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CAS No. : | 10068-07-2 | MDL No. : | MFCD00062870 |
Formula : | C5H5NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BBFWUUBQSXVHHZ-UHFFFAOYSA-N |
M.W : | 143.10 | Pubchem ID : | 2724585 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 30.61 |
TPSA : | 72.3 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) : | -7.33 cm/s |
Log Po/w (iLOGP) : | 1.09 |
Log Po/w (XLOGP3) : | -0.22 |
Log Po/w (WLOGP) : | -0.25 |
Log Po/w (MLOGP) : | -0.5 |
Log Po/w (SILICOS-IT) : | 0.84 |
Consensus Log Po/w : | 0.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.83 |
Solubility : | 21.3 mg/ml ; 0.149 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.84 |
Solubility : | 20.6 mg/ml ; 0.144 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.2 |
Solubility : | 9.07 mg/ml ; 0.0634 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.4 |
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 |
---|---|---|
95% | In dichloromethane; | 3-[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester To a solution of [6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech., 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for 1 h under argon. The reaction mixture was cooled to 0 C. and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0 C. for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield). 1H NMR (300 MHz, CDCl3) 8.76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J=2.1 Hz, 1H), 5.43 (dd, J=2.1 Hz, 1H), 5.14 (dd, J=3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J=3.9 Hz, 1H), 4.49 (dd, J=5.7 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18H18ClN5O7 (MH+) 452, found 452 by LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 1h; | Example 1; 7V-(3-Chloro-4-fluorophenyl)-iV-hydroxy-3-(3-morpholin-l-ylpropoxy)isoxazole-5- carboximidamide; Step A: Methyl 3-(3-bromopropoxy)isoxazole-5-carboxylate; A solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (3.5 g, 24 mmol) in N,N- dimethylformamide (20 mL) was treated with potassium carbonate (6.8 g, 49 mmol) and 1,3- dibromopropane (2.5 mL, 24 mmol) was added and the mixture was stirred at 40 0C for 1 h.The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo.The crude residue was purified by flash chromatography (0-70% ethyl acetate/ hexanes) to give the desired product (1.6 g, 25%). MF = C8H11BrNO4; LCMS calculated for C8H11BrNO4 |
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; for 1.5h; | Step 1 Methyl 3-(3-bromopropoxy)isoxazole-5-carboxylate To a solution of methyl S-hydroxyisoxazole-S-carboxylate (1 0150 g, 7 09 mmol) m DMF (5 mL) at 0 0C was added potassium carbonate (1 0872 g, 7 87 mmol) and 1,3- dibromopropane (3 6 mL, 35 5 mmol) The yellow suspension was warmed and heated to 60 0C for 1 5 h The reaction mixture was poured into aqueous 1 N HCl, extracted with EtOAc and washed with 1 N HCl and b?ne The organic layer was d?ed (Na2SO4) and filtered Solvents were removed under diminished pressure to afford the crude product The crude product was purified by column chromatography on silica gel (gradient 10-30% EtOAc/hexanes) to afford the title compound as a white solid ^H NMR (500 MHz, acetone-^) delta 6 81 (s, IH), 4 45 (t, 2H), 3 95 (s, 3H), 3 67 (t, 2H), 2 39 (p, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 2h; | A mixture of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N,N-dimethylformamide (100 ml) was stirred at 60C for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.78 g, yield 78%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 133-134C |
78% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 2h; | A mixture of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N,N-dimethylformamide (100 ml) was stirred at 60C for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.78 g, yield 78%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 133-134C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Example 3. Synthesis of 5'-isoxazole derivatives:; 3- [6- (6-Chloro-purin-9-yl)-2, 2-dimethyl-tetrahydro-furo [3, 4-d] [1, 3] diol-4- ylmethoxy]-isoxazole-5-carboxylic acid methyl ester:; To a solution of [6- (6-Chloro-purin-9-yl)-2, 2-dimethyl-tetrahydro-furo [3,4- d] [1, 3] dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP ; Argonaut Tech. , 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for lh under argon. The reaction mixture was cooled to 0 C and under argon flow diethylazodicarboxylate (0.33 g, 1. 1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0 C for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield).'H NMR (300 MHz, CDC13) 6 8. 76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J= 2. 1Hz, 1H), 5.43 (dd, J= 2.1 Hz, 1H), 5.14 (dd, J= 3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J= 3. 9Hz, 1H), 4.49 (dd, J= 5.7Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C, 8H, 8ClNsO7 (MH+) 452, found 452 by LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | <strong>[10068-07-2]3-Hydroxy-isoxazole-5-carboxylic acid methyl ester</strong> (0.859 g., 6.00 mmol) and 3-piperidin-1-yl-propan-1-ol (0.860 g., 6.00 mmol) were dissolved in DCM (30 mL), and polymer-supported Ph3P resin (3 mmol/g, 3.1 g, 9.30 mmol) was added. The mixture was stirred for 10 min and di-tert-butyl azodicarboxylate (2.14 g, 9.30 mmol) was then added. The reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with 1 N NaOH (20 mL) and was stirred for 30 min. The resulting mixture was extracted with DCM (3*30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield a crude oily product (3.1 g), which was purified (SiO2: 5% 2 M NH3 in MeOH/DCM) to yield the title compound (0.88 g, 58%). MS (ESI): exact mass calcd. for C13H20N2O4, 268.14; m/z found, 269.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.53 (s, 1H), 4.34-4.30 (m, 2H), 3.94 (s, 3H), 2.47-2.34 (m, 6H), 2.02-1.94 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.39 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.2 g (87%) | With potassium carbonate; citric acid; | F. Methyl 3-(4-cyanobenzyloxy)-5-isoxazolecarboxylate. A mixture of o-bromo-p-tolunitrile (18.8 mmol, 3.69 g), <strong>[10068-07-2]methyl 3-hydroxy-5-isoxazolecarboxylate</strong> (18.8 mmol, 2.69 g) and potassium carbonate (25 mmol, 3.5 g) was heated at 50 C. overnight. After cooling to room temperature, the solution was added to 1% citric acid and the precipitate was filtered, washed with water and cold ether several times and dried. Yield 4.2 g (87%). NMR (DMSO-d6): delta 7.90 (d, 2H); 7.68 (d, 2H); 7.18 (s, 1H); 5.43 (s, 2H); 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triphenylphosphine; In tetrahydrofuran; ethyl acetate; | A. Methyl 3-[3-(tert-butyloxycarbonylamino)propyloxy]-5-isoxazolecarboxylate: Diethylazodicarboxylate (1.46 g, 8.39 mmol) was added dropwise to a mixture of <strong>[10068-07-2]methyl 3-hydroxy-5-isoxazolecarboxylate</strong> (1 g, 4.55 mmol), triphenylphosphine (1.46 g, 8.39 mmol), and 3-tert-butyloxycarbonylamino-1-propanol (1.50 g, 8.39 mmol) in anhydrous tetrahydrofuran (10 mL) at 0 C. under nitrogen. After 1 h remove the ice bath and warm to room temperature overnight. Dilute with ethyl acetate (75 mL) and wash with water (25 mL), saturated NaHCO3 (25 mL), and brine (25 mL). Dry over MgSO4 then evaporate the solvent in vacuo. The residue was chromatographed over silica gel (75 g, 25 to 60% ethyl acetate/hex) to give the title compound (1.95 g, 95%) as a waxy solid: 1 H NMR (300 MHz, CDCl3) delta6.53 (s, 1H), 4.74 (bs, 1H), 4.36 (t, 2H), 3.95 (s, 3H), 3.28 (q, 2H), 2.00 (m, 2H), 1.44 (s, 9H); MS (CI-NH3) m/e 318 (M+NH4)+; HRMS calc'd for C13 H20 N2 O6 +H: 301.1400, found 301.1403. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 1 - 30℃; for 15h; | To a mixture of 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.64 g), <strong>[10068-07-2]methyl 3-hydroxy-5-isoxazolecarboxylate</strong> (8.00 g), tributylphosphine (15.9 g) and tetrahydrofuran (200 mL) was added a solution (100 mL) of 1,1'-(azodicarbonyl)dipiperidine (19.9 g) in tetrahydrofuran at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give crystals (9.50 g, 73%) of methyl 3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals.melting point: 90-91 DEG C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethyloxonium fluoroborate; In dichloromethane; | EXAMPLE 78 Methyl 3-ethoxy-5-isoxazolecarboxylate A stirred suspension of 3.53 g (24.67 mmole) of a commercial sample of <strong>[10068-07-2]methyl 3-hydroxy-5-isoxazolecarboxylate</strong> in 50 ml of methylene chloride was treated dropwise with a solution of triethyloxonium tetrafluoroborate (5.62 g, 29.60 mmole) dissolved in 30 ml of methylene chloride at room temperature. After stirring overnight the solution was washed with water (2*30 ml), 5% sodium bicarbonate (2*30 ml) and water once again. The organic layer was dried (magnesium sulfate) and evaporated in vacuo to furnish the title compound (3.61 g, 86% yield) as a light yellow solid, m.p. 77-9 C. 1 H-NMR (DMSO-d6)delta, 6.65 (1H, s), 3.93 (2H, q, J=7.4 Hz), 3.87 (3H, s) and 1.21 (3H, t, J=7.4 Hz); EIMS (m/z): 171 (M+, 48%), 56 (M+ --CH3, 4%), 143 (C5 H 5 NO4, 31%), 112 (C4 H2 NO3, 12%) and 69 (C3 H3 NO, base); ir (potassium bromide): 3105, 1744, 1611, 1441, 1241, 1106, 974 and 797 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In methanol; water; | a Methyl (3-hydroxy)isoxazole-5-carboxylate To a solution of N-hydroxyurea (3.80 g, 0.05 mol) and diazabicyclo[5.4.0]undec-7-ene (8.37 g, 0.055 mol) in methanol (50 ml) at 0 C. under nitrogen was added dimethylacetylene dicarboxylate (7. 10 g, 0.05 mol). The reaction was stirred at 0 C. for 1 h then at room temperature for 12 h. The solvent was evaporated in vacuo and the residue taken up into water (20 ml) and acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3*25 ml), dried (Na2SO4) and evaporated in vacuo. The resulting solid was recrystallized from chloroform to give the title-ester (2.20 g, 31%), 1H NMR (250 MHz, CDCl3) delta 3.97 (3H, s, CH3), 6.61 (1H, s, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | Preparation of 3-(2-TrimethyIsiIanyI-ethoxymethoxy)-isoxazole-5-carboxylic acid methyl esterTo a solution of 0.258 g of methyl 3-hydroxy-S-isoxazolecarboxylate in 1.8 mL of anhydrous CH2CI2 was added 1.25 mL of DIPEA (7.21 mmol) followed by 0.636 mL of 2-(trimethyIsilyI)ethoxymethyl chloride. The reaction was maintained at ambient temperature for 2 h. The reaction was diluted with H2O and extracted with CH2CI2 (3 x 20 mL). The combined organics were washed with brine, dried over Na2SO<j, filtered, and concentrated. Purification by flash chromatography (25-40% EtOAc/hexanes) afforded the desired product as a pale yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a solution of [6- (6-Chloro-purin-9-yl)-2, 2-dimethyl-tetrahydro-furo [3,4- d] [1, 3] dioxol-4-yl] -methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech. , 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for lh under argon. The reaction mixture was cooled to 0 C and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0 C for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield).'H NMR (300 MHz, CDC13) 6 8.76 (s, 1H), 8.23 (s, IH), 6.42 (s, 1H), 6.23 (d, J= 2. 1Hz, 1H), 5.43 (dd, J= 2.1 Hz, IH), 5.14 (dd, J = 3. 6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J= 3. 9Hz, IH), 4.49 (dd, J= 5. 7Hz, IH), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18Hl8CIN507 (MH+) 452, found 452 by LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Compound 26a (10.0 g, 69.9 mmol) was dissolved in N,N-dimethylformamide (70 ml), then cooled to 0C, and then 60% sodium hydride/mineral oil (3.07 g, 77.0 mmol) was added thereto. After stirring at 0C for 30 minutes, p-methoxybenzyl chloride (11.4 ml, 77.0 mmol) was added. The reaction solution was then stirred at 50C overnight. Sodium hydride (3.07 g, 77.0 mmol), p-methoxybenzyl chloride (11.4 ml, 77.0 mmol) and sodium iodide (12.6 g, 84.0 mmol) were added, and then stirred for another 1 hour, and then ethyl acetate and distilled water were added, followed by extraction. The organic layer separated was washed with saturated brine and dried with anhydrous sodium sulfate. After the inorganic substance was filtered, the filtrate was concentrated, dried under reduced pressure, and then purified by column chromatography, Compound 26b was obtained as a brown oil.Yield: 11.7 g (64%)1H-NMR (CDCl3) delta: 7.38 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 6.53 (1H, s), 5.24 (2H, s), 3.94 (3H, s), 3.82 (3H, s). | |
47% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; for 10h; | <strong>[10068-07-2]3-Hydroxyisoxazol-5-carboxylic acid methyl ester</strong> (4.73 g, 33 mmol) was dissolved in 66 mL of DMF. K2CO3(5.0 g, 36.3 mmol) and 4-methoxybenzyl chloride (4.5 mL, 33 mmol) were added thereto at 0C, and the mixture wasstirred at 60C for 10 hours. The reaction solution was concentrated under reduced pressure, diluted with water andextracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to obtain thetitle compound (4.06 g, 47 %).1H-NMR (CDCl3) delta 7.39 (2H, d), 6.92 (2H, d), 6.54 (1H, s), 5.24 (2H, s), 3.95 (3H, s), 3.81 (3H, s) |
To a stirred solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.0 g, 35 mmol) in DMF (20 mL, 300 mmol) at 0 C. was added K2CO3 (5.4 g, 39.4 mmol). After 10 minutes at room temperature p-methoxybenzyl chloride (5.5 mL, 40.2 mmol) was added in one portion. The resulting mixture was heated at 60 C. for 2 hours and then cooled to room temperature and stirred overnight. 1.0 M HCl in water (150 mL) and EtOAc (150 mL) were added and the phases were separated. The organic layer was washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, and the solvent removed by rotary evaporation to yield a thick oil. The oil was dissolved in THF (35 mL) and MeOH (35 mL), followed by addition of LiOH monohydrate (2.9 g, 69.9 mmol) dissolved in water (35 mL). The resulting mixture was stirred at room temperature and the reaction monitored for completion (?3 hours). Solvent was removed by rotary evaporation at 30 C. to yield a pasty solid. Toluene (100 mL) was added and the volume was reduced (to ?50 ml). EtOAc (200 mL) was added and the volume was reduced (to ?50 ml). Filtration and drying yielded a solid (10 g), which was dissolved in water (200 mL), and the pH was adjusted slowly with concentrated HCl to ?2. EtOAc (200 mL) was added and the phases were separated. The aqueous layer was back extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, followed by solvent removal. The product was reslurried in EtOAc:hexanes (1:1) followed by filtration to yield Compound 3 (purity >99%). Compound 2 (18.0 g, 26.8 mmol) in DMF (90 mL) was combined with Compound 3 (7.3 g, 29 mmol) in DIPEA (12 mL, 67 mmol). The mixture was cooled at 0 C. followed by the portion-wise addition of PyBOP (18 g, 35 mmol) and the reaction monitored for completion (?30 minutes at 0 C.). Water (540 mL) and EtOAc (540 mL) were added and the phases were separated. The organic layer was washed with saturated aqueous NaCl (500 mL) and dried over Na2SO4, followed by solvent removal. The crude product was purified (SiG chromatography; 300 g column, 10-30-50% EtOAc/hexanes) to yield the title compound (9 g, purity >98%). |
