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General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
55%
With triethylamine; trifluoroacetic anhydride In tetrahydrofuran at 20℃; for 3 h;
Step 2. Syntheis of compound 3A mixture of compound 2 (340 mg, 2.79 mmol), TFAA (0.99 mL) and Et3N (2.35 mL) in THF (10 mL) was stirred at room temperature for 3 h. Then the mixture was concentrated in vacuo to give the residue. The mixture was partitioned between H20 (20 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo to the crude product, which was purified by preparative TLC (petroleum ether: ethyl acetate = 1 : 1) to give compound 3 (160 g, 55percent) as a yellow solid.
Reference：
[1] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0150; 0151; 0152; 0162
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 6, p. 628 - 633
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1203 - 1208
[4] Patent: WO2011/106414, 2011, A1, . Location in patent: Page/Page column 83
[5] Journal of the Chemical Society [Section] C: Organic, 1969, p. 707 - 710
Preparation of nitrile intermediates (Method B); The desired carboxylic acid (1.0 g, 1 eq), t-butylamine (1 eq), EDCI (1.2 eq), NEt3 (2 eq) and HOBT (20 mg) were dissolved in 15ml of dichloromethane. The solution was stirred at room temperature over night, a further 15 ml dichloromethane added, and the solution washed with 1 N NaOH and brine, dried and concentrated to afford the amide. This was refluxed in POCl3 overnight, evaporated under reduced pressure, and the crude product purified by column chromatography. EDCI = l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide HOBT = 1 -hydroxybenzotriazole.
<i>N</i>-[4-(<i>N</i>-hydroxycarbamimidoyl)-thiazol-2-ylmethyl]-2-[3-(3-methoxy-benzenesulfonylamino)-2-oxo-2<i>H</i>-pyridin-1-yl]-acetamide[ No CAS ]
<i>N</i>-[4-(<i>N</i>-hydroxycarbamimidoyl)-thiazol-2-ylmethyl]-2-(6-methyl-2-oxo-3-phenylmethanesulfonylamino-2<i>H</i>-pyridin-1-yl)-acetamide[ No CAS ]
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