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With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5 h;
A solution of 33 (29.13?g, 0.207?mol) in THF (206?mL) was added dropwise to a suspension of LiAlH4 (7.85?g, 0.207?mmol) in THF (206?mL) at 0?°C. The reaction mixture was stirred for 30?min?at 0?°C (at this point TLC indicated consumption of the SM) and quenched by successive addition of water (8?mL), 10percent NaOH (8?mL) solution, and water (24?mL). The temperature should not exceed 0?°C). The precipitate was filtered and washed several times with THF. The filtrate was evaporated to give 34, which was used without purification. M?=?17.7?g. Yield?=?86percent.
70%
With sodium tetrahydroborate In ethanol at 0 - 20℃;
Example A.8 Ethyl oxazole-5-carboxylate (1 g, 7.09 mmol, 1 eq) was dissolved in EtOH(l4mL) and the mixture was cooled to 0°C. Sodium borohydride (0.54 g, 14.1 7mmol, 2eq) was added portionwise while stirring, and then the mixture was allowed to warm to r.t.. After overnight stirring at r.t. the conversion was complete by TLC (95/5 DCM/MeOH). The mixture was cooled to 0°C and 2N HC1 was added dropwise till gas evolution ceased (pH 5-6). The obtained suspension was concentrated at reducedpressure, and the residue was purified by flash chromatography (5i02) using as eluent a mixture DCM/MeOH = 95/5. The pure intermediate (11) were obtained as colourless oil (0.49 g, yield 70percent).
58%
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 16 h; Inert atmosphere
[000282] Synthesis of oxazol-5-ylmethanol (343): To a stirred solution of ethyl oxazole-5- carboxylate 342 (2 g, 14.18 mmol) in EtOH (20 mL) under argon atmosphere was added sodium borohydride (1.07 g, 28.36 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with 5percent MeOH/ CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5percent MeOH/ CH2C12 to afford compound 343 (810 mg, 58percent) as colorless syrup. TLC: 5percent MeOH/ CH2C12 (R 0.3); 1H-NMR (DMSO-d6, 500 MHz): ? 8.28 (s, 1H), 7.04 (s, 1H), 5.36 (t, J 6.0 Hz, 1H), 4.47 (d, J 6.0 Hz, 2H).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 367 - 391
[2] Tetrahedron Letters, 2006, vol. 47, # 4, p. 549 - 552
[3] Tetrahedron, 2008, vol. 64, # 21, p. 4778 - 4791
[4] Collection of Czechoslovak Chemical Communications, 2009, vol. 74, # 6, p. 887 - 900
[5] Patent: WO2015/118019, 2015, A1, . Location in patent: Page/Page column 35; 36
[6] Chemistry - A European Journal, 2007, vol. 13, # 19, p. 5515 - 5538
[7] Organic Letters, 2010, vol. 12, # 22, p. 5088 - 5091
[8] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000282
[9] Patent: CN103848814, 2016, B, . Location in patent: Paragraph 0323-0325
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; toluene; at 0 - 20℃; for 3h;
INTERMEDIATE 171 - PREPARATION OF ethyl oxazole-5-carboxylate; 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (0.574 ml 3.84 mmol) was added simultaneously with ethyl glyoxalate (50% in toluene, 0.659 ml 3.33 mmol) to a mixture of tosylmethyl isocyanide (0.500 g; 2.560 mmol) in dichloromethane (10 ml.) at 00C. The resulting mixture was stirred at room temperature for 3 hours, diluted in dichloromethane and washed with sodium hydrogen sulphate, sodium carbonate, dried over magnesium sulphate and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 5 to 60 % ethyl acetate in heptane) to yield 0.194 g (54 %) of ethyl oxazole-5-carboxylate as a colorless oil.ESI/APCI(+): 142(M+H).
51%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; toluene; at 0 - 20℃; for 8h;
To a stirred solution of TosMIC (50.0?g, 256?mmol) in CH2Cl2 (255?mL) was added ethyl glyoxylate (~50% in toluene, 56?mL, 283?mmol, 1.1 equiv). The solution was cooled to 0?C, and at this temperature, DBU (38?mL, 254?mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 8?h. The reaction mixture was washed with water (~300?mL), organic layers was dried over Na2SO4 and evaporated. The residue was distilled at reduced pressure. bp?=?98?C (25?mbar). M?=?18.3?g. Yield?=?51%. 1H NMR: (CDCl3, 400?MHz) delta?=?1.35 (t, J?=?7.2?Hz, 3?H), 4.35 (q, J?=?7.1?Hz, 2?H), 7.73 (s, 1?H), 7.99 (s, 1?H). 13C NMR (CDCl3, 100?MHz): delta?=?14.2, 61.7, 133.3, 142.9, 153.3, 157.6.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; toluene; at 0℃; for 1.33333h;Inert atmosphere;
All weights, volumes and equivalents are relative to toluenesulfonylmethyl isocyanide. Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) is dissolved in DCM (61.6 ml, 5 vols) at 0 C under N2. In a seperate vessel, ethyl glyoxalate (50 wt% solution in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution. The second solution is added to the TosMIc solution over 1 hr, maintaining temperature at 0 C, then checked by HPLC for completion after a further 20 mins. The reaction is quenched by slow addition of 2M HCI (10 vols, 123 ml) and the DCM layer separated. The aqueous layer is re-extracted with DCM (5 vols, 61.6 ml), and the combined organics dried over Na2S04, then evaporated on Buchi, 25 C, 100 mbar to remove DCM and toluene. Distilled at 12 mbar, jacket temperature 105 C, vapour temperature 60-80 C to afford ethyl oxazole-5-carboxylate as a colourless oil.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; toluene; at 0℃; for 1.33333h;Inert atmosphere;
All weights, volumes and equivalents are relative to toluenesulfonylmethyl isocyanide.Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) is dissolved in DCM (61.6 ml, 5 vols) at 0 C. under N2. In a seperate vessel, ethyl glyoxalate (50 wt % solution in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution. The second solution is added to the TosMIc solution over 1 hr, maintaining temperature at 0 C., then checked by HPLC for completion after a further 20 mins. The reaction is quenched by slow addition of 2M HCl (10 vols, 123 ml) and the DCM layer separated. The aqueous layer is re-extracted with DCM (5 vols, 61.6 ml), and the combined organics dried over Na2SO4, then evaporated on Buchi, 25 C., 100 mbar to remove DCM and toluene. Distilled at 12 mbar, jacket temperature 105 C., vapour temperature 60-80 C. to afford ethyl oxazole-5-carboxylate as a colourless oil.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 33 (29.13?g, 0.207?mol) in THF (206?mL) was added dropwise to a suspension of LiAlH4 (7.85?g, 0.207?mmol) in THF (206?mL) at 0?C. The reaction mixture was stirred for 30?min?at 0?C (at this point TLC indicated consumption of the SM) and quenched by successive addition of water (8?mL), 10% NaOH (8?mL) solution, and water (24?mL). The temperature should not exceed 0?C). The precipitate was filtered and washed several times with THF. The filtrate was evaporated to give 34, which was used without purification. M?=?17.7?g. Yield?=?86%.
70%
With sodium tetrahydroborate; In ethanol; at 0 - 20℃;
Example A.8 Ethyl oxazole-5-carboxylate (1 g, 7.09 mmol, 1 eq) was dissolved in EtOH(l4mL) and the mixture was cooled to 0C. Sodium borohydride (0.54 g, 14.1 7mmol, 2eq) was added portionwise while stirring, and then the mixture was allowed to warm to r.t.. After overnight stirring at r.t. the conversion was complete by TLC (95/5 DCM/MeOH). The mixture was cooled to 0C and 2N HC1 was added dropwise till gas evolution ceased (pH 5-6). The obtained suspension was concentrated at reducedpressure, and the residue was purified by flash chromatography (5i02) using as eluent a mixture DCM/MeOH = 95/5. The pure intermediate (11) were obtained as colourless oil (0.49 g, yield 70%).