Step 1 Methyl 3-|~(4-methoxybenzyl)oxy'|isoxazole-5-carboxylateTo a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (20 1055 g, 141 mmol) in DMF (100 mL) at 0 0C was added potassium carbonate (22 0119 g, 159 mmol), and after 10 min 4-methoxybenzyl chlo?de (23 mL, 169 mmol) The yellow suspension was stirred 15 mm at 0 C, 15 min at room temperature and 1 5 h at 60 0C The reaction mixture was poured into aqueous IN HCl, extracted with EtOAc and washed four times with IN HCl and b?ne The organic layer was d?ed (Na2SO4) and filtered Solvents were removed under diminished pressure to afford the crude product The crude product was purified by column chromatography on silica gel (gradient 10-30% EtOAc/hexanes) to afford the title compound as a colorless oil leta NMR (500 MHz, acetone-^) delta 7 50-7 44 (m, 2H), 7 01-6 97 (m, 2H), 6 80 (s, IH), 5 27 (s, 2H), 3 94 (s, 3H), 3 83 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at -78 - 20℃; for 24h; | Step 1 Methyl 3-[2-(2-bromo-5-fluorophenoxy)ethoxy]isoxazole-5-carboxylateTo a solution of 2-(2-bromo-5-fluorophenoxy)ethanol (510 mg, 2 170 mmol) (INTERMEDIATE 6) and <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (461 mg, 3 22 mmol) in TetaF (10 ml) was added di-tert-butyl azodicarboxylate (737 mg, 3 20 mmol) The yellow solution was cooled to -78 0C and treated with a solution of t?phenylphosphme (846 mg, 3 23 mmol) in Ceta2CI2 (5 ml) The final mixture was warmed and stirred for 24 h at room temperatureSolvents were removed under diminished pressure to afford the crude product The crude mate?al was pu?fied by column chromatography on silica gel (gradient from 0 to 30% EtOAc/hexanes) to afford the title compound as a white solid lH NMR (500 MHz, acetone-^) 5 7 61 (dd, IH), 7 06 (dd, IH), 6 87 (s, IH), 6 77 (td, IH), 4 75-4 72 (m, 2H), 4 56-4 53 (m, 2H), 3 95 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | To a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (7.20 g, 50.31 mmol, 1.00 eq) in acetone (150 mL) was added potassium carbonate (13.91 g, 100.62 mmol, 2.00 eq). The mixture was heated to 80 C for 1 hr, then (bromomethyl) benzene (10.33 g, 60.37 mmol, 1.20 eq) was added. The resulting mixture was stirred at 80 C for another 3 hr. LC/MS showed the reaction was completed. The solid was filtered off and the filtrated was concentrated under vacuum. The residue was further purified by silica gel column chromatography (petroleum ether: Ethyl acetate = 15: 1 to 10: 1) to afford methyl 3-benzyloxyisoxazole-5-carboxylate (9.50 g, 40.73 mmol, 81% yield) as a colorless oil. The oil was solidified after standing at 15 C for 15 hr. LC- MS (ESI) m/z: 256.0 [M+Na+] ; 1H NMR (400MHz, CDC13) delta 7.49 - 7.41 (m, 5H), 6.60 (s, 1H), 5.34 (s, 2H), 3.97 (s, 3H). | |
81% | To a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (7.20 g, 50.31 mmol, 1.00 eq) in acetone (150 mL) was added potassium carbonate (13.91 g, 100.62 mmol, 2.00 eq). The mixture was heated to 80 C for 1 hour, then (bromomethyl) benzene (10.33 g, 60.37 mmol, 1.20 eq) was added. The resulting mixture was stirred at 80 C for another 3 hours. The solid was filtered off and the filtrated was concentrated in vacuum. The residue was further purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 15:1 to 10:1) to afford methyl 3-benzyloxyisoxazole-5-carboxylate (9.50 g, 40.73 mmol, 81% yield) as a colorless oil. The oil was solidified after standing at 15 C for 15 hr. LC/MS (ESI) m/z· 256.0 [M+23] +; 'H- NMR (400MHz, CDCL) d 7.49 - 7.41 (m, 5H), 6.60 (s, 1H), 5.34 (s, 2H), 3.97 (s, 3H). | |
59% | With potassium carbonate; In acetone; for 1h;Reflux; | Methyl 3-hydroxyisoxazole-5-carboxylate (5.18 g, 36.2 mmol) was dissolved in acetone (90 mL) and treated with potassium carbonate (10.21g, 73.8 mmol) at reflux for 1 hour. At that time, benzyl bromide (6.5 mL, 54.3 mmol) was added, and the mixture was heated at reflux for an additional 3 hours. The reaction mixture was removed from the oil bath and stirred at room temperature for 18 hours. The mixture was filtered and concentrated in vacuo leaving a yellow oil. The oil was purified by silica gel chromatography eluting with hexane/ethyl acetate (3: 1) which gave the title compound as a light yellow solid (5.0g, 59%). |
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | (A) Methyl 3-(benzyloxy)isoxazole-5-carboxylate A mixture of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.0 g, 34.9 mmol), benzyl bromide (6.84 g, 40 mmol) and potassium carbonate (8.3 g, 60 mmol) in N,N-dimethylformamide (100 mL) was stirred at 50 C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 95:5 to 50:50). Solvent was removed to obtain a solid (1.68 g, 21%). 1H NMR (300 MHz, CDCl3) delta ppm 3.94 (s, 3H), 5.31 (s, 2H), 6.57 (s, 1H), 7.31-7.53 (m, 5H). |
Example 3; To a solution of Compound 1(14g) in dimethylformamide (140ml) was added potassium carbonate(19g), then the resulting mixture was stirred at 70 C for 1hr. Benzyl bromide(18ml) was slowly added dropwisely to the reaction mixture at 70 C and the reaction solution was stirred for 3hrs. After termination of the reaction, the reaction solution was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate and concentrated. | ||
To a solution of 29 (1.0g) in acetone(20mL) was added potassium carbonate(1.9g) under N2 atmosphere and the resulting mixture was stirred at 70 C for 1hr. Benzyl bromide(1.3mL) was added to the mixture and the whole mixture was stirred at 70 C for 2hrs and at room temp. for 16hrs. After termination of this reaction, the reaction mixture was filtrated by filter paper. The resulting solution was concentrated in vacuo and the residue was purified by silicagel columnchromatography to give 30 (1.3g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.01 g) in N,N-dimethylformamide (70 ml) was added sodium hydride (60% in oil, 1.40 g) at 0C and the mixture was stirred for 15 min. Then 4-chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added and the mixture was stirred at 60C for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96 g, yield 72%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 123-124C. | |
72% | Sodium hydride (60%, oily, 1.40 g) was added to a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.01 g) in N,N-dimethylformamide (70 ml) at 0C, which was stirred for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added to the mixture. After being stirred at 60C for 2 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96g, yield 72%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 123-124C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 0℃; | A mixture of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (1.0 g, 7.0 mmol) and K2C03 (1.9 g, 14 mmol) in dry DMF (15 mL) was added Me2504 (1.0 g, 8.4 mmol) at 0 C. The reaction solution was stirred at 0C continuously, and monitored by TLC until all the starting material was consumed completely; 50 mL of water was added. The residue was extracted by EA for two times (25 mL X 2), and the organic layer was washed with brine (25 mL X 3), and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to afford the desired product (850 mg, 77%) without further purification. MS [M+H]calcd for C6H7N04158.0, found 158.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | c) 3-[3-(4-Fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester A solution of methyl 3-hydroxy-5-isoxazolcarboxylate (4.2 g, 28.8 mmol) in THF (314 mL) was added to a solution of [3-(4-fluoro-phenyl-5-((E)-styryl)-isoxazol-4-yl]-methanol (8.5 g, 28.8 mmol) in THF (349 mL) containing triphenylphosphine (10.1 g, 37.4 mmol) at 5 C. and then DIAD (7.89 mL, 37.4 mmol) was added dropwise to the reaction mixture. The resulting mixture was then stirred overnight at room temperature. Evaporation of the mixture followed by chromatography (silica, ethyl acetate:heptane=1:3) afforded the title compound (6.84 g, 57%) as a light yellow solid. MS: m/e=479.0 [M+OAc]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1,5-Diazabicyclo[5.4.0]undec-5-ene; In methanol; at 0℃;Cooling; | a) 3-Oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester Prepared according to Synthesis 1985, 1100. To a stirred solution of <strong>[127-07-1]N-hydroxyurea</strong> (3.80 g, 50 mmol) and 1,5-diazabicyclo[5.4.0]undec-5-ene (8.37 g, 55 mmol) in methanol (50 mL) with cooling (ice bath) was added dimethyl ethyne dicarboxylate (7.11 g, 50 mmol) dropwise over 20 min. A dark red colour appeared then dissipated with each drop added, until finally a deep orange/red clear solution had formed. After an additional 20 min the mixture was concentrated to give a red oil which was then acidified with cooling in an ice/water bath to pH 1 with HCl (conc.). The resulting yellow mixture was extracted with diethyl ether (3*40 mL) then the aqueous phase was saturated with brine and extracted with ether (2*50 mL). The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated to afford the title compound (2.89 g, 40%) as white crystals after recrystallisation from chloroform. MS: m/e=143.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 20: S-Hydroxy-isoxazole-delta-carboxylic acid; To a solution of S-hydroxy-isoxazole-delta-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1 N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1 N HCI is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions. | ||
Intermediate 43: 3-Hydroxy-isoxazote-5-carboxylic acid; To a solution of S-hydroxy-isoxazole-delta-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1N HCI is added to the residue. The resulting solution is tyophilized to give the product which is used as is in subsequent reactions. | ||
With hydrogenchloride; In methanol; | 3-Hydroxy-isoxazole-5-carboxylic acid To a solution of 3-hydroxy-isoxazole-5-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1N HCl is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions. |
With hydrogenchloride; In methanol; | 3-Hydroxy-isoxazole-5-carboxylic acid To a solution of 3-hydroxy-isoxazole-5-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1N HCl is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions. | |
To a solution of 3-hydroxy-isoxazole-5-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1 N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1 N HCl is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; In dichloromethane; for 15h; | Step 1 Compound 16a (2.5 g, 17.47 mmol) was dissolved in 100 mL of CH2Cl2 and to the resulting solution was added N,N'-dimethylaminopyridine (DMAP, 2.77 g, 22.67 mmol) and chloro-tert-butyldimethylsilane (3.29 g, 21.83 mmol). The resulting reaction was allowed to stir for about 15 hours, then was diluted with 100 mL of CH2Cl2, washed with a saturated NaHCO3 aqueous solution and brine and dried over Na2SO4. The dried solution was then filtered through a one-inch silica gel pad, and the pad was rinsed with CH2Cl2. The filtrate was concentrated in vacuo to provide 3.96 g (88%) of compound 16b as a colorless oil, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; | e) Methyl 3-[5-(4-Fluoro-phenyl)-3-methyl-3H-[1,2,3]-triazol-4-ylmethoxy]-isoxazole-5-carboxylate; To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (290 mg, 1.4 mmol) in THF (30 mL) was added methyl 3-hydroxy 5-isoxazolecarboxylate (200 mg, 1.4 mmol) and triphenylphosphine (477 mg, 1.82 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (641 muL, 3.5 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (464 mg, 100%) as a white solid. MS: m/e=333.2 [M+H]+. |
100% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; | To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[l,2,3]triazol-4-yl]-methanol (290 mg, 1.4 mmol) in THF (30 mL) was added methyl 3-hydroxy 5-isoxazolecarboxylate (200 mg, 1.4 mmol) and triphenylphosphine (477 mg, 1.82 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (641 mu, 3.5 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. Concentration and purification bychromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (464 mg, 100%) as a white solid. MS: m/e = 333.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; for 5h;Reflux; | o a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (20 g) , tert-butyl [ (IS) -2-hydroxy-l-methylethyl] carbamate (25 g) and triphenylphosphine (55.1 g) in THF (800 mL) was added dropwise a toluene solution (1.9 M, 110 mL) of diisopropyl azodicarboxylate, and the mixture was refluxed for 5 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added thereto. The mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (25 g) .lR NMR (300 MHz, DMSO-d6) delta 1.09 (3H, d, J = 6.8 Hz), 1.37 (9H, s), 3.77-3.93 (4H, m) , 4.11 (2H, d, J = 6.4 Hz), 6.94 (1H, d, J = 8.0 Hz) , 7.08 (1H, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | A mixture of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong>(1.88 g) , 2- (fluoromethyl) oxirane (1.00 g) , potassiumcarbonate (1.82 g) and DMF (2 mL) was stirred at roomtemperature for 2 hr, and then at 70C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound as a white powder (585 mg) .MS (ESI+) : [M+H]+ 220.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Intermediate 14; 3-Methoxy-isoxazole-5-carboxylic acid To a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (958 mg, 6.69 mmol) in DMF (10 ml) was added potassium carbonate (935 mg, 6.76 mmol) at -5 C. Then dimethyl sulfate (644 muL, 6.76 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred over night. Then 2N NaOH (5.02 mL, 10.0 mmol) was added and the mixture was stirred for 4 h. After slow addition of 2N HCl (6.69 mL, 13.4 mmol), the mixture was extracted three times with diethyl ether. The combined organic extracts were washed with brine and evaporated. The remaining yellow oil was co-evaporated four times with toluene to give a solid that was dried for 4 h at 40 C. under high vacuum. The title compound as obtained as light brown solid (576 mg, 60%). | |
60% | Intermediate 143-Methoxy-isoxazole-5-carboxylic acidTo a solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (958 mg, 6.69 mmol) in DMF (10 ml) was added potassium carbonate (935 mg, 6.76 mmol) at -5C. Then dimethyl sulfate (644 mu, 6.76 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred over night. Then 2N NaOH (5.02 mL, 10.0 mmol) was added and the mixture was stirred for 4 h. After slow addition of 2N HC1 (6.69 mL, 13.4 mmol), the mixture was extracted three times with diethyl ether. The combined organic extracts were washed with brine and evaporated. The remaining yellow oil was co- evaporated four times with toluene to give a solid that was dried for 4 h at 40C under high vacuum. The title compound as obtained as light brown solid (576 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20℃; for 16h; | <strong>[10068-07-2]3-Hydroxy-isoxazole-5-carboxylic acid methyl ester</strong> (716 mg, 5.00 mmol) and K2CO3 (1.73 g, 12.5 mmol) were suspended in acetone (25 mL), and CH3I (0.800 mL, 12.5 mmol) was added. The resulting mixture was stirred at room temperature for 16 h, diluted with EtOAc (10 mL), and filtered. The solvent was removed under reduced pressure, and the residue was chromatographed using a 40-g SiO2 pre-packed column eluting with 0:1 to 1:4 EtOAc-hexanes to yield a residue. 1H-NMR (400 MHz, CDCl3) delta: 6.40 (s, 1H), 3.96 (s, 3H), 3.62 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methyl 3-hydroxy-isoxazole-5-carboxylate was reacted with l-[3-(bromomethyl)phenyl]-4- phenyl-lH-indole (1) in DMF and 1 equivalent of sodium hydride as base. After aqueous work-up, ester hydrolysis was performed using 2 equivalents 1 N aqueous sodium hydroxide in ethanol heated at 60 C for 6.5 hours. Acidic aqueous work-up and purification by chromatography (4 g silica gel, 0% to 5% methanol-dichloromethane with 0.5% acetic acid) affords 3-[3-(4-phenyl-lH-indol-l-yl)benzyloxy]-5-isoxazolecarboxylic acid (6) (5 mg) as a clear film; 1H NMR (300 MHz, CDC13): delta 5.36 (d, 2H), 6.63 (s, 1H), 6.83 (s, 1H), 7.23-7.62 (m, 11H), 7.70 (d, 2H); Calcd mass for C25Hi8N204: 410.13; LRMS (ESI) m/z [M + Na]+ = 433.49. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (5.0 g, 35 mmol) in DMF (20 mL, 300 mmol) at 0 C. was added K2CO3 (5.4 g, 39.4 mmol). After 10 minutes at room temperature p-methoxybenzyl chloride (5.5 mL, 40.2 mmol) was added in one portion. The resulting mixture was heated at 60 C. for 2 hours and then cooled to room temperature and stirred overnight. 1.0 M HCl in water (150 mL) and EtOAc (150 mL) were added and the phases were separated. The organic layer was washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, and the solvent removed by rotary evaporation to yield a thick oil. The oil was dissolved in THF (35 mL) and MeOH (35 mL), followed by addition of LiOH monohydrate (2.9 g, 69.9 mmol) dissolved in water (35 mL). The resulting mixture was stirred at room temperature and the reaction monitored for completion (?3 hours). Solvent was removed by rotary evaporation at 30 C. to yield a pasty solid. Toluene (100 mL) was added and the volume was reduced (to 50 mL). EtOAc (200 mL) was added and the volume was reduced (to 50 mL). Filtration and drying yielded a solid (10 g), which was dissolved in water (200 mL), and the pH was adjusted slowly with concentrated HCl to ?2. EtOAc (200 mL) was added and the phases were separated. The aqueous layer was back extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, followed by solvent removal. The product was reslurried in EtOAc:hexanes (1:1) followed by filtration to yield Compound 3 (>99% purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: 5-phenyl-3-hydroxyisoxazole (161 mg, 1.0 mmol, 1 equiv) was dissolved in anhydrous THF (14 mL), followed by isopropanol (96 muL, 1.25 mmol, 1.25 equiv) and PPh3 (341 mg, 1.3 mmol, 1.3 equiv). The reaction mixture was stirred for 2 min at rt. DIAD (256 lL, 1.3 mmol, 1.3 equiv) was added dropwise. After stirring for a further 15 min at rt under an inert (N2) atmosphere, TLC analysis confirmed the reaction was complete. The solvent was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluent gradient: 100% Hexane to 9:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) to give O-regioisomer (5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | Step 4: 3,5-Dichlorobenzyl 4-(2-(3-hydroxy-N-methylisoxazole-5-carboxamido)ethyl)piperidine-1-carboxylate A solution comprising of <strong>[10068-07-2]methyl 3-hydroxyisoxazole-5-carboxylate</strong> (20.72 mg, 0.145 mmol), 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 3) (50 mg, 0.145 mmol) and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (20.16 mg, 0.145 mmol) in DMF (483 mul) was refluxed for 18 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound; 1H NMR (400 MHz, MeOD) 7.4 (1H, s), 7.3 (2H, s), 6.35 (1H, d), 5.1 (2H, s), 4.15 (2H, bs), 3.6 (2H, q), 3.2 (3H, d), 2.9 (2H, bs), 1.9 (1H, d), 1.6 (4H, m), 1.1 (2H, m), LC-MS: Rt 5.24 mins; MS m/z 456 [M+H]+; Method 10minLowpHv01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In toluene; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 4-Hydroxybenzoic acid methyl ester 79 (0.20g, 1.314mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one 76 (0.33g, 1.577mmol), Ph3P (0.345g, 1.314mmol) and