Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate

INTERMEDIATE 4 - PREPARATION OF Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate.; To a mixture of propargyl alcohol (1.0 mlReference Production Example 42 (0684) Ethyl nitroacetate (198 mL, 1.78 mmol), propargyl alcohol (100 g, 1.78 mmol) and 1, 4-diazabicyclo[2.2.2]octane (20.0 g, 178.3 mmol) were added to ethanol (1 L), and the mixture was heated at 80°C for 16 hours. Thereafter, the mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 180 g of ethyl 5-hydroxymethylisoxazole-3-carboxylate represented by the following formula. A solution of ethyl chlorooximidoacetate (15 g, 0.1 mol) in CH2Cl2 is added dropwise over 4 h to propargyl alcohol (29 mL, 0.5 mol) and Et3N (14 mL, 0.1 mmol) in 200 mL CH2Cl2. When the addition is complete, the reaction mixture is concentrated and triturated with Et2O. The solid is filtered and the organics are concentrated again. The remaining oil is chromatographed over silica gel (EtOAc/Hex:20/80) to give ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate an oil. The remaining propargyl alcohol is removed by azeotroping from n-heptane to yield 11.7 g (69percent yield). 1H NMR (400 MHz, CDCl3) δ 6.69, 4.84, 4.44, 1.42. To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (4.0 g, 23 mmol) and TBSCl (3.7 g, 25 mmol) in DMF is added Et3N (3.4 mL, 24 mmol) dropwise over 20 minutes. The reaction is allowed to stir for 30 minutes after which it is diluted with EtOAc (300 mL), washed with 1 M HCl (3.x.100 mL), 5percent CuSO4 (2.x.50 mL) and concentrated in vacuo to yield 6.91 g (>100percent yield) of oily material with visible TBS impurities by NMR. 1H NMR (400 MHz, CDCl3) δ 6.49, 4.69, 4.31, 1.30, 0.80, 0.02. A mixture of ethyl-5-({[tert-butyl(dimethylsilyl)]oxy}methyl)isoxazole-3-carboxylate (1.68 g, 5.9 mmol) and hydrazine hydrate (044 g, 8.8 mmol) in ethanol (30 mL) is heated to 60° C. for 4 h. The mixture is cooled to RT and the solvents are removed in vacuo to yield 1.40 g (87percent yield) of orange crystals. 1H NMR (400 MHz, DMSO-d6) δ 9.95, 6.61, 4.74, 4.51, 0.79. A mixture of 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)isoxazole-3-carbohydrazide (1.32 g, 4.9 mmol) in concentrated hydrochloric acid (40 mL) is cooled to 0° C., followed by a dropwise addition of aqueous NaNO2 (0.42 g, 6.1 mL), maintaining the temperature below 5° C. After 1 h, the yellow mixture is diluted with water (100 mL) and extracted with EtOAc (3.x.50 mL). Organics are dried (MgSO4) and concentrated in vacuo to yield 0.93 g (>100percent yield) of 5-(hydroxymethyl)isoxazole-3-carbonylazide as tan crystals. 1H NMR (400 MHz, DMSO-d6) δ 6.82, 4.64. Example 611 is obtained according to Method F. Yield 20percent. MS (ESI) for C13H14BrN3O5 m/z 372 (M-H)-.Propargyl alcohol (11 .42 mL; 191 .36 mmol) was added to a mixture of ethyl 2-chloro-2-(hydroxyimino)acetate (14.50 g; 95.68 mmol) and sodium hydrogen carbonate (16.08 g;191.36 mmol) in ethyl acetate (400 mL) and water (40 mL) and stirred at roomtemperature for 24 hours. The two phases were separated and the organic layer was concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 10 percent ethyl acetate in dichloromethane) to yield 8.67 g (53 percent) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil.(a) B. Synthesis of ethyl 5-(hydroxymethyl)isoxazole-3-carboxy1ate (C88). A solution of compound C87 (19.00 g, 126.0 mmol) in dichloromethane (200 mL) at O°C was treated drop- wise with prop-2-yn-1-ol (7.06 g, 126.0 mmol), followed by the drop-wise addition of triethylamine (12.73 g, 126.0 mmol), The resultant mixtuie was stirred at 25°C foi about 18 hours. The mixture was then washed with water (50 mL), dried over sodium sulfate and concentrated, The resultant residue was purified by silica gel chromatography (isocratic; βluting with 1 1 ethyl acetate hexanes) to provide C88 as a light orange oil. Yield: 8.98 