum to give the title compound l-b (6,2 g, 98%). H NMR (400 MHz, DMSO-cfe) H NMR (400 MHz, DMSO-d6) delta 9.01 (d, J = 2.0 Hz, 1 H), 8.45 (dd, J = 4.7, 1 .5 Hz, 1 H), 8.12 (dt, J = 7.9, 1 .9 Hz, 1 H), 7.39 (dd, J = 8.0, 4.8 Hz, 1 H), 7.20 (s, 1 H), 7.19 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-(1-methanesulfonyl) benzotriazole; triethylamine; In tetrahydrofuran; at 160℃; for 0.166667h;Microwave; | Methanesulfonic acid 3- [ (4-PYRIDIN-4-YL-THIAZOL-2-YLCARBAMOYL)-METHYL]- phenyl ester: 4- (4-PYRIDYL)-2-AMINOTHIAZOLE (317 mg, 1.79 MMOL), 3-HYDROXYPHENYLACETIC acid (343 mg, 2.25 mmol) and N- (1-METHANESULFONYL) benzotriazole (927 mg, 4.70 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). THF (2 mL) was added followed by triethylamine (1.24 mL, 8.93 mmol) and the mixture heated in the sealed tube at 160C for 10 minutes. Upon cooling to room temperature the solvent was concentrated and ethanol added. The mixture was stored at -20C and then the precipitated product was filtered, washed with ethanol and dried. (910 mg, 65%). LH NMR (500 MHz, DMSO-d6) 12.62 (1H, s), 8.63 (2H, d), 7.98 (1H, s), 7.84 (2H, d), 7.47 (1H, m), 7.36 (2H, m), 7.27 (1H, m), 3.89 (2H, s), 3.40 (3H, s). LC-MS Rt = 2.1 min, [M+H] + = 390, [M-H]-= 388. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-(1-methanesulfonyl) benzotriazole; triethylamine; In tetrahydrofuran; at 160℃; for 0.166667h;Microwave; | 2- (2-FLUOROPHENYL)-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE : 4- (4-PYRIDYL)-2- aminothiazole (329 mg, 1.86 mmol), 2-fluorophenylacetic acid (377 mg, 2.25 mmol) and N- (1-methanesulfonyl) benzotriazole (440 mg, 2.23 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). THF (2 ML) was added followed by triethylamine (0.52 ML, 3.73 mmol) and the mixture heated in the sealed tube at 160 C for 10 minutes. Upon cooling to room temperature the product 2- (2-FLUOROPHENYL)-N- (4-PYRIDIN- 4-yl-thiazol-2-yl) -acetamide precipitated, was filtered, washed with acetonitrile and dried. (462 mg, 76%).'H NMR (500 MHz, DMSO-d6) 6 12.68 (1H, s), 8.63 (2H, d), 8.00 (1H, s), 7.84 (2H, d), 7.43-7. 17 (4H, m), 3.90 (2H, s). LC-MS Rt = 1.9 min, [M+H]+= 314, [M-H]-= 312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In 1,4-dioxane;Heating / reflux; | 2-CHLORO-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE : A solution of 4-pyridin-4- yl-thioazol-2-ylamine (3.64 g, 0.02 mol) and chloroacetyl chloride (3.39 g, 0.03 mol) in dioxane was refluxed overnight then cooled to room temperature. The solid precipitate was filtered, then the filtration cake was suspended in saturated KHC03, then filtered again. The filtration cake was washed with water dried in dessicator over P205. 2-CHLORO-N- (4-PYRIDIN- 4-yl-thiazol-2-yl)-acetamide (4.3 g, 85%).'H NMR (500 MHz, DMSO-d6) 8 4.42 (s, 2H), 7.9 (d, 2H), 8.77 (d, 2H). |
With triethylamine; In tetrahydrofuran; at 0℃; for 2h; | 4-(Pyridin-4-yl)thiazol-2-amine (0.025 moles, 4.41 g) andtriethylamine (0.03 mole, 4.21 mL) were dissolved in THFwith constant stirring at 0-5C. Then, chloro-acetyl chloride(0.03 mole, 2.90 mL) was added dropwise gradually to thissolution. The reaction mixture thus obtained was further agitatedfor 2 h at 0C. After the solvent was vaporized to dryness,the solid was washed with water and filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; | 3- (3-METHOXY-PHENYL)-1- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-PIPERIDIN-2-ONE : 2- (3- METHOXY-PHENYL)-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE (prepared according to General Method A from 4- (4-PYRIDYL)-2-AMINOTHIAZOLE and 3-methoxyphenylacetic acid: 1 mmol), triphenylphosphine (1.2 mmol), diisopropyl azodicarboxylate (1.2 mmol) and THF were were stirred overnight at room temperature. The mixture was then cooled to 0 C and NaH (1.2 mmol) added and reaction mixture was stirred at 0 C for 30 minutes. MEOH was added to quench the reaction. The solvent was evaporated and the residue dissolved in ethyl acetate and washed with H20 and dried over NA2SO4. The product was purified by flash column chromatography on silica gel to afford 3- (3-methoxyphenyl)-1- (4-pyridin-4-yl-thiazol-2-yl)- piperidin-2-one in 60% YIELD.'H NMR (500 MHz, DMSO-d6) 8 8.67 (d, 2H), 7.80 (d, 2H), 7.46 (s, 1H), 7.30 (m, 1H), 6.85 (m, 3H), 4.57 (m, 1H), 4.32 (m, 1H), 3.93 (m, 1H), 3.82 (s, 3H), 2.36 (m, 1H), 2.25 (m, 1H), 2.15 (m, 2H). LC-MS (10-90% CH3CN in H20), Rt = 2.40 min, [M+H] + = 366, [M-H]-= 364. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With ammonia; In water; | 4-PYRIDIN-4-YL-THIAZOL-2-YLAMINE : To 4- (BROMOACETYL)-PYRIDINE hydrobromide (Can. J. Chem. , 1970,7, 1137) (97.5 g, 0.35 mol) and thiourea (26.5 g, 0.35 mol) was added ethanol (900 mL) and the mixture heated to reflux for 2 hours. After cooling to 4 C the product was filtered, washed with ethanol and diethyl ether and dried under suction. The solid 4-pyridin-4-yl-thiazol-2-ylamine dihydrobromide (88.7 g) was dissolved in warm water (500 mL) and the desired 4-PYRIDIN-4-YL-THIAZOL-2-YLAMINE obtained as a light brown solid upon addition of 7% aqueous ammonium hydroxide (800 mL). 43.5 g, 71%. LH NMR (500 MHz, DMSO-d6) 6 8.53 (2H, d), 7.71 (2H, d), 7.38 (1H, s), 7.16 (2H, br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In acetone; at 0 - 20℃; for 2.5h; | A solution of 1 (1 eq) and sodium carbonate (1.5 eq) in acetone was stirred in an ice bath under an atmosphere of nitrogen. Thiophosgene (1.5 eq) was added drop wise over 30 minutes. The reaction was stirred for another 30 minutes in the ice bath before being removed and allowed to warm to RT. The reaction was stirred at RT for 1.5 h before the reaction solution was concentrated under vacuum. Toluene was added to the crude product and removed under vacuum to azetrope off any residual thiophosgene and afford the product 2. MS: MH+=219 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
410 mg (65%) | (B) 4-(4-Pyridyl)-1,3-thiazol-2-amine Reactions were performed in the same manner as in Example 8, (A) by using 2-bromo-1-(4-pyridyl)-1-ethanone (1 g, 3.56 mmol) to obtain 410 mg (65%) of the title compound. 1H-NMR (CD3OD) delta:7.26 (1H, s), 7.80 (2H, d, J=6.35 Hz), 8.50 (2H, d, J=6.35 Hz) EI/MS; m/z: 176 (M+-1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Example 1-657V-(3-Methylbenzyl)-4-(4-pyridinyl)- 1 ,3-thiazol-2-amine (103). [0319] 7V-(3-Methylbenzyl)-4-(4-pyridinyl)-l,3-thiazol-2-amine (103). A mixture of 2-aminothiazole 98 (0.31 g, 1.8 mmol) and 3-methylbenzaldehyde (0.25 mL, 2.1 mmol) in THF (20 mL) was stirred at reflux temperature for 4 h. The mixture was cooled to 20 0C and a solution OfNaBH4 (265 mg, 7.0 mmol) in water (4 mL) was added dropwise and the mixture was stirred at 20 0C for 30 min. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 25 mL). The combined organic fraction was dried and the solvent evaporated. The crude solid was purified by column chromatography, eluting with a gradient (50-100%) of EtO Ac/pet, ether, to give amine 103 (0.11 g, 22%) as a cream powder: mp (MeOH/EtOAc) 192-194 0C; 1H NMR delta 8.54 (dd, J= 4.5, 1.6 Hz, 2 H, H-2', H- 6'), 8.30 (t, J= 5.8 Hz, 1 H, NH), 7.75 (dd, J= 4.5, 1.6 Hz, 2 H, H-3', H-5'), 7.42 <n="138"/>(s, 1 H, H-5), 7.17-7.24 (m, 3 H, H-2", H-4", H-5"), 7.07 (br d, J= 6.9 Hz, 1 H, H- 6"), 4.48 (d, J= 5.8 Hz, 2 H, CH2N), 2.30 (s, 3 H, CH3); MS m/z 282.5 (MH+, 100%). Anal, calcd for Ci6Hi5N3S-1Z4CH3OH: C, 67.87; H, 5.48; N, 14.72. Found: C, 67.78; H, 5.42; N, 14.92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | COMPOUND 3a4-(Pyridin-4-yl)thiazol-2-amine. Synthesis of batch 1. A mixture of 4-(bromoacetyl)pyridine hydrobromide (2) (2.21 g, 7.90 mmol), thiourea (0.60 g, 7.90 mmol) in anhydrous EtOH (10 ml) was stirred in a Biotage microwave at 100 C for 30 min. After colling to room temperature, the solid precipitate was filtered, dried under vacuum.Synthesis of batch 2. A mixture of 4-(bromoacetyl)pyridine hydrobromide (2) (2.54 g, 9.06 mmol), thiourea (0.69 g, 9.06 mmol) in anhydrous EtOH (10 ml) was stirred in a Biotage microwave at 100 C for 30 min. After colling to room temperature, the solid precipitate was filtered, dried under vacuum.Synthesis of batch 3. A mixture of 4-(bromoacetyl)pyridine hydrobromide (2) (2.16 g, 7.73 mmol), thiourea (0.58 g, 7.73 mmol) in anhydrous EtOH (10 ml) was stirred in a Biotage microwave at 100 C for 30 min. After colling to room temperature, the solid precipitate was filtered, dried under vacuum.Batches 1, 2, and 3 were combined, suspended in an aqueous sat. solution of NaHC03 , filtered, dried under vacuum to provide the title compound as a pale pink solid (5.53 g, 31.27 mmol, 95%), 1H NMR (400 MHz, CD3OD) delta 8.49 (d, J= 6.3 Hz, 2H), 7.79 (d, J= 6.3 Hz, 2H), 7.25 (s, 1H). | |
93% | A mixture of 2-bromo-l-pyridin-4-yl-ethanone hydrobromide (10 g, 35.59 mmol) and thiourea (2.71 g, 35.59 mmol) in absolute EtOH (100 mL) was re fluxed overnight. After cooling, the reaction mixture was diluted with water (400 mL), the pH was adjusted to 11 with ammonium hydroxide solution, and it was further stirred for 2h. The resulting precipitate was filtered, washed with water, and dried in vacuo to provide 5.85 g of 4-(2-amino- thiazol-4-yl)-pyridine as a pinkish solid (93% yield): 1H NMR (DMSO-dtf, ppm) delta 7.23 (broad s, 2H), 7.42 (s, 1H), 7.74 (d, 2H), 8.56 (d, 2H); [M+H]+ m/z 178 | |
Example 1-61N- [4-(4-Pyridinyl)- 1 ,3-thiazol-2-yl] benzamide (99). [0314] 4-(4-Pyridinyl)-l,3-thiazol-2-amine (98). A mixture of bromoketone hydrobromide 1 (5.0 g, 17.8 mmol) and thiourea (1.36 g, 17.8 mmol) in EtOH (100 mL) was stirred at reflux temperature for 2 h. The mixture was cooled to 20 0C, diluted with water (50 mL), the pH adjusted to ca. 8 with aqueous NH3 and the mixture stirred at 0 0C for 1 h. The precipitate was filtered, washed with water (5 mL) and ether (5 mL) and dried to give amine 98 (2.70 g, 86%) as a pink powder: mp (EtOH/H2O) 278-282 0C [lit. (Westphal, G. et al, J Prakt. Chemie (Leipzig) 1976, 318, 875) mp (EtOH) 276-277 0C]; 1H NMR delta 8.53 (dd, J= 4.6, 1.6 Hz, 2 H, H-2', H-6'), 7.91 (dd, J= 4.6, 1.6 Hz, 2 H, H-3', H-5'), 7.38 (s, 1 H, H-5), 7.16 (br s, 2 H, NH2); MS m/z 178.3 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With pyridine; dmap; at 20℃; for 16h; | Example 1-644-Methoxy-7V-[4-(4-pyridinyl)-l,3-thiazol-2-yl]benzamide (102). <n="137"/>[0318] 4-Methoxy-7V-[4-(4-pyridinyl)-l,3-thiazol-2-yl]benzamide (102). 4-Methoxybenzoyl chloride (0.77 mL, 5.5 mmol) was added to a stirred solution of amine 98 (0.89 g, 5.0 mmol) and DMAP (60 mg, 0.5 mmol) in pyridine (30 mL) and the solution stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between water (70 mL) and EtOAc (70 mL). The organic fraction was washed with water (30 mL), dried and the solvent evaporated. The crude solid was purified by column chromatography, eluting with a gradient (0- 10%) of MeOH/DCM, to give benzamide 102 (448 mg, 61%) as a white powder: mp (MeOH/DCM) 271-274 0C; 1H NMR delta 12.66 (s, 1 H, NHCO), 8.63 (dd, J = 4.5, 1.6 Hz, 2 H, H-2", H-6"), 8.15 (ddd, J= 8.9, 2.9, 2.0 Hz, 2 H, H-2, H-6), 8.01 (s, 1 H, H-5'), 7.88 (dd, J= 4.5, 1.6 Hz, 2 H, H-3", H-5"), 7.09 (ddd, J= 8.9, 2.9, 2.0 Hz, 2 H, H-3, H-5), 3.86 (s, 3 H, OCH3); 13C NMR delta 164.6, 162.7, 159.2, 150.1 (2), 146.5, 141.0, 130.2 (2), 123.8, 119.9 (2), 113.8 (2), 112.4, 55.4; MS m/z 312.5 (MH+, 100%). Anal, calcd for Ci6Hi3N3O2S: C, 61.72; H, 4.21; N, 13.50. Found: C, 61.38; H, 4.48, N, 13.41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With pyridine; dmap; at 20℃; for 16h; | [0315] TV- [4-(4-Pyridinyl)- 1 ,3-thiazol-2-yl] benzamide (99). Benzoyl chloride (0.44 mL, 3.8 mmol) was added to a stirred solution of amine 98 (0.44 g, 2.5 mmol) and DMAP (30 mg, 0.25 mmol) in pyridine (30 mL) and the solution stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between water (70 mL) and EtOAc (70 mL). The organic fraction was washed with water (30 mL), dried and the solvent evaporated. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give benzamide 99 (448 mg, 61%) as a white powder: mp (MeOH/DCM) 241-243 0C; 1H NMR delta 12.84 (s, 1 H, NHCO), 8.64 (dd, J= 4.5, 1.6 Hz, 2 H, H-2", H-6"), 8.14 (br d, J= 7.1 Hz, 2 H, H-2, H-6), 8.04 (s, 1 H, H-5'), 7.90 (dd, J= 4.5, 1.6 Hz, 2 H, H-3", H-5"), 7.56 (tt, J= 7.4, 1.3 Hz, 1 H, H-4), 7.35-7.39 (m, 2 H, H-3, H- 5); 13C NMR delta 165.3, 159.0, 150.1 (2), 146.6, 140.9, 132.6, 131.7, 128.5 (2), 128.1 (2), 119.9 (2), 112.6; MS m/z 282.4 (MH+, 100%). Anal, calcd for CI5HHN3OS: C, 64.04; H, 3.94; N, 14.94. Found: C, 63.75; H, 4.12, N, 14.93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 16h; | Example 1-623-Methyl-7V- [4-(4-py ridinyl)-. ,3-thiazol-2-yl] benzamide (100). [0316] 3-Methyl-7V-[4-(4-pyridinyl)-l,3-thiazol-2-yl]benzamide (100). Oxalyl chloride (0.26 mL, 3.0 mmol) was added to a stirred solution of m-toluic acid (0.41 g, 3.0 mmol) and DMF (3 drops) in DCM (30 mL) and the solution stirred at 20 0C for 1 h. A solution of amine 98 (354 mg, 2.0 mmol) was added and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between water (70 mL) and EtOAc (70 mL). The organic fraction was washed with water (30 mL), dried and the solvent evapporated. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 100 (110 mg, 19%) as a cream powder: mp (MeOH/EtOAc) 201- 202 0C; 1H NMR delta 12.77 (br s, 1 H, CONH), 8.64 (dd, J= 4.6, 1.6 Hz, 2 H, H-2", H-6"), 8.05 (s, 1 H, H-5), 7.98 (br s, 1 H, H-2), 7.92 (br d, J= 6.9 Hz, 1 H, H-6), 7.88 (dd, J= 4.6, 1.6 Hz, 2 H, H-3", H-5"), 7.42-7.48 (m, 2 H, H-4, H-5), 2.41 (s, <n="136"/>3 H, CH3); 13C NMR delta 165.4, 159.0, 150.1 (2), 146.5, 140.9, 137.8, 133.1, 131.7, 128.6, 128.3, 125.2, 119.2 (2), 112.5, 20.7; MS m/z 296.4 (MH+, 100%). Anal, calcd for Ci6Hi3N3OS: C, 65.06; H, 4.44; N, 14.23. Found: C, 65.19 H, 4.56; N, 14.31%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 16h; | Example 1-634-Methyl-7V- [4-(4-py ridinyl)-l ,3-thiazol-2-yl] benzamide (101). [0317] 4-Methyl-7V-[4-(4-pyridinyl)-l,3-thiazol-2-yl]benzamide (101). Oxalyl chloride (0.26 rnL, 3.0 mmol) was added to a stirred solution of/>toluic acid (0.41 g, 3.0 mmol) and DMF (3 drops) in DCM (30 mL) and the solution stirred at 20 0C for 1 h. A solution of amine 98 (354 mg, 2.0 mmol) was added and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between water (70 mL) and EtOAc (70 mL). The organic fraction was washed with water (30 mL), dried and the solvent evaporated. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 101 (328 mg, 56%) as a cream powder: mp (MeOH/EtOAc) 238- 241 0C; 1H NMR delta 12.74 (s, 1 H, CONH), 8.63 (dd, J= 4.5, 1.6 Hz, 2 H, H-2", H- 6"), 8.04 (br d, J= 8.0 Hz, 2 H, H-2, H-6), 8.02 (s, 1 H, H-5), 7.89 (dd, J= 4.6, 1.6 Hz, 2 H, H-3", H-5"), 7.35 (br d, J= 8.0 Hz, 2 H, H-3, H-5), 2.39 (s, 3 H, CH3); 13C NMR delta 165.2, 159.0, 150.1 (2), 146.5, 142.9, 140.9, 129.2 (2), 128.9, 128.1 (2), 119.2 (2), 112.5, 20.9; MS m/z 296.4 (MH+, 100%). Anal, calcd for Ci6Hi3N3OS: C, 65.06; H, 4.44; N, 14.23. Found: C, 64.96 H, 4.62; N, 14.24%. |
Yield | Reaction Conditions | Operation in experiment |
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64% | 2- [3- (3-CHLOROPROPOXY)-PHENYL]-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE : A suspension of 1-methylsulfonylbenzentriazole (2.87 g, 0.0146 MOL), [3- (3-CHLORO-PROPOXY)- phenyl]-acetic acid (3.33 g, 0.0146 mol) and triethylamine (2.94 g, 0.0291 mol) was stirred at room temperature for 3 hours, then to the suspension was added 4-pyridin-4-yl-thiazol-2- ylamine, and the reaction mixture was refluxed for 20h, then cooled to room temperature. The precipitated solid was filtered, washed and dried to afford 2- [3- (3-CHLOROPROPOXY)- PHENYL]-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE, (2. 5g, 64%).'H NMR (500 MHz, CD30D) 8 2.18 (m, 2H), 3.78 (s, 2H), 3.80 (t, 2H), 4.05 (t, 2H), 6.85 (dd, 1H), 6.9 (dd, 1H), 6.95 (d, 1H), 7.26 (dd, 1H), 7.85 (d, 2H), 8.02 (s, 1H), 8.63 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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53% | In N,N-dimethyl-formamide; at 150℃; for 0.166667h; | COMPl-Phenyl-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. A mixture of 3a (0.081 g, 0.457 mmol), phenyl isocyanate (0.065 g, 0.559 mmol) in anhydrous DMF (0.5 ml), was stirred in a Biotage microwave at 150 C for 10 min After cooling to room temperature, the solvent was removed under reduced pressure and chromatography on silica gel performed using the FlashMaster 3 purification station afforded 6a as an off white solid (0.072 g, 0.243 mmol, 53%). 1H NMR (400 MHz, DMSO-d6) delta 10.77 (bs, 1H), 8.91 (bs, 1H), 8.60 (d, J= 6.0 Hz, 2H), 7.90 (s, 1H), 7.81 (d, J= 6.1 Hz, 2H), 7.47 (d, J= 8.3 Hz, 2H), 7.32 (t, J= 7.9 Hz, 2H), 7.04 (t, J= 7.4 Hz, 1H); HRMS (ESI +ve) m/z calculated for Ci5Hi3N4OS (M + H)+ 297.0804, found 297.0809. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In N,N-dimethyl-formamide; at 150℃; for 0.333333h;Biotage microwave; | COMPOUND 6cl-(4-Fluorophenyl)-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. A mixture of 3a (0.095 g, 0.536 mmol), 4-fluorophenyl isocyanate (0.147 g, 1.073 mmol) in anhydrous DMF (0.6 ml), was stirred in a Biotage microwave at 150 C for 20 min After cooling to room temperature, the solvent was removed under reduced pressure and chromatography on silica gel performed using the FlashMaster 3 purification station afforded 6c as an off white solid (0.047 g, 0.149 mmol, 28%). 1H NMR (400 MHz, DMSO-d6) delta 10.82 (s, 1H), 8.96 (s, 1H), 8.59 (d, J= 6.0 Hz, 2H), 7.91 (s, 1H), 7.81 (d, J= 6.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H); HRMS (ESI +ve) m/z calculated for Ci5Hi2N4FOS (M + H)+ 315.0710, found 315.0713. |
Yield | Reaction Conditions | Operation in experiment |
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35% | In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.333333h; | COMPOUND laal-Benzyl-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. A mixture of 3a (0.251 g, 1.41 mmol), benzyl isocyanate (0.357 g, 2.82 mmol) in anhydrous NMP (1.4 ml), was stirred in a Biotage microwave reactor at 150 C for 20 min. After cooling to room temperature, DCM was added and the organic layer washed with water and brine, dried over Na2S04 and the solvent removed under reduced pressure. Chromatography on silica gel performed using the FlashMaster 3 purification station afforded laa as an off white solid (0.156 g, 0.503 mmol, 35%). 1H NMR (400 MHz, DMSO-d6) delta 10.82 (s, 1H), 8.56 (d,J= 5.8 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J= 5.7 Hz, 2H), 7.34-7.22 (m, 5H), 7.01 (t, J= 5.6 Hz, 1H), 4.34 (d, J= 6.0 Hz, 2H); 13C NMR (400 MHz, DMSO-d6) delta 161.00, 154.63, 150.85, 146.80, 141.70, 140.18, 129.08, 127.82, 127.62, 120.48, 111.74, 43.57. HRMS (ESI +ve) m/z calculated for Ci6Hi4N4OS (M + H)+ 311.0961 , found 311.0970. |
Yield | Reaction Conditions | Operation in experiment |
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10% | In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.333333h;biotage microwave; | COMPOUND labl-(4-Chlorobenzyl)-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. This was prepared from3a (0.097 g, 0.548 mmol) and 4-chlorobenzyl isocyanate (0.183 g, 1.09 mmol) in the same manner as described for laa. Chromatography on silica gel performed using theFlashMaster 3 purification station afforded lab as an off white solid (0.019 g, 0.055 mmol, 10%). 1H NMR (DMSO-de) delta 10.89 (s, 1H), 8.56 (d, J= 6.0 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J= 6.1 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.31 (d, J= 8.3 Hz, 2H), 7.04 (t, J= 7.0 Hz, 1H), 4.32 (d, J= 5.7 Hz, 2H); HPLC purity 9% {tR = min, Flow lml/min, [(CH3CN/(0.1% TFA in H2O):30/70]; purity % {tR = min, Flow lml/min, [(MeOH/(0.1% TFA in H2O):50/50]; HRMS (ESI +ve) m z calculated for Ci6Hi4FlN4OS (M + H)+ 345.0571, found. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.333333h;Biotage microwave; | COMPOUND lajl-(3-Fluorobenzyl)-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. This was prepared from 3a (0.105 g, 0.593 mmol) and 3-fiuorobenzyl isocyanate (0.179 g, 1.18 mmol) in the same manner as described for laa. Chromatography on silica gel performed using theFlashMaster 3 purification station afforded laj as an off white solid (0.019 g, 0.030 mmol, 5%). 1H NMR (400 MHz, DMSO-d6) delta 10.90 (s, 1H, disappeared on D20 shake), 8.57 (d, J = 6.1 Hz, 2H,), 7.82 (s, 1H), 7.78 (d, J= 6.1 Hz, 2H,), 7.39-7.34 (m, 1H), 7.149-7.04 (m, 4H), 4.36 (d, J= 6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) delta 162.90 (d, J= 241.9 Hz, C-F), 160.98, 154.72, 150.85, 146.81 , 143.39 (d, J= 7.0 Hz, C), 141.70, 131.02 (d, J= 8.25 Hz, CH), 123.74 (d, J= 2.67 Hz, CH), 120.49, 1 14.48 (d, J= 1 1.8 Hz, CH), 1 14.26 (d, J = 1 1.15 Hz, CH), 1 1 1.79, 43.10 (d, J = 1.4 Hz, CH2); HPLC purity 99.27% {tR = 6.400 min, Flow lml/min, [(CH3CN/(0.1% TFA in H2O):30/70] ; purity 99.1 1% {tR = 7.133 min, Flow lml/min, [(MeOH/(0.1% TFA in H2O):50/50] ; HRMS (ESI +ve) m/z calculated for Ci6Hi4FN4OS (M + H)+ 329.0866, found 329.0870 |
Yield | Reaction Conditions | Operation in experiment |
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54% | In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.333333h; | COMPOUND lah(R)-l-(l-Phenylethyl)-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. This was prepared from 3a (0.126 g, 0.711 mmol) and (R)-(+)-alpha-methylbenzyl isocyanate (0.209 g, 1.42 mmol) in the same manner as described for laa. Chromatography on silica gel performed twice using the FlashMaster 3 purification station, afforded lah as a white solid (0.125 g, 0.385 mmol, 54%). 1H NMR (400 MHz, DMSO-d6) delta 10.51 (s, 1H), 8.56 (d, J= 5.8 Hz, 2H), 7.80 (s, 1H), 7.76 (d, J= 6.0 Hz, 2H), 7.36-7.31 (m, 4H), 7.26-7.24 (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.84 (quint, J= 7.3 Hz, 1H), 1.40 (d, J= 6.9 Hz, 6H); 13C NMR (400 MHz, DMSO-d6) delta 160.80, 153.72, 150.84, 146.77, 145.01, 141.64, 129.14, 127.61, 126.47, 120.48, 1 1 1.71 , 49.71 , 23.54; HPLC purity 99.22% {tR = 7.907 min, Flow lml/min,[(CH3CN/(0.1% TFA in H2O):30/70] ; purity 99.51% {tR = 8.653 min, Flow lml/min, [(MeOH/(0.1% TFA in H2O):50/50] ; HRMS (ESI +ve) m z calculated for C17H17N4OS (M + H)+ 3251 1 17, found 325.1 1 16.The enantiomeric excess was determined by HPLC using a Chiralcel OJ column[(/so-propanol/Hexane:50/50), Flow lml/min], tRi = 9.067 min, Area %> 0.404 (minor), 14.300 min, Area % 98.378 (major). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.333333h;Biotage microwave; | COMPOUND lai(S)-l-(l-Phenylethyl)-3-(4-(pyridin-4-yl)thiazol-2-yl)urea. This was prepared from 3a (0.1 10 g, 0.621 mmol) and (S)-(-)-alpha-methylbenzyl isocyanate (0.182 g, 1.24 mmol) in the same manner as described for laa. Chromatography on silica gel performed twice using the FlashMaster 3 purification station, afforded lai as a white solid (0.87 g, 0.268 mmol, 43%). 1H NMR (400 MHz, DMSO-d6)5 10.52 (s, 1H), 8.57 (d, J= 6.0 Hz,2H), 7.80 (s, 1H), 7.76 (d, J= 6.1 Hz, 2H), 7.37-7.32 (m, 4H), 7.27-7.21 (m, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.84 (p, J= 6.6 Hz, 1H), 1.41 (d, J= 6.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) delta 160.79, 153.71 , 150.85, 146.76, 145.01 , 141.64, 129.14, 127.61 , 126.47, 120.48, 1 1 1.72, 49.71 , 23.54; HPLC purity 99.74% {tR = 7.480 min, Flow lml/min,[(CH3CN/(0.1% TFA in H2O):30/70] ; purity 99.541% {tR = 8.653 min, Flow lml/min, [(MeOH/(0.1% TFA in H2O):50/50] ; HRMS (ESI +ve) m/z calculated for Ci7Hi7N4OS (M + H)+ 3251 1 17, found 325.1 1 16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | COMPPhenyl 4-(pyridin-4-yl)thiazol-2-ylcarbamate. Phenyl chlorophormate (2.10 g,13.53 mmol) was added dropwise at 0 C, under Argon to a mixture of 3a (1.69 g, 9.59 mmol) in anhydrous pyridine (5 ml) and anhydrous DCM (5 ml). Anhydrous pyridine (4 ml) was then added. After stirring at room temperature for 3h, the reaction mixture was quenched with sodium bicarbonate (aq. sat. solution). The crude material was extracted twice with DCM. The organic extracts were collected, dried over Na2S04 and the solvent removed under reduced pressure. The solid residue was trituraturated with hexane/ethyl acetate (8/2, 30 ml), filtered, dried under vacuum. The pure carbamate 9 was obtained as a pale orange solid (2.15 g, 7.23 mmol, 73%). 1H NMR (400 MHz, DMSO-d6) delta 12.58 (s, 1H), 8.61 (d, J= 6.0 Hz, 2H), 8.02 (s, 1H), 7.82 (d, J= 6.1 Hz, 2H), 7.44 (t, J= 7.7 Hz, 2H), 7.30 (d, J= 6.9 Hz, 2H), 7.27 (t, J= 8.6 Hz, 1H). |