triethyl amine (0.20ml, 1.577mmol) in dry toluene (10ml) at 0 C, DIAD (0.3mL, 0.788mmol) was added drop wise under argon atmosphere. The reaction mixture was allowed to warm to room temperature and heated at 80 C for 24h. The reaction mixture was quenched with 5% HCl (10ml) and the compound was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33g, 73%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In toluene; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 4-Hydroxybenzoic acid methyl ester 79 (0.20g, 1.314mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one 76 (0.33g, 1.577mmol), Ph3P (0.345g, 1.314mmol) and triethyl amine (0.20ml, 1.577mmol) in dry toluene (10ml) at 0 C, DIAD (0.3mL, 0.788mmol) was added drop wise under argon atmosphere. The reaction mixture was allowed to warm to room temperature and heated at 80 C for 24h. The reaction mixture was quenched with 5% HCl (10ml) and the compound was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33g, 73%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In toluene; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 4-Hydroxybenzoic acid methyl ester 79 (0.20g, 1.314mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one 76 (0.33g, 1.577mmol), Ph3P (0.345g, 1.314mmol) and triethyl amine (0.20ml, 1.577mmol) in dry toluene (10ml) at 0 C, DIAD (0.3mL, 0.788mmol) was added drop wise under argon atmosphere. The reaction mixture was allowed to warm to room temperature and heated at 80 C for 24h. The reaction mixture was quenched with 5% HCl (10ml) and the compound was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33g, 73%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In toluene; at 0 - 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 4-Hydroxybenzoic acid methyl ester 79 (0.20g, 1.314mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one 76 (0.33g, 1.577mmol), Ph3P (0.345g, 1.314mmol) and triethyl amine (0.20ml, 1.577mmol) in dry toluene (10ml) at 0 C, DIAD (0.3mL, 0.788mmol) was added drop wise under argon atmosphere. The reaction mixture was allowed to warm to room temperature and heated at 80 C for 24h. The reaction mixture was quenched with 5% HCl (10ml) and the compound was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33g, 73%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; 1,8-diazabicyclo[5.4.0]undec-7-ene; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; | In 100 ml round bottom flask is added in this embodiment 1.1 preparation of compound 3 - hydroxy isoxazole -5 - carboxylic acid methyl ester (286 mg, 2.0 mmol), N - Boc - D - the dried meat ammonia is mellow (240 mg, 1.2 mmol), triphenylphosphine (540 mg, 2.0 mmol) and 20 ml anhydrous THF, condition and stirred under nitrogen protection, in the system added dropwise 0.3 ml DIAD, after the end of the dropping, removed ice temperature to room temperature naturally, the reaction stirring overnight. After the reaction, the solvent turns on lathe does, add 30 ml ethyl acetate to dissolve the, washing the organic phase with water first and then the saturated salt water for washing, anhydrous Na2SO4Drying. Turns on lathe does the solvent, the crude product is rapid column chromatography to obtain the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In dichloromethane; for 1h; | The compound 62a (5.0 g, 34.9 mmol) was dissolved in dichloromethane (50 ml). Diphenyldiazomethane (8.14g, 41.9 mmol) was added to the solution. The mixture was stirred for 1 hour. The reaction mixture was concentratedunder reduced pressure. Then, the residue was subjected to silica gel column chromatography, followed by elution withchloroform/ethyl acetate. Fractions containing the desired compound were concentrated under reduced pressure toafford the compound 62b (5.77 g, 53%).1H-NMR (CDCl3) delta: 7.43-7.28 (10H, m), 6.74 (1H, s), 6.62 (1H, s), 3.92 (3H, s). |
53% | In dichloromethane; for 1h; | The compound 62a (5.0 g, 34.9 mmol) was dlssolved ln dlchloromethane (50 ml). Dlphenyldlazomethane (8.14g, 41.9 mmol) was added to the solutlon. The mlxture was stlrred for 1 hour. The reactlon mlxture was concentratedunder reduced pressure. Then, the resldue was subjected to slllca gel column chromatography, followed by elutlon wlthchloroform/ethyl acetate. Fractlons contalnlng the deslred compound were concentrated under reduced pressure toafford the compound 62b (5.77 g, 53%). |
Tags: 10068-07-2 synthesis path| 10068-07-2 SDS| 10068-07-2 COA| 10068-07-2 purity| 10068-07-2 application| 10068-07-2 NMR| 10068-07-2 COA| 10068-07-2 structure
[ 65685-49-6 ]
5-Methylbenzo[d]isoxazol-3(2H)-one
Similarity: 0.59
[ 1004-96-2 ]
Methyl 3-methylisoxazole-5-carboxylate
Similarity: 0.53
[ 63366-79-0 ]
Ethyl 3-methylisoxazole-5-carboxylate
Similarity: 0.52
[ 105174-97-8 ]
Ethyl 3-bromoisoxazole-5-carboxylate
Similarity: 0.51
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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