g, 42percent Ethyl chlorooximidoacetate (10 g, 66 mmol) in CHCl3 (80 mL) is slowly added to propargyl alcohol (4.7 mL, 81 mmol) and K2CO3 (27 g, 198 mmol) in CHCl3 (80 mL). The addition is accompanied by an exothermic reaction which causes the chloroform to reflux. After being allowed to cool to RT, the mixture is stirred overnight. The reaction mixture is filtered and the residue is rinsed with chloroform and concentrated in vacuo. The crude product is purified by chromatohraphy (Biotage 40M, EtOAc/Hex:20/80) to yield 3.23 g (29percent yield) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil. 1H NMR (400 MHz, CDCl3) δ 6.69, 4.86, 4.45, 4.42. A solution of diethylaminosulfur trifluoride (DAST) (2.8 mL, 21 mmol) in 30 mL CH2Cl2 is added dropwise to a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (3.0 g, 18 mmol) in 30 mL CH2Cl2 at -78° C. The mixture is stirred at -78° C. for 1 h and then warmed to RT over 3 h. Water (10 mL) and 30 mL of 2.5percent aqueous sodium bicarbonate solution are added successively and the organic layer is separated, dried (MgSO4) and evaporated in vacuo. The residue is purified by chromatography (Biotage 40M, EtOAc/Hex:20/80) to give 1.83 g (60percent yield) of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate as an oil. 1H NMR (400 MHz, CDCl3) δ 6.82, 5.54, 5.42, 4.47, 1.43. 10percent Aqueous sodium hydroxide solution (5 mL) is added to a solution of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate (1.82 g, 10 mmol) in ethanol (30 mL) at RT. The mixture is stirred for 2 h and the solvents are evaporated in vacuo. The residue is dissolved in water and acidified to pH 1 with 35percent HCl. Ethanol is added, solvents are evaporated in vacuo and the residue is azeotroped with ethanol. Ethanol is added and the mixture filtered to remove inorganic solids. Evaporation in vacuo of the filtrate gives 0.95 g (63percent yield) of 5-(fluoromethyl)isoxazole-3-carboxylic acid as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 7.05, 5.67, 5.56. Oxalyl chloride (0.85 mL, 9.8 mmol) is added dropwise to a suspension of 5-(fluoromethyl)isoxazole-3-carboxylic acid (0.94 g, 6.5 mmol) and a catalytic amount of DMF in 20 mL CH2Cl2. After 1 h, the volatiles are removed in vacuo and the remaining residue is dissolved in acetone. To this solution is added an aqueous solution of sodium azide (0.59 g, 9.1 mmol) at 0° C. with vigorous stirring. Volatiles are removed in vacuo and the residue washed with water and dried under nitrogen to yield 0.57 g (51percent yield) of 5-(fluoromethyl)isoxazole-3-carbonyl azide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.21, 5.71, 5.59. Example 605 is prepared according to Method F, making non-critical modifications. Yield 37percent. HRMS (ESI) calcd for Cl3H13ClFN3O4+H 330.0657 found 330.0649In a 100 mL round-bottomed flask (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (164.96 mmol) and propargyl alcohol (824.82 mmol) were taken in tetrahydrofuran (200 mL) to give a yellow solution. Reaction mass was cooled to 0 °C and triethyl amine (197.96 mmol) in tetrahydrofuran (100 mL) was added slowly over 45 min. Reaction mass was then allowed to cool to 25 °C and stirred overnight. The reaction mass was diluted with brine (250 mL) and extracted with dichloromethane (3x 300 mL). Dichloromethane layers were collected and dried over sodium sulphate and concentrated to give crude mass which on purification over combiflash gave ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (81 percent) as pure liquid. 1H MR (300 MHz, DMSO-i) δ ppm 3.82 (t, J=7.06 Hz, 3 H) 6.74 - 6.98 (m, 2 H) 7.08 - 7.18 (m, 2 H) 8.25 - 8.39 (m, 1 H) 9.25 (s, 1 H) MS (ESa

Molecular Weight:171.15
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:171.05315777
Monoisotopic Mass:171.05315777
Topological Polar Surface Area:72.6
Heavy Atom Count:12
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes