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CAS No. : | 23012-13-7 | MDL No. : | MFCD06797151 |
Formula : | C4H3NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JBCFJMYPJJWIRG-UHFFFAOYSA-N |
M.W : | 113.07 | Pubchem ID : | 14281430 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 23.46 |
TPSA : | 63.33 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) : | -6.85 cm/s |
Log Po/w (iLOGP) : | -0.08 |
Log Po/w (XLOGP3) : | 0.2 |
Log Po/w (WLOGP) : | 0.37 |
Log Po/w (MLOGP) : | -1.21 |
Log Po/w (SILICOS-IT) : | 0.31 |
Consensus Log Po/w : | -0.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.06 |
Solubility : | 9.77 mg/ml ; 0.0864 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.09 |
Solubility : | 9.22 mg/ml ; 0.0815 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.55 |
Solubility : | 31.6 mg/ml ; 0.279 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.86 |
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 |
---|---|---|
The combination of 75 and 94 to give 95 was carried out by the procedure of Cornforth and Cornforth in J. Chem. Soc. 1947, 96-102. |
Yield | Reaction Conditions | Operation in experiment |
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1) 10.32. 3-fluoro-10-[5-(4-oxazolyl)-1,2,4-oxadiazol-3-yl]-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine, m.p. 301-302 C., from 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo-[1,5-d][1,4]benzodiazepine-10-carboxamidoxime and <strong>[23012-13-7]oxazole-4-carboxylic acid</strong>; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1 ,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (30 mg) in DMF (4 mL) was added DIPEA (125 mg), followed by HATU (138 mg). The reaction was stirred at room temperature for 15 mins. Methyl 5-(4-aminophenyl)-3-[[(frans-4-methylcyclohexyl)carbonyl](1 -methylethyl)amino]-2- thiophenecarboxylate (100 mg, a synthesis of which is described as Intermediate 9) was added and the reaction mixture was stirred at 5O0C for 5 h. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between DCM and sodium bicarbonate. The organic phase was collected and dried by passing through a hydrophobic frit and was concentrated in vacuo. The residue was loaded onto a 4Og silica ISCO cartridge. The cartridge was eluted with a gradient 5-100% EtOAc in cyclohexane to give the title compound.MS calcd for (C27H31N3O5S + H)+: 510MS found (electrospray): (M+H)+ = 510 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | A solution of <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (150 mg, 1.3 mmol) in N,N-dimethylformamide (DMF) (2 mL) was treated with N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.61 g, 1.6 mmol) at 0 C. and stirred for 5 min. The reaction mixture was treated with 3-chloro-4-fluoroaniline (290 mg, 2.0 mmol) and stirred at 25 C. for 16 h. The reaction mixture was poured into saturated NaHCO3 (30 mL) and extracted with ethyl acetate (EtOAc) (50 mL). The organic layer was separated and washed with 0.5 M HCl (30 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to a crude solid. Purification of the crude solid by column chromatography (SiO2, 100% hexane to 35% ethyl acetate/hexane) gave the desired product (300 mg, 93%) as a white solid. MF=C10H6ClFN2O2; LCMS calculated for C10H7ClFN2O2 (M+H)+: m/z=241.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | (v) N-{6-[3-({ [3-(l-cyano-l- methylethyl) phenyl] carbonyl }amino) phenoxy] [1,2,4] triazolo [1,5- a]pyridin-2-yl}-l,3-oxazole-4-carboxamide; To a solution of 1, 3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (145 mg, 1.29 mmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (157 muL, 1.80 mmol) and N,N-dimethylformamide (20 muL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and the above-mentioned N-{3-[(2- amino [1,2, 4] triazolo [1, 5-a]pyridin-6-yl) oxy] phenyl} -3- (1-cyano-l- methylethyl)benzamide (213 mg, 516 mumol) were dissolved in pyridine (8 mL) , and the mixture was stirred at room temperature for 25 hr. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 2x10 mL) . The combined organic layer was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0?97/3) , and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (211 mg, 81%) as a colorless powder.1H-NMR (DMSO-de, 300 MHz) delta 1.73 (6H, s) , 6.88 (IH, ddd, J = 8.2, 2.5, 0.8 Hz), 7.39 (IH, t, J = 8.2 Hz), 7.51 (IH, t, J = 2.2 Hz), 7.57 - 7.64 (3H, m) , 7.74 (IH, ddd, J = 7.9, 2.0, 1.0 Hz), 7.84 (IH, dd, J = 9.5, 0.8 Hz), 7.87 - 7.94 (IH, m) , 8.00 (IH, t, J = <n="396"/>1.7 Hz), 8.62 (IH, d, J = 0.9 Hz), 8.92 (IH, d, J = 0.9 Hz), 9.04 (IH, dd, J = 2.2, 0.8 Hz), 10.37 (IH, s) , 10.81 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | (v) N-{ 6- [5- ( { [3- (1-cyano-l-methylethyl) phenyl] carbonyl}amino) -2- methylphenoxy] [1, 2,4] triazolo [1, 5-a]pyridin-2-yl}-l, 3-oxazole-4- carboxamide; To a solution of 1, 3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (107 mg, 946 mumol) in tetrahydrofuran (3 mL) were added oxalyl chloride (123 muL, 1.42 mmol) and N,N-dimethylformamide (20 muL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[ (2-amino[l,2,4] triazolo [1, 5-a]pyridin-6-yl) oxy] -4- methylphenyl }-3- (1-cyano-l-methylethyl)benzamide (202 mg, 473 mumol) were dissolved in pyridine (5 mL) , and the mixture was stirred at room temperature for 15 hr. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, <n="402"/>2x10 HiL) . The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was 5 purified by basic silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0-»98/2) , and fractions containing the desired product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (196 mg, 79%) as a colorless powder.10 1H-NMR (DMSO-de, 300 MHz) delta 1.71 (6H, s) , 2.29 (3H, s) , 7.24 - 7.38 (2H, m), 7.48 - 7.62 (3H, m) , 7.71 (IH, ddd, J = 7.9, 2.0, 0.9), 7.83 (IH, dd, J = 9.6, 0.9 Hz), 7.87 (IH, dt, J = 7.8, 0.9 Hz), 7.96 (IH, t, J = 1.7 Hz), 8.61 (IH, d, J = 0.9 Hz), 8.89 (IH, dd, J = 2.4, 0.9 Hz), 8.90 (IH, d, J = 0.9 Hz), 10.25 (IH, s) ,15 10.79 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2,6-dimethylpyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | Example 4. Synthesis of compound 258; 258 Methyl 3-hydroxy-2-(oxazole-4-carboxamido)propanoate(244). Oxazole-4- carboxylic acid (3.88 g, 34.4 mmol), serine methyl ester (5.35 g, 34.4 mmol), EDC (13.2 g, 68.8 mmol) and HOBT (9.31 g, 68.8 mmol) were dissolved in dry DMF (100 niL) and placed under argon and 2,6-lutidine (2.8 mL, 172 mmol) was then added. The reaction was stirred at room temperature overnight after which solvent was removed by Kugelrohr distillation (50 C, 5 mm Hg). The residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed sequentially with saturated sodium bicarbonate, 5% HCl, and brine. The extract was dried with Na2SO4 and evaporated under reduced pressure to give a white solid, 6 g, 81%; mp 87-89 0C; 1H NMR (CDCl3) delta 4.52 (d, IH, J=Ll), 7.86 (m, 2H), 4.84 (dt, IH, J=3.7, 8.1), 4.55 (br s, IH), 4.06 (ddd, 2H, J=4, 8.8, 11.4) 3.8 (s, 3H); 13C NMR (CDCl3) delta 669.6, 159.8, 149.9, 141.1, 134.5, 125.7, 125.4, 1 16.4, 110.2, 62.1, 53.6, 51.9; IR (Nujol) 3419, 3379, 3189, 3160, 3140, 1753, 1650, 1638, 1594, 1508, 1376, 1282, 1226, 1182, 1131, 1109, 1065, 1034, 969, 897, 887, 859, 822, 766, 741, 604 cm"1; HRMS (ESI) m/z calculated for C8Hj0N2O5Na (M+Na) 237.0487; found 237.0487. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | 5-methyl<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> B.24 (490 mg, 3.9 mmol) and CDI (940 mg, 5.8 mmol) were stirred in 3 mL DMF at room temperature for 4 hours. In a separate flask, triethylamine (2.36 g, 23.4 mmol) was added to a stirring solution of N-methoxymethanamine hydrochloride (1.90 g, 19.5 mmol) in DMF (16 mL) at 0 0C. To this solution was added the first mixture, and the reaction was allowed to warm to room temperature and stirred 17 hours. After being partitioned between water and ethyl acetate, the aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried over Mg SO4 and condensed. The residue was purified by flash chromatography (1-100% gradient ethyl acetate in hexane) to give N- methoxy-N,5-dimethyloxazole-4-carboxamide B.25 (425 mg, 64%). IH NMR (500 MHz, DMSO-dbeta) delta ppm 8.31 (1 H, s), 3.73 (3 H, s), 3.29 (3 H, s), 2.46 (3 H, s) Mass Spectrum (ESI) m/e = 170.9 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Methyl 5-methyloxazole-4-carboxylate B.23(l g, 7.1 mmol) was dissolved in 4 mL THF and LiOH (0.205 g, 8.5 mmol) in 12 mL water was added. After 2 hours, the THF was evaporated, and the aqueous layer was acidified with 6 N HCl and placed in the freezer to crystallize. The crystallized product was filtered and dried to give 5-methyloxazole-4-carboxylic acid. B.24 (0.69 g, 77%) IH NMR (500 MHz, DMS0-d6) delta ppm 12.92 (1 H, br. s.), 8.29 (1 H, s), 2.56 (3 H, s) Mass Spectrum (ESI) m/e = (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity; | Example A4 Production of N-[6-(3-[3-(1-cyanocyclopropyl)benzoyl]amino}-4-methylphenoxy)-1,3-benzothiazol-2-yl]-1,3-oxazole-4-carboxamide; [Show Image] To a solution of <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (81 mg, 0.715 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (70 muL, 0.817 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 1,3-oxazole-4-carbonyl chloride as a yellow oily substance. To a solution of 1,3-oxazole-4-carbonyl chloride synthesized above in N,N-dimethylacetamide (3 mL) was added N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) produced in Example A3(iv), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of 1,3-oxazole-4-carbonyl chloride synthesized in the same manner as in the above from <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (30 mg, 0.265 mmol), oxalyl chloride (27 muL, 0.316 mmol), N,N-dimethylformamide (1 drop) and tetrahydrofuran (1 mL) in N,N-dimethylacetamide (1 mL), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, diluted with 5% aqueous sodium hydrogencarbonate solution (200 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50?0/100), and triturated with ethyl acetate/hexane to give the title compound (3.84 g, 75%) as a colorless solid. 1H-NMR (DMSO-d6, 300 MHz) delta 1.50 - 1.65 (2H, m), 1.75 - 1.88 (2H, m), 2.22 (3H, s), 6.90 (1H, dd, J = 2.4, 8.4 Hz), 7.06 (1H, d, J = 2.4 Hz), 7.18 (1H, dd, J = 2.4, 8.7 Hz), 7.30 (1H, d, J = 8.4 Hz), 7. 48 - 7. 62 (2H, m), 7.74 (1H, d, J = 2.4 Hz), 7.76 - 7.85 (2H, m), 7.85 - 7.92 (1H, m), 8.65 (1H, s), 9.04 (1H, s), 9.95 (1H, s), 12.63 (1H, s). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; | To a stirred solution of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (0.18 g, 1.60 mmol) and DMF (2 drops) in THF (3.0 mL) was added oxalyl chloride (0.22 g, 1.76 mmol) dropwise. After the addition was complete the mixture was stirred at room temperature for 0.5 h. Then, the reaction mixture was concentrated under reduced pressure to provide oxazole-4-carbonyl chloride which was dissolved in methylene chloride (3.0 mL) and added to a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.37 g, 1.60 mmol) and triethylamine (0.49 g, 4.80 mmol) in methylene chloride (6.0 mL) at room temperature. After 16 h reaction mixture was directly purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(oxazol-4-yl)methanone (0.27 g, 56%) as a yellow orange solid. 1H NMR (500 MHz, DMSO-d6) delta 8.69 (d, J = 0.8 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 7.27 (dd, J = 7.8, 1.6 Hz, 1H), 7.17 (dt, J = 7.4, 1.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.17-5.13 (m, 1H), 4.99-4.95 (m, 1H), 4.55-4.51(m, 1H), 4.43-4.40 (m, 1H), 3.99-3.96 (m, 1H), 1.36 (s, 9H). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere; Molecular sieve; | General procedure: To an oven-dried round bottom flask with stir bar under nitrogen were added the carboxylic acid, dry DCM, and 3 A molecular sieves. Oxalyl chloride (1.2 eq.) and a catalytic amount of DMF (1-2 mol %) were added and the reaction was stirred while attached toa bubbler (to monitor production of CO2) at 20 C for 2-3 h. The amine HCl salt (1 eq.) in DCM and DIPEA (2 eq.) were added and the reaction was stirred under nitrogen for 3-6 h. The reaction was diluted with EtOAc and washed with half-saturated aq. NaHCO3, 1M HCl (30 mL), and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure prior to purification by flash chromatography (SiO2). The following parmodulins were synthesized utilizing this method: 7,11, 18, and 36-40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 28h; | (iv) Production of N-[6-(3-[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)-1,3-benzothiazol-2-yl]-1,3-oxazole-4-carboxamide; To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxylphenyl}-3-(1-cyanocyclopropyl)benzamide (330 mg, 774 mumol) in pyridine (10 mL) were added <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (120 mg, 1.06 mmol), N,N-dimethylpyridine-4-amine (52.3 mg, 428 mumol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (126 mg, 1.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (652 mg,3.40 mmol) and the mixture was further stirred at room temperature for 16 hr. To the reaction mixture were added methanol (10 mL) and 2N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at the same temperature for 3 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), 0.1N hydrochloric acid (50 mL), and saturated aqueous sodium hydrogencarbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase silica gel column chromatography (containing 0.1% trifluoroacetic acid, water/acetonitrile=95/5?5/95) and concentrated. The obtained trifluoroacetate was suspended in ethyl acetate (100 mL) and methanol (10 mL), and washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (156 mg, 34%) as colorless crystals. 1H-NMR (DMSO-d6, 300 MHz) delta 1.60 (2H, dd, J = 5.4, 8.4 Hz), 1.80 (2H, dd, J = 5.4, 8.4 Hz), 6.81 (1H, ddd, J = 0.9, 2.7, 8.1 Hz), 7.21 (1H, dd, J = 2.7, 8.7 Hz), 7.38 (1H, t, J = 8.1 Hz), 7.48-7.59 (4H, m), 7.74-7.86 (4H, m), 8.65 (1H, s), 9.03 (1H, s), 10.34 (1H, br s), 12.65 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example A24 Production of N-[6-(5-([3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methoxyphenoxy)-1,3-benzothiazol-2-yl]-1,3-oxazole-4-carboxamide; [Show Image] A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (230 mg, 0.50 mmol) produced in Example A21(iv), <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.00 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (183 mg, 66%) as a white solid. 1H-NMR (CDCl3, 300 MHz) delta 1.75 (6H, s), 3.88 (3H, s), 7.05 (1H, d, J = 9.0 Hz), 7.19 (1H, dd, J = 2.4, 8.7 Hz), 7.27 (1H, s), 7.41 (1H, d, J = 2.4 Hz), 7.45 - 7.52 (2H, m), 7.66 - 7.78 (4H, m), 7.93 (1H, br s), 7.95 (1H, s), 8.42 (1H, s), 10.07 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example A28 Production of N-{6-[3-([4-(trifluoromethyl)phenyl]amino}carbonyl)phenoxy]-1,3-benzothiazol-2-yl}-1,3-oxazole-4-carboxamide; [Show Image] A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), <strong>[23012-13-7]1,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong></strong> (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (90 mg, 34%) as a white solid. 1H-NMR (CDCl3, 300 MHz) delta 7.16 - 7.22 (2H, m), 7.41 - 7.50 (2H, m), 7.58 (2H, d, J = 8.7 Hz), 7. 69 - 7.76 (2H, m), 7.80 (1H, d, J = 8.7 Hz), 7.93 (2H, d, J = 8.7 Hz), 8.05 (1H, d, J = 0.9 Hz), 8.52 (1H, d, J = 0.9 Hz), 9.74 (1H, br s), 10.61 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; | 8-(8-Aminodibenzothiophen-4-yl)-2-morpholin-4-ylchromen-4-one (A8, 183 mg, 0.43 mmol) was added to 1 ,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (58 mg, 0.51 mmol), N,N-diisopropylethylamine(0.179 mL, 1.03 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,Nl,N'-tetramethyluronium hexafluorophosphate (195 mg, 0.51 mmol) in DMA (1 mL). The reaction mixture was evaporated to dryness and redissolved in EtOAc (50 mL), and washed with water (50 mL). The precipitate was collected by filtration. The organic layer was separated then dried over MgSO4, filtered and evaporated onto silica gel (5 g). The resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-[6-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen- 2-yl]-1 ,3-oxazole-4-carboxamide (158 mg, 71%) as a white solid. The precipitate was dissolved in MeOH/DCM (100 mL) then evaporated onto silica gel (5 g). The resulting powder was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-[6-(2-morpholin-4-yl-4-oxochromen-8- yl)dibenzothiophen-2-yl]-1 ,3-oxazole-4-carboxamide (53.4 mg, 26%) as a white solid; 1H NMR (400 MHz, DMSO) delta 3.33 (4H, t), 3.46 (4H, t), 5.68 (1H, s), 7.23 (1 H, t), 7.63 - 7.67 (2H, m), 7.94 (2H, s), 8.07 (1 H, dd), 8.26 - 8.30 (1 H, m), 8.67 (1 H, s), 8.82 (1 H, s), 8.86 (1 H, s), 8.94 (1 H, dd), 10.38 (1 H1 s); m/z: 524.13 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h; | A solution of 4-oxazole carboxylic acid, 12 mul of DiPEA and 25 mg of TBTU in 1 ml of dichloromethane was stirred for 15 min, then 21 mg of 12f was added, and the reaction mixture was stirred for 16 hr. Then water was added and the organic layer was separated and washed with water, dried and concentrated and the residue was purified over a silica gel column, using a gradient of toluene and ethyl acetate as eluent, to provide 15 mg of 12g; MS-ESI: [M+H]+ 514.3. NMR (CDCl3) delta 1.52 (s, 9, tertC4H9), 2.38 (s, 3, CH3), 2.85 and 2.95 (2×m, 4, CH2CH2), 3.14 (s, 3, NCH3), 3.97 (s, 3, OCH3), 6.86, 7.86, 8.01 and 8.21, (4×s, 4, ArH+oxazole-H), 7.20-7.40 (4×m, 4, mCH3Phe-H), 9.08 (bs, 1, NH). | |
A solution of 4-oxazole carboxylic acid, 12 mul of DiPEA and 25 mg of TBTU in 1 ml of dichloromethane was stirred for 15 min, then 21 mg of 12f was added, and the reaction mixture was stirred for 16 hr. Then water was added and the organic layer was separated and washed with water, dried and concentrated and the residue was purified over a silica gel column, using a gradient of toluene and ethyl acetate as eluent, to provide 15 mg of 12g ; MS-ESI: [M+H]+ 514.3. NMR (CDCl3) delta 1.52 (s, 9, tertC4H9), 2.38 (s, 3, CH3), 2.85 and 2.95 (2x m, 4, CH2CH2), 3.14 (s, 3, NCH3), 3.97 (s, 3, OCH3), 6.86, 7.86,8.01 and 8.21, (4x s, 4, ArH + oxazole-H), 7.20-7.40 (4x m, 4, mCH3Phe-H), 9.08 (bs, 1, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Example 91 : {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl}-oxazol-4-yl-methanone; Step 2; To the <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added Nu,Nu-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HC03 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1H NMR (400 MHz, DMSO-d6, 298K) delta ppm 2.1 1 - 2.39 (m, 2 H) 2.80 - 3.01 (m, 2 H) 3.22 - 4.29 (m, 1 1 H) 5.59 - 5.80 (m, 1 H) 7.72 - 7.94 (m, 1 H) 8.10 - 8.29 (m, 1 H) 8.41 - 8.55 (m, 1 H) 8.57 - 8.77 (m, 2 H) LCMS: [M+H]+=491.1 , Rt (1)= 1.69 min. | |
36% | To the <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1 H NMR (400 MHz, DMSO-d6, 298K) delta ppm 2.1 1 - 2.39 (m, 2 H) 2.80 - 3.01 (m, 2 H) 3.22 - 4.29 (m, 11 H) 5.59 - 5.80 (m, 1 H) 7.72 - 7.94 (m, 1 H) 8.10 - 8.29 (m, 1 H) 8.41 -8.55 (m, 1 H) 8.57 - 8.77 (m, 2 H) LCMS: [M+H]+=491.1 , Rt (1)= 1.69 min. | |
36% | Example 91 {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone Step 2 To the <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1H NMR (400 MHz, DMSO-d6, 298K) delta ppm 2.11-2.39 (m, 2H) 2.80-3.01 (m, 2H) 3.22-4.29 (m, 11H) 5.59-5.80 (m, 1H) 7.72-7.94 (m, 1H) 8.10-8.29 (m, 1H) 8.41-8.55 (m, 1H) 8.57-8.77 (m, 2H) LCMS: [M+H]+=491.1, Rt(1)=1.69 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Step C: N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrrazin-8-yl)-4-methylcyclopentyl)-N-methyloxazole-4-carboxamide To a solution of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (0.12 g, 1.05 mmol) and TEA (0.56 mL, 4.0 mmol) in DMF (3.00 mL) was added HBTU (0.46 g, 1.20 mmol). The mixture was stirred for about 10 min at ambient temperature. To the resulting very dark colored mixture was added (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N,4-dimethylcyclopentanamine (0.27 g, 1.00 mmol) and stirred at ambient temperature for about 1.5 h. The reaction mixture was quenched with a saturated aqueous NaHCO3 (30 mL) and extracted into DCM (2*50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated, under reduced pressure. The material was purified by chromatography on silica gel (0-10% MeOH in DCM). The fractions containing the desired product were combined and concentrated under reduced pressure. The resulting material was purified by mass triggered purification (Table 1, method d). The recovered fractions were evaporated and taken up in acetonitrile/water. The volatiles were removed under reduced pressure, frozen and lyophilized repeatedly to remove all traces of ammonium acetate to give N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-N-methyloxazole-4-carboxamide (0.074 g, 20%); LC/MS (Table 1, Method a) Rt=1.34 min; MS m/z: 365 (M+H)+. Jak3 IC50=B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 2h; | 7-Oxa-10,13,17,18,21 -pentaazatetracyclo[12.5.2.1^2,61.0^17,20}]docosa- 1 (20),2,4,6(22),14(21 ),-15,18-heptaene hydrochloride (128 mg, 0.386 mmol), oxazole- 4-carboxylic acid (48 mg, 0.425 mmol) and N,N-diisopropylethylamine (230 muIota, 1.35 mmol) were dissolved in N,N-dimethylformamide (1.16 ml). 0-(Benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU) (174 mg, 0.46 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and methanol was added. The precipitate was filtered and dried under reduced pressure.Yield: 125 mg of example 20 (83%)LCMS method 2: MH+ = 391 , RT = 2.988 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of Intermediate 11(100 mg, 0.305 mmol) in 2 mL of DMF was treated with <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (100 mg, 0.884 mmol) and HATU (2-(1H-7- azabenzotriazol- l-yl)-l ,1,3,3 -tetramethyl uronium hexafluorophosphate methanaminium; 200 mg, 0.526 mmol). The reaction mixture was stirred overnight, then diluted with DCM andwashed with sat?d NaHCO3, dried (Na2SO4) and concentrated. Purification by reverse phase chromatography followed by lyophilization of the desired fraction provided the TFA salt of 2-88.?H NMR (600 MHz, DMSO-d6) 3 8.64-8.6 1 (m, 1 H), 8.48-8.47 (m, 1 H), 8.44 (s, 1 H), 7.96 (s, 1 H), 5.88 (m, 1 H), 4.21 (m, 1 H), 4.14 (q, J= 7.3 Hz, 2 H), 4.10 (m, 1 H), 3.95-3.60 (m, 2 H),3.81-3.80 (m, 3 H), 2.52 (s, 3 H), 2.35-2.20 (m, 2 H), 1.32 (t, J= 7.4 Hz, 3 H); MS (El) Calc?dfor C20H23N803 [M+H]t, 423; found 423. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A reaction vessel was charged with Intermediate VIII (as the TFA salt) (0.052 g, 0.11 mmol) and <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (0.024 g, 0.21 mmol). Next was added DCM (1.1 mL), and DIEA (0.060 mL, 0.32 mmol) and the reaction was allowed to stir for 5 minutes. Next was added propylphosphonic anhydride solution (0.10 mL, 50% w/w in DMF). The reaction vessel was capped and stirred at ambient temperature for 6 hours. The reaction was diluted with water (2.0 mL), and was extracted with DCM (5.0 mL) using a phase separator SPE cartridge. The collected organics were concentrated in vacuo to afford (S)-(3-((9-ethyl-8-iodo-9H-purin-6- yl)amino)pyrrolidin-l-yl)(oxazol-4-yl)methanone as a crude residue. MS ESI calc'd. for CisHivINyOz [M + H]+ 454, found 454. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 16h; | (1(S and R), 3(S and R))-N1-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl)cyclo-hexane- 1,3-diamine (230 mg, 0.653 mmol) was dissolved in DCM (10 ml) and TEA (0.364 ml, 2.61 mmol) was added, followed by <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (81 mg, 0.72 mmol) and HATU (273 mg, 0.718 mmol). The reaction was allowed to stir at room temperature for 16 h. The mixture was then concentrated and the residue was purified by silica gel chromatography (0-10% methanol in DCM) to afford N-(1(S and R), (3(S and R))-3-(3-[9-ethyl-8-(2-methylpyrimidin- 5-yl)-9H-purin-6-yl]amino}cyclohexyl)-l,3-oxazole-4-carboxamide as a mixture of racemic diastereomers. The mixture was then separated by chiral SFC (Chiralpak AD-H, 21 x 250 (mm), 70 ml/min, 20% (Ethanol + 0.25% dimethyl ethyl amine) in C02) to provide N-((1S, 3S) or (1R, 3R))-3-(3-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]amino}cyclohexyl)-l,3-oxazole- 4-carboxamide (5-8) (retention time 3.3 min). 1H NMR (600 MHz, DMSO-d6, 95C) delta 9.04 (s, 2H), 8.45 (s, 1H), 8.31 (broad s, 1H), 8.23 (s, 1H), 7.51 (d, / = 7.5, 1H), 7.27 (d, / = 7.2, 1H), 4.69 - 4.60 (m, 1H), 4.27 (q, / = 7.2, 2H), 4.27 - 4.23 (m, 1H), 2.71 (s, 3H), 2.04 - 1.94 (m, 1H), 1.94 - 1.86 (m, 1H), 1.86 - 1.77 (m, 1H), 1.77 - 1.69 (m, 1H), 1.69 - 1.56 (m, 4H), 1.29 (t, / = 7.2, 3H). MS (EI) Calc'd for C22H26N902 [M+H]+, 448; found 448. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In dichloromethane; at 20℃; for 0.5h; | [1215] A mixture of 606-2 (45 mg. 0.1 mmol). 606-1 ( 16 mg, 0.1 mmol) and TEA (1 mmol) is dissolved in anhydrous DCM (4 mL) with stirring. The solution was treated with HATU (38 mg, 0.1 mmol) in one portion. After stirring at r.t. for 30 mins, TFA (1 mL) was added. The solution was stirred at r.t. for 2 h. The mixture was concentrated to dryness. The residue was isolated by acidic prep-HPLC to afford 606 (26 mg, 45%) as a white solid. +ES1-MS: m/z 452.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Step 1: N-Methoxy-N-methyloxazole-4-carboxamideA suspension of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (0.50 g, 4.42 mmol) and HOBT (0.74g, 4.86 mmol) was stirred for 10 mm and then N,O-dimethylhydroxylamine, HC1 (0.47 g,4.86 mmol) and DIEA (0.85 mL, 4.86 mmol) were added. After 10 mm, EDC (0.93 g,4.86 mmol) was added. The resulting reaction mixture was stirred overnight and thendiluted with 1M HC1. The layers were separated, and the aqueous layer was extracted with CH2C12. The organic layer was washed sequentially with sat. NaHCO3 and sat. NaC1, dried over Na2SO4 and concentrated to give the title compound (0.22 g, 33 %). ?H NMR (400 MHz, CDC13) oe 8.22 (s, 1H), 7.93 (s, 1H), 3.78 (s, 3H), 3.41 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; for 0.333333h; | A suspension of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (0.50 g, 4.42 mmol) and HOBT (0.74 g, 4.86 mmol) was stirred for 10 min and then N,O-dimethylhydroxylamine, HCl (0.47 g, 4.86 mmol) and DIEA (0.85 mL, 4.86 mmol) were added. After 10 min, EDC (0.93 g, 4.86 mmol) was added. The resulting reaction mixture was stirred overnight and then diluted with 1M HCl. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The organic layer was washed sequentially with sat. NaHCO3 and sat. NaCl, dried over Na2SO4 and concentrated to give the title compound (0.22 g, 33%). 1H NMR (400 MHz, CDCl3) delta 8.22 (s, 1H), 7.93 (s, 1H), 3.78 (s, 3H), 3.41 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | Example 78 Synthesis of Compound 81 Z?NH, p=0, n=11, q=1, m=0; Synthesis of 4-(oxazol-4-yl)carbonylaminopentafluorosulfanylbenzene Into a 100 ml flask equipped with a stirrer, 1.0 g (8.84 mmol) of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong>, 10 ml of ethyl acetate, and subsequently 1.58 g (9.72 mmol) of carbonyl diimidazole (CDI) were added, and refluxed for 2.5 hours. Subsequently, 1.84 g (8.40 mmol) of 4-aminopentafluorosulfanylbenzene was added and refluxed again for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitated crystals were filtered off. After the filtrate was concentrated, 5 ml of acetonitrile was added to precipitate crystals, which were collected by filtration to obtain 4-(oxazol-4-yl)carbonylaminopentafluorosulfanylbenzene 0.21 g (yield 8%) as white powder. Herein, 4-(oxazol-4-yl)carbonylaminopentafluorosulfanylbenzene is a novel compound having the following property values. 1H-NMR (DMSO-d6, delta (ppm)); 7.86-7.93 (2H, m), 8.02-8.08 (2H, m), 8.67 (1H, d, J=0.9 Hz), 8.89 (1H, d, J=1.0 Hz), 10.66 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 4h; | N-ethyl-N-isopropylpropan-2-amine (0.10 ml,0.573 mmol) was added to a mixture of the product of Example 10A (0.070 g, 0.21 mmol), <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (ArkPharm, Inc., 0.029 g, 0.26 mmol) and dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 0.098 g, 0.26 mmol) in tetrahydrofuran (1.0 ml). The reaction mixture was stirred at ambient temperature for 4h and was then diluted with ethyl acetate (5.0 ml). The mixture was transferred to an addition funnel and was washed with water (1 x 5 ml), 1N HCl (1 x 5 ml), saturated aqueous NaHCO3 (1 x 5 ml) and brine (1 x 5 ml). The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 100% CH2Cl2 to 5% methanol in CH2Cl2) to give the title compound (0.068 g, 0.16 mmol, 76% yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.67(d, J=7.2 Hz, 1H), 8.52(d, J=16.4 Hz, 1H), 8.27(d, J=14.0 Hz, 1H), 7.68(td, J=7.8,1.5 Hz, 1H), 7.64-7.52(m, 2H), 7.51-7.40(m, 2H), 7.30(d, J=7.5 Hz, 1H), 7.26(dd, J=8.4,2.9 Hz, 1H), 4.53-4.31(m, 2H), 4.11-3.98(m, 1H), 3.92-3.75(m, 2H), 3.62-3.40(m, 2H), 3.29-3.14(m, 1H); MS (ESI+) m/z 432 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 50℃; for 16h; | A solution of 1 ,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (31 mg, 0.28 mmol) and HATU (105 mg, 0.28 mmol) in DMA (1 mL) was added to a mixture of N-{4-[4-oxo-3-(phenylamino)-4,5,6,7- tetrahydro-1 H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}acetamide (24; 50 mg, 0.14 mmol) and DIPEA (48 pL, 0.28 mmol) in DMA (1 mL) and stirred for 16 h at 50. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (40 mg, 60%). 1H-NMR (400 MHz, DMSO-d6), delta [ppm]= 2.08 (3H), 4.30+4.69 (2H), 5.03+5.43 (2H), 6.56 (2H), 6.60 (1 H), 7.02 (2H), 7.23 (1 H), 7.43 (1 H), 8.13 (1 H), 8.28 (1 H), 8.54-8.74 (2H), 10.41 (1 H), 12.29+12.32 (1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | A suspension of <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (115 mg, 1.02 mmol) in DCM (10 mL) under Ar was treated with DMF (5 drops) followed by oxalyl chloride (2 M in DCM, 0.75 mL, 1.5 mmol). The mixture was stirred for 3 h and evaporated. The residue dissolved in fresh DCM (10 mL) at 0 C. Amine 74g (135 mg, 0.5 16 mmoL) was added followed by Et3N, 250 muL, 1.79 mmol). After 30 minutes the cold bath was removed, and the mixture stirred overnight at it The mixture was diluted with water and extracted with DCM (4 x 50 mL). Combined extracts were washed sequentially with 1 M HC1 solution, saturated NaHCO3 solution, and saturated NaCl solution. The product was purified on a column of silica gel eluting with hexanes/EtOAc (3:2), followed by recrystallization from EtOH to give a white solid (114 mg, 62%): mp 226-227 C; ?HNMR (400 MHz, DMSO-d6) oe 10.47 (s, 111), 8.86 (dd, J 1.0, 0.3 Hz, 1H), 8.67 (dd, J 1.0, 0.3 Hz, 1H), 8.64 (dd, J 2.1, 0.5 Hz, 111), 8.17 (ddd, J 11.3, 7.7, 2.2 Hz, lH), 8.12 (dd, J 8.7, 0.5 Hz, 1H), 7.96 (dddd, J= 8.7, 3.9, 2.2, 1.3 Hz, 1H),7.92 (dd, J= 8.8, 2.0 Hz, 1H), 7.66 (dt, J 10.5, 8.4 Hz, 1H); ElMS m/z 358.0 (M + 1). HPLC 100 area % (290 nm). Anal. Calcd for C17H9F2N30S: C, 57.14; H, 2.54; N, 11.76. Found: C, 56.87; H, 2.61;N, 11.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | General procedure: The appropriate carboxylic acid (34.2 lmol, 2 eq), EDCIHCl(5.30 mg, 34.2 lmol, 2 eq) and DMAP (17.1 lmol, 1 eq) were combinedin CH2Cl2 (2 mL) and stirred at RT for 10 min. Amine 15(10.0 mg, 17.1 lmol, 1 eq) was added and the resulting mixturestirred at RT overnight. Reaction was, quenched by the additionof saturated aqueous NH4Cl solution (5 mL), extracted with EtOAc(3 5 mL) and the combined organic layers washed with 0.1 Maqueous KOH solution, brine, dried (MgSO4), filtered and concentratedin vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice; | General procedure: Following the general procedure below, the data are reported as a) mass of starting material; b) mass of acid; c) mass of EDCI; d) volume of DCM; e) volume of NEt3; f) mass of product obtained.To an ice cold solution of corresponding primary amine 6a-d (0.05 - 0.38 mmol, 1 eq), corresponding acid (0.06 - 0.48 mmol, 1.3 eq) and EDCI (0.05 - 0.49 mmol, 1.3 eq) in DCM was added NEt3 (0.06 - 0.53 mmol, 1.4 eq) and the mixture was warmed to RT and stirred for 16 h. The reaction mixture was loaded directly onto a pre-equilibrated silica column and purified by silica gel column chromatography (gradient = 0-100% EtOAc in petroleum ether (bp. 40-60)). The appropriate fractions were combined and concentrated in vacuo to give the corresponding Boc-protected final compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice; | General procedure: Following the general procedure below, the data are reported as a) mass of starting material; b) mass of acid; c) mass of EDCI; d) volume of DCM; e) volume of NEt3; f) mass of product obtained.To an ice cold solution of corresponding primary amine 6a-d (0.05 - 0.38 mmol, 1 eq), corresponding acid (0.06 - 0.48 mmol, 1.3 eq) and EDCI (0.05 - 0.49 mmol, 1.3 eq) in DCM was added NEt3 (0.06 - 0.53 mmol, 1.4 eq) and the mixture was warmed to RT and stirred for 16 h. The reaction mixture was loaded directly onto a pre-equilibrated silica column and purified by silica gel column chromatography (gradient = 0-100% EtOAc in petroleum ether (bp. 40-60)). The appropriate fractions were combined and concentrated in vacuo to give the corresponding Boc-protected final compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | At 25 C and N 2 atmosphere,To <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (12 mmol)And pyridine (20 mmol)To a solution of 20 mL of anhydrous dichloromethane was added 1,3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2-((1-amino-2-methylpropan-2-yl)amino)-1-(5-hydroxy-1H-pyrrole[3,2]pyridin-1-yl)B was added. Ketone (10 mmol) and the mixture was stirred overnight. TLC (95:5 in dichloromethane: methanol containing 2% ammonia) indicated that all of the starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a pad of Celite. The plug was rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with EtOAc EtOAc m. The crude product was purified by flash chromatography using EtOAc (EtOAc):Yield 3.3 g of white powder as N-(2-((2-(5-hydroxy-1H-pyrrole[3,2] pyridin-1-yl)-2-ethoxy)amino)-2-methylpropane Base)-oxazole-4-carboxamide,The yield was 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.2% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 70℃;Sealed tube; | [0451] To a 4 mL vial was added 3-amino-4-(4-(2,4-difluorophenoxy)piperidin-l- yl)benzonitrile (50 mg, 0.152 mmol), HATU (66.4 mg, 0.175 mmol), DMF (1.00 mL) and DIPEA(0.079 mL, 0.455 mmol). The contents of the vial were thoroughly mixed and oxazole-4- carboxylic acid (18.88 mg, 0.167 mmol) was added. The vial was capped and the reaction mixture was stirred at 70C overnight. The reaction was subsequently quenched with water (3 mL). The mixture was vortexed for 2 minutes and the supernatant was removed. Methanol (2 mL) was added to the residue and the resulting mixture was stirred and heated until ail the material was dissolved. A solid precipitated upon cooling. The solid was isolated by filtration, washed with a small amount of cold methanol, and dried to afford the title compound as an off- white solid (11.1 mg, 17.2%). NuMKappa (4)0 MHz, DMSO-cfe) delta ppm 1.89 - 2.05 (m, 2 H), 2.11 - 2.25 (m. 2 H), 2.83 - 2.99 (m, 2 H), 3.09 - 3.21 (m, 2 H), 4.58 (dt,./ 7.58. 4.04 Hz, 1H), 6.99 - 7.1 1 (m, 1H), 7,29 - 7.39 (m, 2 H), 7.43 (d, J=8.34 Hz, 1H), 7.63 (dd,.7=8.21, 1.89 Hz, 1H), 8.65 (d, J=2,02 Hz, 1H), 8,74 (d, J=0,76 Hz, 1H), 8,97 (d,,7=1.01Hz, 1H), 9,71 (s, 1H); ESI- MS m/z [M+H]+ 425.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h; | The title compound was prepared from 5-(6-[[6-methoxy-5-(4-methylpiperazin- l-yl)pyridin-2- yl]amino]pyrimidin-4-yl)-2-(piperidin-4-yloxy)benzonitrile and l,3-<strong>[23012-13-7]oxazole-4-carboxylic acid</strong> using Method A. The final product was purified by prep-HPLC under the following conditions: column, XBridge Prep C 18 OBDColumn, 150 x 19 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1 % NH3.H2O), 30 % to 40 % gradient in 7 min; detector, UV 254 nm. 5-(6-[[6-methoxy-5-(4-methylpiperazin- l-yl)pyridin-2- yl]amino]pyrimidin-4-yl)-2-([l-[(l,3-oxazol-4-yl)carbonyl]piperidin-4-yl]oxy)benzonitrile was obtained as yellow solid (27 mg, 16 %). HPLC: 98.8 % purity, RT = 1.23 min. MS: m/z = 596.4 [M+H]+. lH NMR (300 MHz, DMSO-d6) delta 9.97 (s, 1 H), 8.72 (s, 1 H), 8.63-8.56 (m, 1 H), 8.55- 8.48 (m, 1 H), 8.39-8.24 (m, 2 H), 8.20 (s, 1 H), 7.60-7.51 (m, 1 H), 7.33-7.23 (m, 1 H), 7.22- 7.13 (m, 1 H), 5.07-5.00 (m, 1 H), 4.16-3.82 (m, 8 H), 3.66-3.59 (m, 1 H), 2.98-2.92 (m, 4 H), 2.48-2.40 (m, 4 H), 2.22 (s, 3 H), 2.16- 1.99 (m, 2 H), 1.90- 1.66 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of 4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide (200 mg, 861 umol, Intermediate GB) and <strong>[23012-13-7]oxazole-4-carboxylic acid</strong> (97.3 mg, 861 umol, CAS23012-13-7) in DMF (3 mL) was added DIPEA (333 mg, 2.58 mmol) and HATU (392 mg, 1.03 mmol). The mixture was stirred at rt for 0.5 hour. On completion, the mixture was diluted with H2O (15 mL), the mixture was filtered and the solid was dried in vacuo to give the title compound (270 mg, 75% yield) as white solid. LC-MS (ESI+) m/z 350.2 (M+Na |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of methyl 4-amino-1-methyl-pyrazole-3-carboxylate (100 mg, 645 umol, Intermediate KQ) and oxazole-4-carboxylic acid (72.9 mg, 645 umol, CAS23012-13-7) in DMF (2 mL) was added DIPEA (333 mg, 2.58 mmol) and HATU (294 mg, 773 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the mixture was quenched with water (30 mL), filtered and the filter cake was dried in vacuo to give the title compound (100 mg, 62% yield) as a white solid. LC-MS (ESI+) m/z 251.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; | General procedure: The syntheses of 1-5 followed a similar procedure. In thesynthesis of 1, CoCl2*2H2O (0.0129 g, 0.100 mmol) and 2-Htza(0.0129 g, 0.100 mmol) were dissolved in distilled water(5.0 ml). The solution was left undisturbed at room temperaturefor several days, from which 1 crystallized. The sameprocedure was adopted for the syntheses of 2 and 3, exceptthat NiCl2*2H2O (0.0129 g, 0.100 mmol) and Cd(NO3)2*4H2O(0.0129 g, 0.100 mmol), respectively, were used instead ofCoCl2*2H2O. The procedure was also applied for the preparationof 4 and 5, except that Co(NO3)2*6H2O (0.0290 g,0.100 mmol) was used as a metal salt, whereas 2-H2ima(0.0112 g, 0.100 mmol) and 4-Hoxa (0.0113 g, 0.100 mmol)were used as the ligands for the preparation of 4 and 5,respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.61% | With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In N,N-dimethyl-formamide; at 20 - 25℃; for 16h;Inert atmosphere; | To a mixture of 36-la (137.9 mg, 1.22 mmol, 1.2 eq), PYAOP (635.7 mg, 1.22 mmol, 1.2 eq) and TEA (308.4 mg, 3.05 mmol, 424.27 uL, 3 eq) in DMF (3 mL) was added 36-1 (0.3 g, 1.02 mmol, 1 eq) in one portion at 20 C under N2. The mixture was stirred at 20 C for 16 h. LCMS showed 7% of starting material was remained and 20% of desired product was detected. The mixture was diluted with EA (50 mL), washed with brine(l5 mL) twice, dried by anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give 36-2 (0.05 g, 0.13 mmol, 12.61% yield). LCMS (ESI): RT = 0.767 min, mass calc forC18H13F3N4O3 390.09, m/z found 390.9 [M+l]+. 1H NMR (400 MHz, DMS0 ) d 10.57 (s, 1H), 10.40 (s, 1H), 9.43 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 7.73 (d, J= 7.5 Hz, 1H), 7.60 (br d, J= 8.4 Hz, 2H), 7.53 - 7.43 (m, 2H), 7.30 (br d, J= 8.3 Hz, 2H), 7.05 (br t, J= 7.2 Hz, 1H). |
Tags: 23012-13-7 synthesis path| 23012-13-7 SDS| 23012-13-7 COA| 23012-13-7 purity| 23012-13-7 application| 23012-13-7 NMR| 23012-13-7 COA| 23012-13-7 structure
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