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CAS No. : | 5437-67-2 | MDL No. : | MFCD00010228 |
Formula : | C5H7NO6 | Boiling Point : | 282.2°C at 760 mmHg |
Linear Structure Formula : | - | InChI Key : | N/A |
M.W : | 177.11 g/mol | Pubchem ID : | - |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With nitric acid at 5 - 10℃; for 6h; Industrial scale; | 1 Example 1 A 50 L glass reactor was charged with 10.0 kg (75.69 mol) of dimethyl malonate,Turn on stirringUnder the ice water bath control temperature about 10 ,Slowly add fuming nitric acid 9.54kg.After the addition was completed, the reaction was continued at a temperature of 5-10 ° C for 6 hours.Add salt water 20L, release the solution and move to 100L reactor,Ethyl acetate 20L was added, stirred for 10 minutes and allowed to stand for delamination.The ethyl acetate layer was washed twice with 10% sodium carbonate 20 and then with distilled water until the pH was 7,The ethyl acetate layer was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated.A 98-102 ° C fraction (1 mmHg) was collected,10.26 kg of dimethyl 2-nitromalonate was obtained,Moore yield 76.5%. |
With nitric acid Darst.; | ||
With nitric acid |
With nitric acid at 0℃; | ||
With nitric acid | ||
With nitric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
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85% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
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90% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
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88% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In 1,3,5-trimethyl-benzene at 150℃; for 12h; | A Preparation of 5-(2-fluorophenyl)isoxazole-3-carboxylic acid 1-ethynyl-2-fluorobenzene [(1] g, 8. 33 mmol) and dimethyl 2- nitromalonate (1.34 g, 7.58 mmol) were dissolved in mesitylene (10 ml). The solution was heated at [150°C] for about 12 h. Mesitylene was removed in vacuo and the residue was recrystallized from ethanol. 1.22 g (73%) of methyl 5- (2-fluorophenyl) isoxazole- 3-carboxylate was yielded as a light brown solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; Microwave irradiation; regioselective reaction; | ||
In toluene at 170℃; for 2h; Microwave irradiation; | 3.3-B 3-B. Methyl 4-propyl-5-(pyridin-2-yl)isoxazole-3-carboxylate; [00137] A solution of 2-(pent-l-ynyl)pyridine (150 mg, 1.03 mmol), dimethyl nitromalonate (0.35 mL, 2.58 mmol), and l-butyl-3-methylimidazolium hexafluorophosphate (0.021 mL, 0.103 mmol) in toluene (3 mL) was heated to 1700C for 120 minutes under microwave. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-propyl-5-(pyridine-2-yl)isoxazole-3-carboxylate (14.3 mg, 0.052 mmol). The compound had an HPLC retention time = 3.05 min. - Column: YMC S5 COMBISCREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO4; Start % B = O; Final % B = 100. LC-MS: M+1 = 247.1. 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, 3H), 1.66 (sxt, J=7.48 Hz, 2H), 3.15 - 3.20 (m, 2H), 4.01 (s, 3H), 7.33 (ddd, J=7.56, 4.81, 1.10 Hz, IH), 7.83 (td, J=7.77, 1.79 Hz, IH), 7.91 (d, J=7.97 Hz, IH), and 8.72 (d, J=4.12 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.8% | In toluene at 170℃; for 2h; Microwave irradiation; | 4.4-B 4-B. Methyl 4-isopropyl-5-(pyridin-2-yl)isoxazole-3-carboxylate; [00142] A solution of (3 -methylbut- 1 -ynyl)pyridine ( 170 mg, 1.17 mmol), dimethyl nitromalonate (0.395 mL, 2.93 mmol), and l-butyl-3-methylimidazolium hexafluorophosphate (0.024 mL, 0.117 mmol) in toluene (7 mL) was heated to 1700C for 120 minutes under microwave. The reaction mixture was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-isopropyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (11 mg, 0.033 mmol, 2.8% yield). The compound had an HPLC retention time = 2.96 min. - Column:YMC S5 COMBISCREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO4; Start % B = O; Final % B = 100. LC-MS: M+1 = 247.15. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 3H), 1.38 (s, 3H), 4.02 (s, 3H), 4.03 - 4.10 (m, IH), 7.33 - 7.38 (m, IH), 7.80 - 7.90 (m, 2H), and 8.72 - 8.76 (m, IH). |
With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; Microwave irradiation; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.1% | In toluene at 170℃; for 2.5h; Microwave irradiation; | 3.3-A Example 3; l-(4-(5-(4-Butyl-5-phenylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)-azetidine-3- carboxylic acid; 3-A. Methyl 4-butyl-5-phenylisoxazole-3-carboxylate; [00151] A solution of hex-1-ynylbenzene (0.274 mL, 1.56 mmol), dimethyl 2- nitromalonate (0.421 mL, 3.12 mmol), 1 -butyl-3 - methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (6 mL) was subjected to the microwave at 170 0C for 150 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-butyl-5- phenylisoxazole-3-carboxylate (0.142 g, 0.531 mmol, 34.1 % yield) as a clear, colorless oil. The product was 97% pure by HPLC with a ret. time = 3.11 min. - Column: CHROMOLITH SpeedROD 4.6 x 50 mm (4 min.); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; Solvent B = 90% MeOH, 10% H2O, 0.1% TFA.LC/MS M+1 = 260.2. |
34% | With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; for 2.5h; Microwave irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.04% | In 1,3,5-trimethyl-benzene at 150℃; for 18h; | 17.17-A Example 17; Preparation of l-(4-(5-(4,5-diphenylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylic acid, 2,2,2-trifluoroacetic acid salt; 17-A. Methyl 4,5-diphenylisoxazole-3-carboxylate; [00222] A mixture of 1,2-diphenylethyne (1.53 g, 8.6 mmol) and dimethyl 2- nitromalonate (1.05 mL, 7.83 mmol) in mesitylene (11 ml) was heated to 1500C for 18 hr. The volatiles were removed in vacuo and the residue was chromatographed on a 5 x 12 cm silica gel column eluting with 0-10% EtOAc/hexanes. The essentially pure fractions containing product were concentrated to afford methyl 4,5- diphenylisoxazole-3-carboxylate (307 mg, 1.1 mmol, 14.04 % yield) as a light yellow solid. HPLC retention time = 1.85 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2 minute gradient. MS:(M+H)= 280.08. 1H NMR (400 MHz, chloroform-d) δ ppm 3.87 (s, 3 H) 7.29 - 7.40 (m, 5 H) 7.43 (m, 3H) 7.47 - 7.53 (m, 2 H). |
14% | In 1,3,5-trimethyl-benzene at 150℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In 1,3,5-trimethyl-benzene at 150℃; Inert atmosphere; | |
In 1,3,5-trimethyl-benzene at 150℃; for 24h; | 5.5-A Example 5; 1 -(2-Bromo-4-(5 -(4-ethyl-5 -phenylisoxazol-3 -yl)- 1 ,2,4-oxadiazol-3 - yl)benzyl)azetidine-3 -carboxylic acid; 5-A. Methyl 4-ethyl-5-phenylisoxazole-3-carboxylate; [00159] A solution of but-1-ynylbenzene (404 mg, 3.11 mmol) and dimethyl nitromalonate (0.381 mL, 2.82 mmol) in mesitylene (5 mL) was heated to 150 0C for 24 h. The reaction mixture was concentrated, and the residue purified on silica gel column with hexanes/ethyl acetate (10/1) to afford methyl 4-ethyl-5-phenylisoxazole- 3-carboxylate (194 mg). The compound had an HPLC ret. time = 3.25 min. -Column: YMC S5 COMBISCREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO; Start % B = O; Final % B = 100. LC-MS: M+1 = 232+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.2% | In toluene at 170℃; for 8.83333h; Microwave irradiation; | 4.4-A Example 4; l-(4-(5-(4-Isobutyl-5-phenylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)-azetidine-3- carboxylic acid; 4-A. Methyl 4-isobutyl-5-phenylisoxazole-3-carboxylate; [00155] A solution of (4-methylpent-l-ynyl)benzene (0.247 g, 1.56 mmol), dimethyl 2-nitromalonate (0.421 mL, 3.12 mmol), l-butyl-3- methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (5 mL) was subjected to the microwave at 1700C for 150 min. By HPLC, the reaction was-40-50% complete and resubjected to the microwave conditions for 360 min.(1700C). The toluene was decanted off leaving a dark gum which was triturated several times with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-isobutyl-5-phenylisoxazole-3- carboxylate (0.122 g, 0.470 mmol, 30.2 % yield) as a clear, colorless oil. The compound had an HPLC ret. time = 2.96 min. - Column: CHROMOLITHSpeedROD 4.6 x 50 mm (4 min.); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA;Solvent B = 90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1 = 259.9. 1H NMR (500 MHz, chloroform-d) δ ppm 0.88 (s, 3H), 0.89 (s, 3H), 1.89 (dt, J=13.75, 6.87 Hz,IH), 2.80 (d, J=7.15 Hz, 2 H), 4.00 (s, 3H), 7.45 - 7.53 (m, 3H), 7.73 (d, J=6.60 Hz,2H). |
30% | With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; Microwave irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | In 1,3,5-trimethyl-benzene at 150℃; for 48h; Inert atmosphere; | |
In 1,3,5-trimethyl-benzene at 150℃; for 48h; | 7.7-B 7-B. Methyl 4-tert-butyl-5-phenylisoxazole-3-carboxylate; [00170] A solution of (3,3-Dimethylbut-l-ynyl)benzene (400 mg, 2.53 mmol) and dimethyl nitromalonate (0.853 mL, 6.32 mmol) in mesitylene (5 mL) was heated at 150 0C for 48 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-tert- butyl-5-phenylisoxazole-3-carboxylate (101 mg). The compound had an HPLC ret. time = 3.39 min. - Column: YMC S5 COMBIS CREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO4; Start % B = O; Final % B = 100. LC-MS: M+1 = 26O+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl 2-nitromalonate; 2-methyl-4-octyne In toluene at 170℃; for 1h; Microwave irradiation; Stage #2: With lithium hydroxide monohydrate; water In methanol at 20℃; Stage #3: (Z)-tert-butyl 1-(4-(N-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate | 18.18-B; 18.18C; 18.18-D 18-B. Methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5- propylisoxazole-3-carboxylate; [00227] A mixture of 6-methylhept-3-yne (220 mg, 2 mmol), dimethyl 2- nitromalonate (567 mg, 3.20 mmol) and l-butyl-3-methylimidazolium hexafluorophosphate (0.04 ml, 0.2 mmol) in toluene (4 mL) was heated to 170°C in the microwave for 1 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to afford an orange oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-5%EtO Ac/Hex gradient. The fractions which contained product were concentrated to afford 228 mg, 54. % yield of a mixture of methyl 4-ethyl-5-isobutylisoxazole-3-carboxylate and methyl 5-ethyl-4- isobutylisoxazole-3-carboxylate as light yellow oil. HPLC retention time = 1.86 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 226.22. 1H NMR indicates a ~1 : 1 mixture of regioisomers. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step.; 18.C 5-Isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5- propylisoxazole-3 -carboxylic acid; [00228] To a mixture of methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5-propylisoxazole-3-carboxylate (164 mg, 0.728 mmol) in MeOH- I l l - (8 mL) and water (2 mL) was added LiOH, hydrate (15.28 mg, 0.364 mmol) and the mixture was allowed to stir overnight at rt. An additional amount of LiOH, hydrate (15.28 mg, 0.364 mmol) was added and the reaction mixture was stirred at rt for 2 hr. The MeOH was removed in vacuo and the remaining aqueous was acidified to pH ~1 with IN HCl. The mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford (144 mg, 0.682 mmol, 94 % yield) of product which was approximately a 1 : 1 mixture of 5- isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5-propylisoxazole-3- carboxylic acid as a light yellow oil. HPLC retention time = 1.72 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS :(M+H)= 212.20.[00229] 1H NMR indicates a ~1 : 1 mixture of regioisomers as shown in the schematic above. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step.; 18-D. tert-Butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate and tert-BvXyl l-(4-(5-(4-isobutyl-5- propylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate; [00230] A mixture of 5-isobutyl-4-propylisoxazole-3-carboxylic acid, and 4- isobutyl-S-propylisoxazole-S-carboxylic acid (42.26 mg, 0.2 mmol), (Z)-tert-butyl 1- (4-(N'-hydroxycarbamimidoyl) benzyl)azetidine-3-carboxylate (61.1 mg, 0.200 mmol), HOBt (38.3 mg, 0.250 mmol), diisopropylethylamine (0.070 mL, 0.400 mmol) and EDC (47.9 mg, 0.250 mmol) in DMF (1 mL) was stirred at rt for 18 hr. DMF (1 mL) was added and the reaction mixture was warmed to 500C for 8 hr. The reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2 x 30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-100%EtO Ac/Hex gradient. The pure fractions were concentrated to afford a mixture of tert-butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3- yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6 % yield) and tert-butyl l-(4-(5-(4-isobutyl-5-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6 % yield) as a colorless oil. HPLC retention time = 1.89 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 481.32. [00231] The mixture was separated on a Berger Prep SFC MGIII Unit on a Chiral AD-H 30 X 3 cm ID, 5μm column, eluting with 70/30 C(V(MeOH, 0.1 % diethylamine) and a flow rate of 88 mL/min, monitored at 220 nm. The fractions from the first peak to elute were concentrated to afford tert-butyl l-(4-(5-(4-isobutyl- 5-propylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (21 mg; 44%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.93 (d, J= 7.3 Hz, 6 H) 1.00 (t, J= 7.4 Hz, 3 H) 1.44 (s, 9 H) 1.79 (m, 2 H) 1.92 (m, 1 H) 2.62 (d, J= 6.7 Hz, 2 H) 2.77 (t, J= 7.4 Hz, 2 H) 3.27 (m, 3 H) 3.53 (m, 2 H) 3.66 (s, 2 H) 7.42 (d, J= 8.1 Hz, 2 H) 8.10 (d, J= 8.1 Hz, 2 H). [00232] The fractions from the second peak to elute were concentrated to afford tert-butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate (24 mg; 50%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.95-1.01 (m, 9 H) 1.44 (s, 9 H) 1.57-1.65 (m, 2 H) 2.10-2.19 (m, 1 H) 2.67 (d, J=7.4 Hz, 2 H) 2.69-2.73 (m, 2 H) 3.22-3.30 (m, 3 H) 3.50-3.56 (m, 2 H) 3.67 (s, 2 H) 7.42 (d, J=8.1 Hz, 2 H) 8.10 (d, J=8.1 Hz, 2 H). | |
24 mg | Stage #1: dimethyl 2-nitromalonate; 2-methyl-4-octyne With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; for 1h; Microwave irradiation; Inert atmosphere; Stage #2: With lithium hydroxide monohydrate; water In methanol at 20℃; Stage #3: (Z)-tert-butyl 1-(4-(N-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 50℃; for 26h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene at 170℃; for 2.5h; | 8.8-B 8-B. Methyl 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylate; [00175] A solution of (5,5,5-trifluoropent-l-ynyl)benzene (215 mg, 1.09 mmol), diethyl nitromalonate (0.758 mL, 4.34 mmol), and l-butyl-3-methylimidazolium hexafluorophosphate (0.023 mL, 0.108 mmol) in toluene (3 mL) was heated to 170 0C for 150 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (9/1) provided methyl 5-phenyl-4-(3,3,3- trifluoropropyl)isoxazole-3-carboxylate (72 mg). The compound had an HPLC ret. time = 3.61 min. - Column: YMC S5 COMBISCREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO4; Start % B = O; Final % B = 100. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene at 170℃; for 1h; Microwave irradiation; | 18.18-B 18-B. Methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5- propylisoxazole-3-carboxylate; [00227] A mixture of 6-methylhept-3-yne (220 mg, 2 mmol), dimethyl 2- nitromalonate (567 mg, 3.20 mmol) and l-butyl-3-methylimidazolium hexafluorophosphate (0.04 ml, 0.2 mmol) in toluene (4 mL) was heated to 170°C in the microwave for 1 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to afford an orange oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-5%EtO Ac/Hex gradient. The fractions which contained product were concentrated to afford 228 mg, 54. % yield of a mixture of methyl 4-ethyl-5-isobutylisoxazole-3-carboxylate and methyl 5-ethyl-4- isobutylisoxazole-3-carboxylate as light yellow oil. HPLC retention time = 1.86 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 226.22. 1H NMR indicates a ~1 : 1 mixture of regioisomers. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step. | |
With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; for 1h; Microwave irradiation; Inert atmosphere; Overall yield = 36 %; Overall yield = 164 mg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl 2-nitromalonate; 2-methyl-4-octyne In toluene at 170℃; for 1h; Microwave irradiation; Stage #2: With lithium hydroxide monohydrate; water In methanol at 20℃; Stage #3: With hydrogenchloride In water | 18.18-B; 18.18C 18-B. Methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5- propylisoxazole-3-carboxylate; [00227] A mixture of 6-methylhept-3-yne (220 mg, 2 mmol), dimethyl 2- nitromalonate (567 mg, 3.20 mmol) and l-butyl-3-methylimidazolium hexafluorophosphate (0.04 ml, 0.2 mmol) in toluene (4 mL) was heated to 170°C in the microwave for 1 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to afford an orange oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-5%EtO Ac/Hex gradient. The fractions which contained product were concentrated to afford 228 mg, 54. % yield of a mixture of methyl 4-ethyl-5-isobutylisoxazole-3-carboxylate and methyl 5-ethyl-4- isobutylisoxazole-3-carboxylate as light yellow oil. HPLC retention time = 1.86 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 226.22. 1H NMR indicates a ~1 : 1 mixture of regioisomers. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step.; 18.C 5-Isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5- propylisoxazole-3 -carboxylic acid; [00228] To a mixture of methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5-propylisoxazole-3-carboxylate (164 mg, 0.728 mmol) in MeOH- I l l - (8 mL) and water (2 mL) was added LiOH, hydrate (15.28 mg, 0.364 mmol) and the mixture was allowed to stir overnight at rt. An additional amount of LiOH, hydrate (15.28 mg, 0.364 mmol) was added and the reaction mixture was stirred at rt for 2 hr. The MeOH was removed in vacuo and the remaining aqueous was acidified to pH ~1 with IN HCl. The mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford (144 mg, 0.682 mmol, 94 % yield) of product which was approximately a 1 : 1 mixture of 5- isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5-propylisoxazole-3- carboxylic acid as a light yellow oil. HPLC retention time = 1.72 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS :(M+H)= 212.20.[00229] 1H NMR indicates a ~1 : 1 mixture of regioisomers as shown in the schematic above. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step. | |
Stage #1: dimethyl 2-nitromalonate; 2-methyl-4-octyne With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 170℃; for 1h; Microwave irradiation; Inert atmosphere; Stage #2: With lithium hydroxide monohydrate; water In methanol at 20℃; Overall yield = 144 mg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In 1,3,5-trimethyl-benzene at 150℃; for 16h; Inert atmosphere; | |
