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With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78℃; for 0.5 h; Inert atmosphere
Step 1: 5-Methylthiazole-4-carbaldehyde. [00670] To a solution of ethyl 5-methylthiazole-4-carboxylate (794 mg, 5.05 mmol) in THF (21.6 mL) was added dropwise 1.0 M of DIBAL-H in toluene (5.56 mL, 5.56 mmol) under an atmosphere of argon at -78 °C and the reaction was stirred for 30 min. The reaction was quenched with water ( 12.4 mL) at -78 °C. The reaction was warmed to rt. The reaction was poured into 300 mL of saturated Rochelle salt in water and diluted with EtOAc. The layers were stirred together for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (x3). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by ISCO column chromatography ( 10percent EtOAc in DCM as eluent) to give 642 mg (54 percent) of the title compound as yellow oil. NMR (400 MHz, Chloroform-if) δ 10.22 (s, 1 H), 8.62 (s, 1H), 2.83 (s, 3H).
Reference:
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 14, p. 2319 - 2332
[2] Patent: WO2016/4136, 2016, A1, . Location in patent: Paragraph 00670
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78℃; for 0.5h;Inert atmosphere;
Step 1: 5-Methylthiazole-4-carbaldehyde. [00670] To a solution of ethyl 5-methylthiazole-4-carboxylate (794 mg, 5.05 mmol) in THF (21.6 mL) was added dropwise 1.0 M of DIBAL-H in toluene (5.56 mL, 5.56 mmol) under an atmosphere of argon at -78 °C and the reaction was stirred for 30 min. The reaction was quenched with water ( 12.4 mL) at -78 °C. The reaction was warmed to rt. The reaction was poured into 300 mL of saturated Rochelle salt in water and diluted with EtOAc. The layers were stirred together for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (x3). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by ISCO column chromatography ( 10percent EtOAc in DCM as eluent) to give 642 mg (54 percent) of the title compound as yellow oil. NMR (400 MHz, Chloroform-if) delta 10.22 (s, 1 H), 8.62 (s, 1H), 2.83 (s, 3H).
34%
With diisobutylaluminium hydride; In tetrahydrofuran; at -78℃; for 0.5h;
To a solution of ethyl 5-methylthiazole-4-carboxylate (900 mg, 5.26 mmol, 1 eq) in tetrahydrofuran (25 mL) was added diisobutylaluminum hydride (1 M, 6.31 mL, 1.2 eq). The mixture was stirred at -78°C for 30 minutes. The reaction mixture was quenched with water (2 mL) at -78°C. The reaction was warmed to room temperature. The reaction was poured into 40 mL of saturated potassium sodium tartrate in water and diluted with ethyl acetate. The layers were stirred for 1 hour and the aqueous layer was extracted with ethyl acetate 60 mL (20*3 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (5i02, petroleum ether: ethyl acetate=8:1 to 7:1) to give the target compound (230 mg, 34percent yield) as a yellow liquid. ?H NMR (400 MHz, CDC13) oe 10.11 (s, 1H), 8.52 (s, 1H), 2.72 (s, 3H).
With diisobutylaluminium hydride; acetic acid; In dichloromethane (CH2Cl2); dichloromethane; water;
EXAMPLE A-1 5-Methyl-thiazole-4-carbaldehyde A solution of 2.48 g (14.4 mmol) of 5-methyl-thiazole-4-carboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1982:159-164) in dichloromethane (CH2Cl2) (50 mL) was cooled to -78° C. under nitrogen. DIBAL (Diisobutylaluminum hydride) (1.0 M in CH2Cl2, 15 mmol) was added dropwise, and the solution was stirred at low temperature for 45 minutes. Another 10 mmol of DIBAL was then added dropwise, and the mixture was stirred for another 45 minutes. A solution of methanol (MeOH):acetic acid (10 mL:5 mL) was added slowly, followed by H2O. The organic layer was separated, washed with brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluding with 2:1 hexane:ethyl acetate (EtOAc), to give the title compound. 1H NMR (CDCl3): delta2.76 (s, 3 H), 8.58 (s, 1 H), 10.14 (s, 1 H).
With acetic acid; In methanol; at 20℃; for 0.166667h;
A solution of 6-nitro-lH-indazol-3-ylamine (260mg, 1.46mmol), 5-Methyl- thiazole-4-carbaldehyde (223mg, 1.75mmol), acetic acid (0.1 OmL) in methanol was stirred at ambient temperature for 10 min. Sodium cyano borohydride (110 mg, 1.75 mL) was added and the mixture was stirred for 15h. The precipitate was filtered and dried to yield the title compound (160mg, 38percent). m/z (M+eta) = 290.13
rac-(3-chlorophenyl)(5-methyl-1,3-thiazol-4-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
Step 2: rac-(3-ChlorophenyI)(5-methyl-l,3-thiazol-4-yl)methanoI. [00671] 3-Chlorobromobenzene (0.65 mL, 5.50 mmol) in THF (24 mL) was cooled at -78 °C under an atmosphere of argon. To the solution was added dropwise 2.5 M of n-BuLi in hexane (2.31 mL, 5.78 mmol) and the solution was allowed to stir at -78 °C for 30 min. To the mixture was added a solution of <strong>[261710-79-6]5-methylthiazole-4-carbaldehyde</strong> (350 mg, 2.75 mmol) in THF ( 12.3 mL) and the reaction was stirred at -78 °C for 1 hour. The resulting mixture was quenched with saturated NH4CI and diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by ISCO column chromatography ( 10percent EtOAc in DCM as eluent) to give 660 mg (56 percent) of the title compound as colorless oil. NMR (400 MHz, Methanol-^) delta 8.70 (s, 1 H), 7.50 - 7.43 (m, 1 H), 7.32 - 7.19 (m, 3H), 6.01 (s, 1 H), 2.51 (s, 3H). LCMS (FA): 241 .9 (M + 1 ).
1-(3-pyridyl)-2-(triphenylphosphanylidene)ethanone[ No CAS ]
[ 261710-79-6 ]
(E)-3-(5-methylthiazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In acetonitrile; at 70℃; for 48h;Inert atmosphere;
General procedure: A mixture of benzaldehyde (490 mg, 4.6 mmol, 467 uL, 1.1 eq) and Example 70-2 (1.56 g, 4.2 mmol, 1.0 eq) in acetonitrile (20 mL) was degassed and purged with nitrogen 3 times. The mixture was stirred at 50°C for 96 hours under a nitrogen atmosphere. The mixture was concentrated. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate= 10/i to 5:1) to give the target compound (600 mg, 72percent yield) as a light yellow solid. [00481] ?H NMR (400 MHz, CDCl3) oe 8.09 (s, 1H), 7.96 - 7.93 (m, 2H), 7.69 - 7.66 (m,2H), 7.47 - 7.45 (m, 3H), 7.33 (d, J = 15.6 Hz, 1H).