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CAS No. : | 2510-36-3 | MDL No. : | MFCD00051657 |
Formula : | C6H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IJEUISLJVBUNRE-UHFFFAOYSA-N |
M.W : | 141.13 | Pubchem ID : | 75636 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.39 |
TPSA : | 63.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 1.25 |
Log Po/w (XLOGP3) : | 0.7 |
Log Po/w (WLOGP) : | 0.99 |
Log Po/w (MLOGP) : | -0.02 |
Log Po/w (SILICOS-IT) : | 1.06 |
Consensus Log Po/w : | 0.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.46 |
Solubility : | 4.89 mg/ml ; 0.0347 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.61 |
Solubility : | 3.48 mg/ml ; 0.0247 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.36 |
Solubility : | 6.15 mg/ml ; 0.0436 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.63 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H317-H319 | 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 |
---|---|---|
94% | With sodium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 8 h; | To a solution of ethyl 3,5-dimethyl-4-isoxazolecarboxylate (2.4 g, 14 mmol) in THF (8 mL) and MeOH (8 mL) was added 5N aqueous NaOH (8.5 mL). The reaction was stirred at room temperature for 8 h. The reaction mixture was removed under reduced pressure and acidified with 6 N aqueous HCl to pH=2. The precipitated product was filtered, washed with water, and dried to afford 9 (2.1 g, 94.0percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.72 (s, 3H), 2.49 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 8h; | To a solution of ethyl 3,5-dimethyl-4-isoxazolecarboxylate (2.4 g, 14 mmol) in THF (8 mL) and MeOH (8 mL) was added 5N aqueous NaOH (8.5 mL). The reaction was stirred at room temperature for 8 h. The reaction mixture was removed under reduced pressure and acidified with 6 N aqueous HCl to pH=2. The precipitated product was filtered, washed with water, and dried to afford 9 (2.1 g, 94.0%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 2.72 (s, 3H), 2.49 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of lithium bis(trimethylsilyl)amide (10 g, 60 mmol, 3 eq) in toluene (60 mL) was added drop wise during 15 min to a solution of <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (2.82 g, 20 mmol) and methyl benzoate (2.5 mL, 1 eq) in THF (20 mL) at a temperature not exceeding 40 deg. After 1 h the reaction was quenched by the addition of a water solution of 0.1M HCl (0.3 L) leaving the water phase still basic and the phases was separated. The water phase was washed with toluene and then reduced in volume by evaporation until most of the residual organic solvents were removed. 1M HCl was added dropwise with stirring. The resulting crystals were filtered and dried in vacuum to yield the title compound. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 2.45 (s, 3H) 4.75 (s, 2H) 7.43-7.51 (m, 2H) 7.55-7.63 (m, 1H) 7.86-8.12 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;dmap; In CH2Cl2 (2 ml); ethyl acetate; | Step A 3,5-Dimethyl-isoxazole4-carboxylic acid [2-(4-methoxy-2-methyl-phenylamino)-phenyl]-amide To a solution of N-(4-methoxy-2-methyl-phenyl)-benzene-1,2-diamine (0.200 g, 0.877 mmol), 3,5-dimethylisoxazole4-carboxylic acid (0.186 9, 1.3155 mmol), triethylamine (0.613 mL, 4.385 mmol), and a catalytic amount of 4-Dimethylaminopyridine in CH2Cl2 (2 ml), was added 50%1-propanephosphonic acid cyclic anhydride added (1.05 mL, 1.754 mmol) in ethyl acetate and stirred overnight at room temperature. The reaction material was diluted with CH2Cl2, washed with saturated sodium bicarbonate and extracted into CH2Cl2. The combined organic material was dried (MgSO4), filtered, and concentrated, giving <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> [2-(4-methoxy-2-methyl-phenylamino)-phenyl]-amide. MS (M+1) 352. | |
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine;dmap; In dichloromethane; ethyl acetate; at 20℃; | To a solution of [N- (4-METHOXY-2-METHYL-PHENYL)-BENZENE-1, 2-DIAMINE] (0.200 g, 0.877 [MMOL),] 3, 5-dimethylisoxazole-4-carboxylic acid (0.186 g, 1.3155 [MMOL),] triethylamine (0.613 mL, 4.385 [MMOL),] and a catalytic amount of 4- Dimethylaminopyridine in [CH2CI2] (2ml), was added 50% 1-propanephosphonic acid cyclic anhydride added (1.05 mL, 1.754 [MMOL)] in ethyl acetate and stirred overnight at room temperature. The reaction material was diluted with [CH2CI2,] washed with saturated sodium bicarbonate and extracted into [CH2CI2.] The combined organic material was dried [(MGS04),] filtered, and concentrated, giving 3, 5-dimethyl- [ISOXAZOLE-4-CARBOXYLIC] acid [[2- (4-METHOXY-2-METHYL-PHENYLAMINO)-PHENYL]-AMIDE.] MS [(M+1)] 352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 16h; | EXAMPLE 166 methyl(1S)-1-([(1S,3S,4S)-4-[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate A solution of 3,5-dimethyl isoxazole 4-carboxylic acid (6.9 mg, 0.49 mmol) in N,N-dimethylformamide (0.3 mL) was treated with Example 2C (25 mg, 0.047 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11 mg, 0.07 mmol), diisopropylethylamine (16.4 muL, 0.09 mmol) at 25 C. for 16 h. The solvents were evaporated, and the crude residue was purified by silica gel chromatography eluding with a gradient of dichloromethane, 100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the title compound (13 mg, 42%). 1H NMR (300 MHz, CDCl3) delta ppm 0.90(s, 9H), 1.77-1.63(m, 2H), 2.27(s, 3H), 2.45(s, 3H), 3.02-2.75(m, 4H), 3.60(s, 3H), 3.77-3.70(m, 2H), 4.20-4.1 1(m, 2H), 4.23-4.22(d, J=4.04 Hz, 1H), 5.25-5.22(d, J=8.82 Hz, 1H), 6.00-5.97(d, J=8.82 Hz, 1H), 6.13-6.11(d, J=6.99 Hz, 1H), 7.25-7.13(m, 8H), 7.68-7.66(m, 1H), 7.78-7.73(m, 1H), 7.87-7.84(d, J=8.09 Hz, 2H), 8.68(m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; trimethylsilylazide; In methanol; | EXAMPLE 2 Synthesis of starting material: STR20 3,5-Dimethyl-4-isoxazolylcarboxylic acid (14.1 g) and thionyl chloride (15.0 g) were mixed and the resulting mixture was heated under reflux for 20 hours. The excess thionyl chloride was distilled off under reduced pressure, and trimethylsilyl azide (30.0 g) was added to the residue thus obtained. The resulting mixture was heated under reflux for 24 hours, and the excess trimethylsilyl azide was distilled off under reduced pressure and then methanol (30 ml) was added to the residue thus obtained. Thereafter, the methanol was distilled off, and the resultant residue was subjected to silica gel chromatography, using chloroform: ethanol=15:1, so that 1-(3,5-dimethyl-4-isoxazolyl)-5(4H)-tetrazolinone (10.5 g) was obtained. m.p. 191.5-193 C. (decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide Using the general method of Example 97 <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188-189 C. Analysis: Calculated for C21H25N7O2: % C, 61.90; % H, 6.18; % N, 24.06; Found: % C, 61.92; % H, 6.15; % N, 24.28. HRMS (EI) calcd for C21H25N7O2 (M+) 407.2069 found 407.2068 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.2% | With N-chloro-succinimide; triphenylphosphine; In methanol; dichloromethane; | Example 110 3,5-Dimethyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluorobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide A mixture of <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> (8.1 mg, 0.057 mmol) in dichloromethane (1.5 mL) cooled to 0 C. was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at 0 C. for 15 min and at 25 C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at 25 C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1*10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2:98 methanol/dichloromethane) afforded <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.4 mg, 23.2%) as an off-white solid: EI-HRMS m/e calcd for C30H29N6O4F (M+) 556.2234, found 556.2229. |
23.2% | A mixture of 3, 5-dimethyl-isoxazole-4-carboxylic acid (8.1 mg, 0.057 mmol) in dichloromethane (1.5 mL) cooled to [0 oC] was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at [0 oC] for 15 min and at [25 oC] for 20 min. At this time, the reaction was treated with [3-CYCLOPROPYLMETHYL-L- (2-FLUORO-BENZYL)-8- (4-METHYLAMINO-BENZYL)-3,] 7- dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at [25 oC] for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution [(1 X 10] mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 2: 98 methanol/ dichloromethane) afforded <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> [{4- [3-] [CYCLOPROPYLMETHYL-L-(2-FLUORO-BENZYL)-2,] 6-dioxo-2,3, 6, 7-tetrahydro-lH-purin-8- ylmethyl] -phenyl} -methyl-amide (7.4 mg, 23.2%) as an off-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Example 1.1; N-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-(5-{3-[6-(methylamino)pyridin-2-yl]propyl}thiophen-2-yl)-L-alanine; To a solution of methyl 3-(5-{3-[6-(methylamino)pyridin-2-yl]propyl}-2-thienyl)-L-alaninate (190 mg, 0.57 mmol) in DMF (1.5 ml) were added TBTU (259 mg, 0.68 mmol) and a solution of <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (80 mg, 0.57 mmol) in DMF (6 ml). The reaction mixture was allowed to stir at room temperature for 48 hours. NaOH 6N (15 drops) was then added. After 3 hours at room temperature, the crude mixture was filtered and purified by C18 reverse phase chromatography (basic conditions) to afford the title compound as a pale yellow solid (190 mg, 76%).1H NMR Spectrum (DMSO-d6) 1.87-1.96 (m, 2H), 2.18 (s, 3H), 2.39 (s, 3H), 2.53 (t, 2H), 2.70-2.77 (m, 5H), 3.16 (dd, 1H), 3.33 (dd, 1H), 4.51 (ddd, 1H), 6.23 (d, 1H), 6.30 (d, 1H), 6.33 (bs, 1H), 6.65 (d, 1H), 6.72 (d, 1H), 7.27 (dd, 1H), 8.28 (d, 1H)Mass Spectrum [M+H]+=443 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.2% | Example 2; N-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]thiophen-2-yl}-L-alanine; O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (268 mg, 0.83 mmol), 4-methylmorpholine (0.084 ml, 0.76 mmol) and <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (98 mg, 0.70 mmol) were added under an argon atmosphere to a stirred solution of methyl 3-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]thiophen-2-yl}-L-alaninate (250 mg, 0.70 mmol) dissolved in DMF (2.5 mL). The resulting solution was stirred at 25 C. for 2 hours. Then NaOH 6N (0.464 ml, 2.78 mmol) was added to the stirred mixture. The resulting solution was stirred at 25 C. for 1 hour. The reaction mixture was purified by C18 reverse phase chromatography (basic conditions). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a beige solid (157 mg, 48.2%); Mass spectrum [M+H]+=467; 1H NMR Spectrum (DMSOd6) 1.70-1.78 (m, 2H), 1.81-1.90 (m, 2H), 2.18 (s, 3H), 2.39 (s, 3H), 2.45 (t, 2H), 2.60 (t, 2H), 2.70 (t, 2H), 3.15 (dd, 1H), 3.20-3.26 (m, 2H), 3.32 (dd partially hidden by H2O, 1H), 4.49 (ddd, 1H), 6.23 (d, 1H), 6.42 (bs, 1H), 6.64 (d, 1H), 6.71 (d, 1H), 7.03 (d, 1H), 8.27 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3,5-Dimethylisoxazole-4-carboxylic acid (35.3 mg, 0.25 mmol) is dissolved in 2 mL dichloromethane. To this solution dicyclohexylcarbodiimide (56.7 mg, 0.275 mmol) are added and the reaction mixture is stirred for 30 min at room temperature. Subsequently (+-)-3-(4-amino-benzyl)-5-ethyl-5-phenyl-imidazolidine-2,4-dione (80 mg, 0.25 mmol) is added to the mixture and the suspension is stirred at room temperature for another 45 min. Then the solvent is evaporated and the residue is purified by preparative HPLC (method 3) and to the product-containing fractions sodium bicarbonate solution is added and the product extracted with dichloromethane to yield (+-)-3,5-dimethyl-isoxazole-4-carboxylicacid [4-(4-ethyl-2,5-dioxo-4-phenyl-imidazolidin-1-ylmethyl)-phenyl]-amide. LC/MS at 254 nm; MH+ 433; Rt 2.992 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; | Example 1; 3,5-Dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-(2(2S)-methyl- [1 ,3'(3 ' S)]bipyrrolidinyl- 1 '-yl)-phenyl] -amide; 2-Methyl-4-(2(2S)-methyl-[l,3'(3'S)]bipyrrolidinyl-r-yl)-phenylamine (330 mg, 1.15 mmol) was dissolved in DCM (6 mL) and DMF (2 mL), and the solution was cooled to an ice- water bath. To this solution was added powdered <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> (168.9 mg, 1.38 mmol, 1.2 equiv.), N-methylmorpholine (280 mg, 3 equiv.), 1- hydroxylbenzotriazole (HOBT) (0.162 g, 1.19 mmol, 1.3 equiv.), sequentially, and finally EDC HCl (0.228 g, 1.19 mmol, 1.3 equiv. ). The resultant clear brown solution was stirred at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS showed that the reaction was complete and the product peak (368) was detected. The reaction was quenched with saturated aqueous sodium bicarbonate solution (3 mL) and 3 mL of DCM. The two layers were separated, and <n="37"/>the aqueous layer was extracted with DCM (5 mLx2). The combined DCM extracts were washed with sodium bicarbonate (5 mL), and brine (5 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get a crude product which was purified on a silica gel column (25 g of silica gel) on Analogix to get the title compound as a tan solid, 200 mg (49% yield).LCMS: Rx = 1.54 minutes, MS: 383 (M+H).1H NMR (CDCl3, 300MHz), delta (ppm): 7.44 (m, IH), 6.92 (bs, IH), 6.40 (bs, IH), 6.39 (bs, IH), 3.50 (m, IH), 3.4-3.2 (m, 4H), 3.00 (m, IH), 2.78 (m, IH), 2.66 (bs, 3H), 2.48 (bs, 3H), 2.5 (m, IH), 2.26 (s, 3H), 2.18 (m, IH), 2.00 (m, 2H), 1.79 (m, 2H), 1.48 (m , IH), 1.14 (d, 6.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | ER-825418-00: As depicted in Scheme 24 above, <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (17.5 mg, 0.124 mmol) was dissolved in CH2Cl2 (2 mL). O-(Benzotriazol-l-yl)- N,N,N',N'-tetramethyluronrum hexafluorophosphate (47.0 mg, 0.124 mmol) and N,N-diisopropylethylamine (29 muL, 0.17 mmol) were added. Reaction stirred for 30 minutes. ER-824188-00 (41.9 mg, 0.113 mmol) was added. Reaction stirred overnight. Purification by LC/MS followed by evaporation using the genevac provided ER-825418-00 (29.9 mg, 54%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (1000 mg, 7.09 mmol) was heated to 80 C in SOCl2 (5.17 ml, 70.8 mmol) for 30 min. The remaining solvent was evaporated and the crude material dissolved in DCM (15 ml). After cooling to 0 C Nu,Omicron-dimethylhydroxlamine hydrochloride ( 1036.8 mg, 10.6 mmol) was added and, dropwise, pyridine (0.86 ml, 10.6 mmol) and the mixture was stirred over night at rt. 1M HC1 and DCM were added and the phases were separated. After flash chromatographic separation N-methoxy-N,3,5-trimethylisoxazole-4-carboxamide (1300 mg, 7.06 mmol) was obtained. | ||
19 g | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 48h; | Preparation 34 N-methoxy-N,3,5-trimethylisoxazole-4-carboxamide A/-methoxy-A/,3,5-trimethylisoxazole-4-carboxamide A solution of <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (15 g, 106 mmol), N,0- dimethylhydroxylamine hydrochloride (11.40 g, 1 17 mmol), HATU (44.5 g, 117 mmol) and Hunig's Base (46.4 ml, 266 mmol) in DCM (304 ml) was stirred at rt for 2 days. Water was added and the aqueous layer was extracted with DCM (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-40% EtOAc/Hexane to give N- methoxy-N,3,5-trimethylisoxazole-4-carboxamide (19 g) as a colorless oil. 'H NMR (500MHz, CHLOROFORM-d) delta 3.53 (s, 3H), 3.36 (s, 3H), 2.48 (s, 3H), 2.34 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of <strong>[2510-36-3]3,5-dimethyl-4-isoxazolecarboxylic acid</strong> (68.5 mg, 0.486 mmol), EDC.HCl (115 mg, 0.598 mmol), HOBt (92 mg, 0.598 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.934 mmol) in N,N-dimethylformamide (1 mL), stirred for 10 minutes, was added l-(5- methyl-7H-pyrrolo[2,3-J]pyrirmdin-4-yl)-4-piperidinamine (100 mg), Dll, and the reaction stirred for 18 h. The solvent was removed in vacuo and the mixture purified by high pH MDAP to give the title compound E28 (60 mg). ¾ NMR (d6- DMSO) 5 11.53 (IH, s), 8.21 (IH, s), 8.00 (IH, d), 7.07 (IH, s), 4.02-3.94 (3H, m), 3.07 (2H, t), 2.48 (3H, s), 2.36 (3H, s), 2.28 (3H, s), 1.96 (2H, d), 1.68 (2H, ddd), MS(ES+) 355[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | A solution of 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2- fluorophenyl}acetohydrazide (400 mg, 0.98 mmol), 3,5-dimethyl-4- isoxazolecarboxylic acid (138 mg, 0.98 mmol), HATU (373 mg, 0.98 mmol) and DIPEA (0.34 mL, 1.96 mmol) in THF (5 mL) was heated at 45 C overnight. The reaction was cooled to rt, Burgess Reagent (933 mg, 3.92 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic extracts were combined, dried over Na2SO4, filtered, concentrated and the crude material was purified by column chromatography (5% to 100% EtOAc/hexanes gradient) to afford the title compound (350 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-c/6): delta ppm 7.55-7.48 (m, 3H), 7.15 (t, 1 H), 7.08 (t, 1 H), 4.46 (s, 2H), 2.62 (s, 3H), 2.38 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.047 g, 0.177 mmol) in DMF (1 mL) were added <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (0.037 g, 0.266 mmol) and TBTU (0.063 g, 0.195 mmol) followed by Huenig's base (0.048 g, 0.372 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was purified directly by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH-H2O (0.05% TEA) gradient to give the title compound (0.041 g, 59%) as a colorless solid. MS: 391.3 (M+H+) |
59% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Example 75 3,5-Dimethyl-isoxazole-4-carboxylic acid [5-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-yl)-pyridin-3-ylmethyl]-amideTo a solution of 6-(5-aminomethyl-pyridin-3-yl)-l-methyl-3,4-dihydro-lH-quinolin-2-one (example 36, 0.047 g, 0.177 mmol) in DMF (1 mL) were added 3,5-dimethylisoxazole-4- carboxylic acid (0.037 g, 0.266 mmol) and TBTU (0.063 g, 0.195 mmol) followed by Hunig's base (0.048 g, 0.372 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was purified directly by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH-H20 (0.05 % TEA) gradient to give the title compound (0.041 g, 59 %) as a colorless solid. MS: 391.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With thionyl chloride; at 70℃; | To a solution of 3,5-dimethylisoxazole-4-carboxy3ic acid (9.2 g, 65.2 mmol) in MeOH (50 mL) was added SOCl2 (15.3 g, 130.4 mmol) very slowly. The reaction mixture was heated to 70 C overnight. The reaction mixture was then cooled to rt, concentrated, and purified by column chromatography (10% EtO Ac/petroleum ether) to afford the title compound (9.0 g, 89%), LCMS- Pl : 156 | ] i l l : R:: 1.404 min. |