64%
With sodium tetrahydroborate; In tetrahydrofuran; at 0 - 25℃; for 49h;
Step 7: Preparation of oxazol-5-ylmethanol. [0747] To a solution of <strong>[118994-89-1]ethyl oxazole-5-carboxylate</strong> (2.00 g, 14.2 mmol) in THF (20 mL) was added NaBTU (1.07 g, 28.3 mmol) at 0 C and then the mixture was stirred at 25 C for 48 h. A white cloudy was formed. To the mixture was added anhydrous Na2S04 (20 g) and the mixture was stirred at 25 C for 1 hour. The mixture was filtered and the cake was washed with MTBE (20 mL). The combined organic layer was concentrated to dryness. The residue was purified by Combi Flash (EtOAc in pentane from 10% to 100%) to give oxazol-5-ylmethanol (900 mg, 64% yield) as colorless oil. NMR (400 MHz, CDCb) d 2.02 (1H, brt, J= 6.0 Hz), 4.74 (2H, d, J= 6.0 Hz), 7.06 (1H, s), 7.89 (1H, s).
58%
With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 16h;Inert atmosphere;
[000282] Synthesis of oxazol-5-ylmethanol (343): To a stirred solution of ethyl oxazole-5- carboxylate 342 (2 g, 14.18 mmol) in EtOH (20 mL) under argon atmosphere was added sodium borohydride (1.07 g, 28.36 mmol) at 0 C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with 5% MeOH/ CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 343 (810 mg, 58%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (R 0.3); 1H-NMR (DMSO-d6, 500 MHz): oe 8.28 (s, 1H), 7.04 (s, 1H), 5.36 (t, J 6.0 Hz, 1H), 4.47 (d, J 6.0 Hz, 2H).
With sodium tetrahydroborate; ethanol; calcium chloride; In tetrahydrofuran; at 0℃;
At 0 under ice-cooling, the solution containing oxazole-5-carboxylate (3.57g, 25.0mmol) in 50mL of ethanol and 50mL of THF was added anhydrous CaCl2(11.1g, 100.0mmol), and stirred until the solid completely dissolved, then the solution was added portionwise NaBH4(2.70g, 71.0mmol).The reaction overnight, the reaction end point detection LCMS, after completion of the reaction, the mixed solution was added saturated NH4Cl solution, and extracted three times of dichloromethane was added 30mL liquid separation, the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give a crude product 1.98g of 5-hydroxymethyl isoxazole, a yield of 80%.
To a solution of ethyl 1 ,3-oxazole-5-carboxylate (0.86 g, 6.07 mmol) in THF (12,2 mL) at -40 0C were added potassium hexamethyldisilylazide (0.5 M; 14.6 niL, 7.29 mmol). After 1 h, a solution of iodine (3.85 g, 15.2 mmol) in THF (8 mL) was slowly added over 15 min. The mixture was stirred at -40 0C for 1 h then allowed to warm to ambient temperature. Sat. NaHCtheta3 and sat. Na2SC^ were added and the mixture was extracted with dchloromethane (3x). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes - ? 90 % hexanes/ ethyl acetate) gave the title compound (0.86 g, 32% pure).
With bromine; lithium hexamethyldisilazane; In tetrahydrofuran; N,N-dimethyl-formamide; at -60℃; for 4h;
To a solution of <strong>[118994-89-1]ethyl oxazole-5-carboxylate</strong> (0.28 g, 2.00 mmol) in THF/DMF (2/2 mL) was added Br2 (0.13 mL, 2.6 mmol, 1.3 eq.) and LHMDS (2.6 mL 2.6 mmol, 1.3 eq) to obtain a reaction mixture, which was stirred at -60 C. for 4 hours. The reaction mixture was extracted with EA and water and the combined organic layer was dried with MgSO4. The residue was purified by flash chromatography with EA/Hex (EA/Hex=1:4) to give OS-a.1 as yellow oil (0.1 g, 30%).
4-bromo<strong>[118994-89-1]oxazole-5-carboxylic acid ethyl ester</strong>To a solution of <strong>[118994-89-1]oxazole-5-carboxylic acid ethyl ester</strong> (12.2 g) in a mixture of tetrahydrofuran (70 ml.) and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (70 ml.) was added, over 30 minutes at -65 to -78C under nitrogen, a 1.0 M solution of 1 ,1 ,1 ,3,3,3-hexamethyldisilazane lithium salt in tetrahydrofuran (110 ml_). The solution was stirred at -780C for 80 minutes, then bromine (5.8 ml_) was added dropwise over 20 minutes and the resulting mixture was stirred at -780C for a further 45 minutes. The cold solution was added to a mixture of te/t-butylmethyl ether (50O mL) and 10% aqueous sodium thiosulfate solution (500 ml_) at room temperature. The phases were separated and the organic layer was washed with water and brine, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and pentane (0:1 to 1 :1 by volume), to afford the title compound (2.44 g) as a solid mass.MS: ESI (+ve) (Method E): 220 (M+H)+, Retention time 3.27 min.
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; bromine;
Ethyl 4-bromooxazole-5-carboxylate (2) To a solution of <strong>[118994-89-1]ethyl oxazole-5-carboxylate</strong> (1) (100.0 g, 0.71 mol) in THF (500 mL) and DMPU (500 mL) was added LiHMDS (1.0 M, 921 mL, 921 mmol) dropwise at -78 C. under N2 atmosphere, and the mixture was stirred for 1.5 hours. Then Br2 (54.5 mL, 1.06 mol) was added dropwise at the same temperature and the resulting mixture was stirred for 0.5 hours. TLC showed the starting material disappeared. The resulting solution was poured into a room temperature saturated aqueous NH4Cl (1000 mL), extracted with EtOAc (500 mL*3). The combined organic layers were washed with brine (500 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by MPLC to give ethyl 4-bromooxazole-5-carboxylate (25.0 g, purity: 90%, yield: 11%) as yellow oil. 1H NMR (400 MHz, CHCl3-d): delta 7.94 (s, 1H), 4.43 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H)
LiHMDS (1M solution, 15 mL, 15.0 mmol) was added at -78 C to a solution of <strong>[118994-89-1]ethyl 5-oxazolecarboxylate</strong> [118994-89-1] (1.26 mL, 10.0 mmol) in THF (50 mL). The reaction mixture was stirred at -78 C for 1 h and ZnCl2 (0.7M solution, 22.8 mL, 16.0 mmol) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 30 min. A solution of I2 (5.13 g, 20.0 mmol) in THF (5 mL) was added drop wise at -78 C. The reaction mixture was stirred at -78 C for 15 min and at room temperature for 1 h. The mixture was diluted with Na2S203 (sat., aq.) and extracted with Et20 (twice). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 95:5) to afford 1-159 (2.2 g, 82%).
42%
To a solution of 1 ,3-oxazole-5-carboxylate (1.02 g, 7.17 mmol) in THF (25 ml.) at - 78 0C was added LHMDS (7.53 ml_, 7.53 mmol). After 1 hour, a solution of diiodoethane (1.04 ml_, 7.88 mmol) in THF (10 ml.) was added over 15 minutes. The mixture was stirred for an additional 1 hr at -78 0C and warmed to room temperature. The mixture was poured onto cold Et2O (200 ml.) and 10% Na2S2O3 (200 ml_). The organic layer was separated, dried over Na2SO4 and purified via column chromatography (silica, 0 - 40% EtOAc/hexanes) affording the product as a white solid (805 mg, 42%).
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