ETHYL 2-CHLOROOXAZOLE-4-CARBOXYLATE

Under a nitrogen atmosphere, 1. 70 ML (14.3 mmol) of tert-butyl nitrite was added to a suspension OF 1. 65 g (12.3 mmol) OF COPPER (II) CHLORIDE in 50 ML of acetonitrile. The resulting suspension was heated to 75 °C, then 1.60 g (10.2 mmol) of ethyl 2-aminooxazole-4- carboxylate (G Crank MJ Foulis, J Med Chem 1971, 14 : 1075-1077) was added in portions over 20 min (gas evolution). After stirring for an additional 30 min, the reaction was allowed to cool to ambient temperature, diluted with 50 ML of EtOAc, and extracted with water (2 x 25 ml). The organic layer was dried over MgS04 and concentrated in vacuo to a dark oily solid. Flash chromatography through neutral silica gel using a 3: 1 mixture of hexane and EtOAc gave 1.27 g (71 percent) OF THE TITLE compound, which crystallized from hexane as white needles. m/z (ES+): 176/177. 1H NMR (CDCL3) No.: 1. 47 (t, 3H, J = 7.16) ; 4.48 (q, 2H, J = 7.16) ; 6.92 8.28 (s, 1H).A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CHTo a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1, 3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60°C. The reaction mixture was heated at 80°C for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract 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 (ethyl acetate/hexane) to give the title compound (1.90 g). The solid (3.16 g, 20.2 mmol) was added portionwise to a 60 0C solution of Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL, 25.3 mmol) in acetonitrile (100 mL) while maintaining the reaction temperature between 60 and 65 0C. After complete addition, the reaction mixture was heated to 80 C for 1 h. Upon cooling to rt, the reaction mixture was poured into a mixture Of CH2Cl2 (150 mL), water (150 mL), and HCl (cone, 10 mL). The organics were separated and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was dissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3 mmol) was added. After stirring overnight at rt, the ethanol was removed under reduced pressure and the reaction mixture was diluted with water (100 mL). The mixture was washed with Et2O (50 mL, discarded) and brought to pH ~2 with cone. HCl. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 2.12 g (31%) of the title compound as a yellow solid. LC-MS: RT = 3.51 min, [M+H]+ = 147.9.Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid A mixture of phenylboronic acid (729 mg, 5.98 mmol), Under a nitrogen atmosphere, 1. 70 ML (14.3 mmol) of tert-butyl nitrite was added to a suspension OF 1. 65 g (12.3 mmol) OF COPPER (II) CHLORIDE in 50 ML of acetonitrile. The resulting suspension was heated to 75 C, then 1.60 g (10.2 mmol) of ethyl 2-aminooxazole-4- carboxylate (G Crank & MJ Foulis, J Med Chem 1971, 14 : 1075-1077) was added in portions over 20 min (gas evolution). After stirring for an additional 30 min, the reaction was allowed to cool to ambient temperature, diluted with 50 ML of EtOAc, and extracted with water (2 x 25 ml). The organic layer was dried over MgS04 and concentrated in vacuo to a dark oily solid. Flash chromatography through neutral silica gel using a 3: 1 mixture of hexane and EtOAc gave 1.27 g (71 %) OF THE TITLE compound, which crystallized from hexane as white needles. m/z (ES+): 176/177. 1H NMR (CDCL3) No.: 1. 47 (t, 3H, J = 7.16) ; 4.48 (q, 2H, J = 7.16) ; 6.92 & 8.28 (s, 1H).A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CH3CN was treated with ethyl 2-amino-1, 3-oxazole-4-carboxylate (1.0 g, 6.4 mmol) stirred 2 hours at room temperature, heated to 80 C. for 30 minutes and concentrated under reduced pressure. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer washed with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 56% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 175 (MH+).The solid (3.16 g, 20.2 mmol) was added portionwise to a 60 0C solution of Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL, 25.3 mmol) in acetonitrile (100 mL) while maintaining the reaction temperature between 60 and 65 0C. After complete addition, the reaction mixture was heated to 80 C for 1 h. Upon cooling to rt, the reaction mixture was poured into a mixture Of CH2Cl2 (150 mL), water (150 mL), and HCl (cone, 10 mL). The organics were separated and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was dissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3 mmol) was added. After stirring overnight at rt, the ethanol was removed under reduced pressure and the reaction mixture was diluted with water (100 mL). The mixture was washed with Et2O (50 mL, discarded) and brought to pH ~2 with cone. HCl. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 2.12 g (31%) of the title compound as a yellow solid. LC-MS: RT = 3.51 min, [M+H]+ = 147.9.Intermediate 39 (3g, 19.2mmol) was added portionwise to a mixture of tert-butyl nitrite (93.4ml, 28.8mmol) and copper (II) chloride (3.87g, 28.8mmol) in acetonitrile (100 ml) warmed at 6O0C. After complete addition the mixture was heated at 750C for 2 hours. The mixture was 30 cooled and poured into IN HCl (300ml), and extracted with CH2Cl2 (3 x 120ml). The combined CH2Cl2 extracts were dried over Na2SO4, filtered and evaporated to give of the title compound. 1HNMR (500 MHz, CDCl3) delta: 8.20 (s, IH), 4.39 (q, J = 7.3, 2H), 1.39 (t, J = 7.3, 3H).Step 2: Preparation of a) Ethyl 2rchlorooxazole-4-carboxylateEthyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite (23 ml, 192 mmol) in ACN (500 ml) at 80 C and the resulting mixture was refluxed for 4 h. The reaction mixture was concentrated and treated with concentrated HC1 and extracted with EtOAc. The product was purified with flash chromatography. Yield 10.5 g. 1H- NMR (400MHz; CDC13): delta 1.36 (t, 3H), 4.39 (q, 2H), 8.47 (s, 1H).To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1, 3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60C. The reaction mixture was heated at 80C for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract 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 (ethyl acetate/hexane) to give the title compound (1.90 g). 1H NMR (400 MHz, CDCl3) delta 1.39 (3H, t, J = 7.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 8.19 (1H, s).Compound 7A was added in portions to a stirred solution of tert-butyl nitrite (6.92 g, 67.12 mmol) and copper (II) chloride (9.02 g, 67.12 mmol) in MeCN(200 mL) at 60C. The mixture was heated at 80C and allowed to stir at this temperature for 2 hours, then the reaction mixture was cooled and patitioned between dichloromethane (250 mL), water (130 mL), and concentrated hydrochloric acid (13 mL). The aqueous layer was further extracted with dichlormethane, and the combined organics were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate 100: 1'50: 1) to provide compound 7B as a solid. MS (ESI) m/z (M+H)+: 176.Preparation of Lambda/-{(1 S)-2-amino-1-r(3-fluorophenyl)methyllethyl}-2-(1-methyl-1 H-pyrazol-5- yl)-1 , 3-oxazole-4-carboxamidea) ethyl 2-chloro-1 , 3-oxazole-4-carboxylate To a solution of ethyl 2-amino-1 , 3-oxazole-4-carboxylate (5.0 g, 32.0 mmol) in acetonitrile (100 ml.) and copper (II) chloride (6.46 g, 48.0 mmol) was added f-butyl nitrite (6.39 ml_, 48.0 mmol) slowly. After stirring at 65 0C 1 h, the solution was concentrated and purified using a silica gel column eluting with chloroform to afford a light- yellow solid as the desired product: LC-MS (ES) m/z 176 (M+H)+.Under a nitrogen atmosphere, 1. 70 ML (14.3 mmol) of tert-butyl nitrite was added to a suspension OF 1. 65 g (12.3 mmol) OF COPPER (II) CHLORIDE in 50 ML of acetonitrile. The resulting suspension was heated to 75 C, then 1.60 g (10.2 mmol) of ethyl 2-aminooxazole-4- carboxylate (G Crank & MJ Foulis, J Med Chem 1971, 14 : 1075-1077) was added in portions over 20 min (gas evolution). After stirring for an additional 30 min, the reaction was allowed to cool to ambient temperature, diluted with 50 ML of EtOAc, and extracted with water (2 x 25 ml). The organic layer was dried over MgS04 and concentrated in vacuo to a dark oily solid. Flash chromatography through neutral silica gel using a 3: 1 mixture of hexane and EtOAc gave 1.27 g (71 %) OF THE TITLE compound, which crystallized from hexane as white needles. m/z (ES+): 176/177. 1H NMR (CDCL3) No.: 1. 47 (t, 3H, J = 7.16) ; 4.48 (q, 2H, J = 7.16) ; 6.92 & 8.28 (s, 1H).A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CH3CN was treated with ethyl 2-amino-1, 3-oxazole-4-carboxylate (1.0 g, 6.4 mmol) stirred 2 hours at room temperature, heated to 80 C. for 30 minutes and concentrated under reduced pressure. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer washed with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 56% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 175 (MH+).The solid (3.16 g, 20.2 mmol) was added portionwise to a 60 0C solution of Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL, 25.3 mmol) in acetonitrile (100 mL) while maintaining the reaction temperature between 60 and 65 0C. After complete addition, the reaction mixture was heated to 80 C for 1 h. Upon cooling to rt, the reaction mixture was poured into a mixture Of CH2Cl2 (150 mL), water (150 mL), and HCl (cone, 10 mL). The organics were separated and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was dissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3 mmol) was added. After stirring overnight at rt, the ethanol was removed under reduced pressure and the reaction mixture was diluted with water (100 mL). The mixture was washed with Et2O (50 mL, discarded) and brought to pH ~2 with cone. HCl. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 2.12 g (31%) of the title compound as a yellow solid. LC-MS: RT = 3.51 min, [M+H]+ = 147.9.Intermediate 39 (3g, 19.2mmol) was added portionwise to a mixture of tert-butyl nitrite (93.4ml, 28.8mmol) and copper (II) chloride (3.87g, 28.8mmol) in acetonitrile (100 ml) warmed at 6O0C. After complete addition the mixture was heated at 750C for 2 hours. The mixture was 30 cooled and poured into IN HCl (300ml), and extracted with CH2Cl2 (3 x 120ml). The combined CH2Cl2 extracts were dried over Na2SO4, filtered and evaporated to give of the title compound. 1HNMR (500 MHz, CDCl3) delta: 8.20 (s, IH), 4.39 (q, J = 7.3, 2H), 1.39 (t, J = 7.3, 3H).Step 2: Preparation of a) Ethyl 2rchlorooxazole-4-carboxylateEthyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite (23 ml, 192 mmol) in ACN (500 ml) at 80 C and the resulting mixture was refluxed for 4 h. The reaction mixture was concentrated and treated with concentrated HC1 and extracted with EtOAc. The product was purified with flash chromatography. Yield 10.5 g. 1H- NMR (400MHz; CDC13): delta 1.36 (t, 3H), 4.39 (q, 2H), 8.47 (s, 1H).To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1, 3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60C. The reaction mixture was heated at 80C for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract 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 (ethyl acetate/hexane) to give the title compound (1.90 g). 1H NMR (400 MHz, CDCl3) delta 1.39 (3H, t, J = 7.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 8.19 (1H, s).Compound 7A was added in portions to a stirred solution of tert-butyl nitrite (6.92 g, 67.12 mmol) and copper (II) chloride (9.02 g, 67.12 mmol) in MeCN(200 mL) at 60C. The mixture was heated at 80C and allowed to stir at this temperature for 2 hours, then the reaction mixture was cooled and patitioned between dichloromethane (250 mL), water (130 mL), and concentrated hydrochloric acid (13 mL). The aqueous layer was further extracted with dichlormethane, and the combined organics were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate 100: 1'50: 1) to provide compound 7B as a solid. MS (ESI) m/z (M+H)+: 176.Preparation of Lambda/-{(1 S)-2-amino-1-r(3-fluorophenyl)methyllethyl}-2-(1-methyl-1 H-pyrazol-5- yl)-1 , 3-oxazole-4-carboxamidea) ethyl 2-chloro-1 , 3-oxazole-4-carboxylate To a solution of ethyl 2-amino-1 , 3-oxazole-4-carboxylate (5.0 g, 32.0 mmol) in acetonitrile (100 ml.) and copper (II) chloride (6.46 g, 48.0 mmol) was added f-butyl nitrite (6.39 ml_, 48.0 mmol) slowly. After stirring at 65 0C 1 h, the solution was concentrated and purified using a silica gel column eluting with chloroform to afford a light- yellow solid as the desired product: LC-MS (ES) m/z 176 (M+H)+.Step 1: ethyl 2-(6-(tert-butoxycarbonyl)-2, 6-diazaspiro[3.3]heptan-2-yl)oxazole-4-carboxylate (35b) To a solution of

Molecular Weight:175.57
XLogP3:1.9
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:175.0036207
Monoisotopic Mass:175.0036207
Topological Polar Surface Area:52.3
Heavy Atom Count:11
Complexity:153
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes