* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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
2
[ 118994-86-8 ]
[ 127232-41-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 602 - 617
[2] Journal of the American Chemical Society, 1990, vol. 112, # 10, p. 4070 - 4072
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%.
With Dess-Martin periodane; In dichloromethane; at 0℃; for 0.5h;
Example A.21General procedure for 5-oxazolyl derivativesSTEP a ) Preparation of ct-ctminonitrilesMethod a)The appropriate oxazole alcohol intermediate (11) or intermediate (12) (0.85 8 mmol, 1 eq) was dissolved in DCM (1.5 mL) and the solution was cooled to 0C. DessMartin periodinane (0.943 mmol, 1.1 eq) was added and the mixture was left stirring at the same temperature. After a few minutes a white suspension formed and after 30 mm. the conversion was complete by TLC (95/5 DCM/MeOH). The aldehyde intermediatewas not isolated. Glacial AcOH (5 mL), AcONa (1.93 mmol, 2.25 eq) and the appropriate amine (1.54 mi-no 1, 1.8 eq) were sequentially added to the suspension and the mixture was allowed to warm to rt. After 1.5 hrs TMSCN (2.57 mmol, 3eq) was added and the mixture was left under stirring at the same temperature overnight. The volatiles were then evaporated and a saturated solution of NaHCO3 (40 mL) was added to the residue. Themixture was extracted with EtOAc (20 mLx3) and the combined organic phases were dried (anh. Na2SO4) and concentrated under reduced pressure. The crude was purified by flash chromatography (Si02) using a mixture of petroleum ether and AcOEt varyng between 9/1 and 4/6. The pure ct-aminonitrile was obtained as a colourless oil (average yield 53%).
E. 5-(Chloromethyl)oxazole Using the procedure of Example 1Q, but replacing 5-(hydroxymethyl)thiazole with 5-(hydroxymethyl)oxazole provided the desired compound.
With thionyl chloride; In hexane; dichloromethane; at 0℃; for 3.0h;Inert atmosphere; Reflux;
[000283] Synthesis of 5-(chloromethyl) oxazole (344): To a stirred solution of compound 343 (800 mg, 8.08 mmol) in CH2C12: n-hexane (1: 1, 10 mL) under argon atmosphere was added thionyl chloride (1.2 mL, 16.16 mmol) at 0 C; heated to reflux and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was neutralized with saturated NaHCO3 solution (20 mL) and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 344 (700 mg) as colorless syrup. TLC: 40% EtOAc/ hexanes (R 0.5); 1H- NMR (CDC13, 400 MHz): oe 7.89 (s, 1H), 7.10 (s, 1H), 4.62 (s, 2H).
D. 5-(Hydroxymethyl)oxazole A solution of <strong>[118994-86-8]5-oxazolecarboxaldehyde</strong> (0.627 g, 0.00646 mol) in MeOH (10 mL) under argon at 0 C. was treated with NaBH4 (0.247 g, 0.00646 mol). After 5 mins the reaction was quenched with acetone and the solvent removed by rotary evaporation in vacuo. Chromatography on a 100 g SiO2 flash column with a gradient of MeOH/CH2 Cl2 (5%, 10%) afforded the desired compound as a colorless oil (0.408 g, 0.00412 mol, 64%): 1 H NMR (CDCl3)delta2.03 (t, J=6.0 Hz, 1H), 4.70 (d, J=6.0 Hz, 2H), 7.04 (s, 1H), 7.87 (s, 1H). MS (Cl/NH3) m/e 117 (m+NH4), 100 (m+H).
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