89% | With thionyl chloride; at 70℃; | 2-(2-(3,5-dimethylisoxazole-4-carbonyl)benzofuran-5-yl)-N-((2,4-dimethylphenyl)(phenyl)methyl) acetamidea) methyl 3,5-dimethylisoxazol -4-carboxylateTo a solution of <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (9.2 g, 65.2 mmol) in MeOH (50 mL) was added SOCI2 (15.3 g, 130.4 mmol) very slowly. The reaction mixture was heated to 70 C overnight. The reaction mixture was then cooled to rt, concentrated, and purified by column chromatography (10% EtO Ac/petroleum ether) to afford the title compound (9.0 g, 89%). LCMS- Pl : 156 [M+H]+; Rt: 1.404 min. |
89% | With thionyl chloride; at 70℃; | (f methyl 3,5-dimethyhsoxazoie-4-carhoxylate: To a solution of 3,5-dimethylisoxazole-4- carboxylic acid (9.2 g, 65.2 mnmol) in MeOH (50 mnL) was added SOd2 (15.3 g, 130.4 nunol) slowly. The resulting mixture was heated to 70 C overnight. When the reaction was complete,the reaction was cooled, concentrated, and purified by silica gel column chromotography (petroleum ether/EtOAc = 10/i) to afford the title compound (9.0 g, yield: 89%). LCMS-P1: 156 [M--HE it, = 1.404 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.0 g | To a solution of <strong>[2510-36-3]3,5-dimethylisoxazole-4-carboxylic acid</strong> (2.4 g, 1.70 mmol) in CH2C12 (15 mL), and DMF (0.5 mL) at 0 C was added (COCl)2 (1.76 mL, 2.04 mmol) and the reaction mixture was stirred for 1 h. Following concentration, the residue was dissolved in CH2C12 (15 mL) and Et3N (8.3 mL, 6.01 mmol) and methyl 2-(3-amino-4-hydroxyphenyl)acetate were added. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water (150 mL), extracted with EtOAc (350 mL), dried over Na2SO/t, filtered, and concentrated to provide the title compound (5.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | 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 2h; | To a solution of 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218, 0.05 g, 0.148 mmol) in dry DMF (1 mL) were added EDCI (0.034 g, 0.077 mmol), hydroxybenzotriazole (0.017 g, 0.077 mmol), Huenig's base (0.057 g, 0.443 mmol) and <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> (0.021 g, 0.148 mmol) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.03 g, 48%) as a colorless solid. MS: 425.4 (M+H+). |
48% | 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 2h; | Example 219 3,5-Dimethyl-isoxazole-4-carboxylic acid [4-chloro-5-(l-methyl-2-oxo-l,2,3,4- tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amideTo a solution of 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-l-methyl-3,4-dihydro-lH- quinolin-2-one hydrochloride (example 218, 0.05 g, 0.148 mmol) in dry DMF (1 mL) were added EDCI (0.034 g, 0.077 mmol), hydroxybenzotriazole (0.017 g, 0.077 mmol), Hunig's base (0.057 g, 0.443 mmol) and <strong>[2510-36-3]3,5-dimethyl-isoxazole-4-carboxylic acid</strong> (0.021 g, 0.148 mmol) and the resulting solution was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc, poured into sat. NaHC03 solution (10 mL) and extracted with EtOAc (2 x 20 mL). Combined organics were dried over Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.03 g, 48 %) as a colorless solid. MS: 425.4 (M+H+). |
Tags: 2510-36-3 synthesis path| 2510-36-3 SDS| 2510-36-3 COA| 2510-36-3 purity| 2510-36-3 application| 2510-36-3 NMR| 2510-36-3 COA| 2510-36-3 structure
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