In 1,3,5-trimethyl-benzene at 150℃; for 16h; | 6.6-B 6-B. Methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate; [00165] A solution of (cyclopropylethynyl)benzene (300 mg, 2.110 mmol) and dimethyl nitromalonate (0.854 mL, 6.33 mmol) in mesitylene (4 mL) was heated to 1500C for 16 h. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate. The compound was re- purified by preparative HPLC [Column: PHENOMENEX SlO 30X100 mm; Gradient time: 10 min; Flow rate = 40 ml/min; Solvent A = 10% MeOH - 90% Water - 0.1% TFA; Solvent B = 90% MeOH - 10% water - 0.1% TFA; Start % B = 20; Final % B = 100] to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate (170 mg). The compound had an HPLC ret. time = 2.77 min. - Column: YMC S5 COMBISCREEN 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH - 90% Water - 0.2% H3PO4; Solvent B = 90% MeOH - 10% water - 0.2% H3PO4; Start % B = O; Final % B = 100. LC-MS: M+1 = 244+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.2% | In water | |
34.2% | In water for 3h; | 1 Synthesis of the zinc complex with nitrodimethyl malonate 10 g (56.8 mmol) of 2-nitro-1,3-dimethyl malonate are initially introduced in 200 ml of dist. water. After addition of 10 g (91.1 mmol of Zn) of hydrozincite, a yellow suspension forms, which is stirred for a further 3 hours. The excess of hydrozincite is then filtered off, and the solution is evaporated to dryness in a rotary evaporator at 65° C. and 130 mbar. The yellow oil remaining is taken up in 50 ml of dichloromethane and filtered. The product is precipitated by dropwise addition of the solution to 200 ml of methyl tert-butyl ether, filtered off and dried in a high vacuum at room temperature, giving a pale-yellowish powder (6.4 g, 34.2%). (0069) Ceramic yield (CY)/elemental analysis (CHN): found CY 39.87%, C, 19.86%, N, 4.50%, H, 2.78%. Calculated for Zn3(OH)4(C5H6NO6)2 CY 39.63%, C, 19.49%, N, 4.54%, H, 2.62%. 1H-NMR (DMSO-d6): 3.57 (-CH3), 3.40 (OH). 13C-NMR/13C-DEPT-NMR (DMSO-d6): 50.91 (-CH3); 109.07 (-C-NO2); 163.72 (-COO). IR: 3460 cm-1, v br (νO-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | With sodium methylate; thiourea In methanol for 10h; Reflux; Industrial scale; | 2 Example 2 100L reactor was added methanol 30L and thiourea 6.45kg (84.69mol),Open the stirring to dissolve,10.0 kg (56.46 mol) of dimethyl 2-nitromalonate was added,Warmed to reflux,Slowly add 30% methanol solution of sodium methylate 15kg,After the completion of the dropwise addition reaction 10 hours,TLC showed the reaction was complete, stop stirring,Cool to 50 ° C after the reaction solution was released,Continue to cool to room temperature, white solid precipitation, 6N hydrochloric acid was added to adjust the pH to 7, centrifuged to give a white solid rejection filter, washed several times,Obtained after vacuum drying5-Nitro-2-thiobarbituric acid9.22kg,Moore yield 86.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.3% | In propan-1-ol; toluene for 0.5h; Inert atmosphere; | 7 Synthesis of the zirconium complex with nitrodimethyl malonate Under protective gas, 1.0 g (3.1 mmol) of zirconium 1-propanolate (70% by weight in 1-propanol) is dissolved in 2 ml of toluene. A solution of 2.0 g (12.4 mmol) of 2-nitrodimethyl malonate in 4 ml of toluene is added. The reaction mixture is stirred for a further 30 minutes. The solvent is condensed off to dryness in vacuo, and the oil remaining is taken up in 3 ml of methyl tert-butyl ether/chloroform (v:v; 1:1). The product is precipitated by dropwise addition to 60 ml of pentane, filtered off and dried in a high vacuum, giving a yellowish-white powder (yield: 1.21 g, 56.3%), which is stable under ambient conditions. (0081) Ceramic yield (CY)/elemental analysis (CHN): found CY 27.17%, C, 27.52%, N, 5.83%, H, 2.84%. Calculated for Zr6O4(OH)4(C5H8NO6)12 CY 26.47%, C, 25.81%, N, 6.02%, H, 2.74%. 1H-NMR (DMSO-d6): 3.80 (-CH3), 3.67 (OH). 13C-NMR/13C-DEPT-NMR (DMSO-d6): 48.54 (-CH3); 108.43 (-C-NO2); 163.10 (-COO). IR: 3436 cm-1, v br (νO-H). |
Tags: 5437-67-2 synthesis path| 5437-67-2 SDS| 5437-67-2 COA| 5437-67-2 purity| 5437-67-2 application| 5437-67-2 NMR| 5437-67-2 COA| 5437-67-2 structure
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