4-METHYL-1,3-OXAZOLE-5-CARBOXYLICACID

White to tan solid

Preparation 14: 3- [ (3-Chloropropyl) thio]-4-methyl-5- (4-methyl-1, 3-oxazol-5-yl)-4H- 1, 2, 4-triazole; Ethyl-2-chloroacetoacetate (1 wt; 1 eq. , 1000 g) was aged with formamide (0.68 vol ; ca. 2.8 eq. ) and the resulting solution was heated to 120 °C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 °C over night under reduced pressure to give 4-methyl-1, 3-oxazole-5-carboxylic acid (498 g, 64.5percent).Preparation 5: 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1 , 3-oxazol-5-yl)-4H- 1, 2, 4-triazole (P5)Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120 Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120 Preparation 11: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H- 1, 2, 4-triazole Ethyl-2-chloroacetoacetate (1 wt; 1 eq. , 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq. ) and the resulting solution was heated to 120 °C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 °C over night under reduced pressure to give 4-methyl-1, 3-oxazole-5-carboxylic acid (498 g, 64.5percent). This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0 °C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25No.2 °C and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25No.2°C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 °C for 30 min. After this time, the mixture was cooled to 25No.2 °C and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 °C and acidified to ca. pH 5 with HCI (aqueous, 16percent; NOTE: keep temperature while adding HCI below +10 °C). The suspended product was isolated by filtration washing with water (2x3 vol). The cake was dried at 40 °C for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-2, 4-dihydro-3H-1, 2, 4-triazole-3- thione (respectively a tautomeric form thereof; 290 g, 37percent). NaOEt (21percent solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl- 5-(4-methyl-1, 3-oxazol-5-yl)-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25No.2°C until a clear solution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40 'C for 24 h then cooled to 25 'C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature -40 'C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66percent). NMR ('H, CDC13): No. 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H). MS (m/z): 273 [MH]+.Preparation 7: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1 , 3-oxazol-5-yl)-4H- 1 , 2, 4-triazole; EPO A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 ml, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120 °C. After 6 hrs the mixture was allowed to cool to RT and stirred under nitrogen O/N. The mixture was treated with 3M NaOH (120 mL, reaction moderately exothermic) and stirred at RT for 4 hours. EtOAc (120 mL) was added and the phases allowed separating. The organic layer was discarded while the aqueous was acidified with 37percent aqueous HCI to pH 2 (~ 40 mL). A precipitate started to form. The suspension was treated with EtOAc (160 mL) and, vigorously shaken until the precipitate had dissolved. Phases were separated and the aqueous one was further extracted with EtOAc twice (120 mL). The combined organic layers were concentrated to low volume. Fresh EtOAc (160 mL) was added and the mixture evaporated to dryness under vacuum. The collected solid was placed in the oven at 45 °C O/N under reduced pressure affording 4-methyl-1 , 3- oxazole-5-carboxylic acid (p53, 8.52 g, y=44percent) as rusty brown solid. MS (/T7/z): 128.0 [MH]A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 mL, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120 °C. After 6 hrs the mixture was allowed to cool to RT and stirred under nitrogen ON. The mixture was treated with 3 M NaOH (120 mL, reaction moderately exothermic) and stirred at RT for 4 hrs. EtOAc (120 mL) was added and the phases allowed separating. The organic layer was discarded while the aqueous was acidified with37percent aqueous HCI to pH 2 (4O mL). A precipitate started to form. The suspension was treated with EtOAc (160 mL) and, vigorously shaken. Phases were separated and the aqueous one was further extracted with EtOAc twice (120 mL). The combined organic layers were concentrated to low volume. Fresh EtOAc (160 mL) was added and the mixture evaporated to dryness under vacuum. The collected solid was placed in the oven at 45 °C ON under reduced pressure to give8.52 g of title compound (p1, y= 44percent), rusty brown solid. MS (m/z): 128.0 [IVII{]tPreparation 1 Ethyl^-chloroacetoacetate (28.6 g, 24.0 ml.) was dissolved in DMF (28.6 ml_) and formamide (19.5 mL) was added. The resulting solution was heated up to 120 Ethyl^-chloroacetoacetate (28.6 g, 24.0 ml.) was dissolved in DMF (28.6 mL) and formamide (19.5 mL) was added. The resulting solution was heated up to 120

Molecular Weight:127.10
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:127.026943022
Monoisotopic Mass:127.026943022
Topological Polar Surface Area:63.3
Heavy Atom Count:9
Complexity:125
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes