Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 767340-03-4, name is (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine, A new synthetic method of this compound is introduced below., SDS of cas: 767340-03-4
Step C: Preparation of (2R)-4-OXO-4-F3- (TRIFLUOROMETHYL)-5, 6- DIHYDROF L, 2. 41TRIAZOLOR4, 3-ALPVRAZIN-7 (8H)-YLL-1-(24*5- TRIFLUOROPHENYL) butan-2-amine (2-5) Into a 500 ml flask were charged chloro (1, 5-cyclooctadiene) rhodium (I) dimer {[Rh (cod) CI] 2} (292 mg, 0.59 mmol) and (R, S) t-butyl Josiphos (708 mg, 1.31 mmol) under a nitrogen atmosphere. Degassed MEOH was then added (200 ML) and the mixture was stirred at room temperature for 1 h. Into a 4 L HYDROGENATOR was charged the enamine amide 2-4 (118 g, 0.29 mol) along with MEOH (1 L). The slurry was degassed. The catalyst solution was then transferred to the hydrogenator under nitrogen. After degassing three times, the enamine amide was hydrogenated under 200 psi hydrogen gas at 50 C for 13 h. Assay yield was determined by HPLC to be 93% and optical purity to be 94% ee. The optical purity was further enhanced in the following manner. The methanol solution from the hydrogenation reaction (18 g in 180 mL MEOH) was concentrated and switched to methyl t-butyl ether (MTBE) (45 mL). Into this solution was added aqueous H3PO4 solution (0.5 M, 95 mL). After separation of the layers, 3N NAOH (35 ML) was added to the water layer, which was then extracted with MTBE (180 mL + 100 mL). The MTBE solution was concentrated and solvent switched to hot toluene (180 mL, about 75 C). The hot toluene solution was then allowed to cool to 0 C slowly (5-10 h). The crystals were isolated by filtration (13 g, yield 72%, 98-99% ee); m. p. 114.1-115. 7 C. 1H NMR (300 MHZ, CD3CN) : 5 7.26 (m), 7.08 (m), 4.90 (s), 4.89 (s), 4.14 (m), 3.95 (m), 3.40 (m), 2. 68 (m), 2.49 (m), 1.40 (bs). Compound 2-5 exists as amide bond rotamers. Unless indicated, the major and minor rotamers are grouped together since the carbon-13 signals are not well resolved: 13C NMR (CD3CN) : 8 171.8, 157.4 (ddd, JCF = 242.4, 9.2, 2.5 HZ), 152.2 (major), 151.8 (minor), 149.3 (DDD ; JCF = 246.7, 14.2, 12.9 Hz), 147.4 (ddd, JCF = 241.2, 12.3, 3.7 Hz), 144.2 (q, JcF = 38. 8 Hz), 124.6 (ddd, JCF = 18. 5,5. 9,4. 0 Hz), 120.4 (dd, JCF = 19.1, 6.2 Hz), 119.8 (q, JCF = 268. 9 Hz), 106.2 (dd, JCF = 29.5, 20.9 Hz), 50.1, 44.8, 44.3 (minor), 43.2 (minor), 42.4, 41.6 (minor), 41.4, 39.6, 38. 5 (minor), 36.9. The following high-performance liquid chromatographic (HPLC) conditions were used to determine percent conversion to product: Column: Waters Symmetry C18, 250 mm x 4.6 mm Eluent: Solvent A: 0.1 vol% HC104/H20 Solvent B : acetonitrile Gradient: 0 min 75% A: 25% B 10 min 25% A: 75% B 12. 5 MIN 25% A: 75% B 15 MIN 75% A: 25% B Flow rate: 1 ML/MIN Injection Vol.: 10 uL UV detection: 210 nm Column temp.: 40 C Retention times: compound 2-4: 9.1 min compound 2-5 : 5.4 min tBu Josiphos: 8.7 min The following high-performance liquid chromatographic (HPLC) conditions were used to determine optical purity: Column: Chirapak, AD-H, 250 mm x 4.6 mm Eluent: Solvent A: 0.2 vol. % diethylamine in heptane Solvent B: 0.1 vol% diethylamine in ethanol Isochratic Run Time: 18 min Flow RATE : 0. 7 mL/min Injection Vol.: 7 uL W detection: 268 nm Column temp.: 35 C Retention times: (-amine 2-5: 13.8 min (-amine : 11.2 min EXAMPLE 2 Methyl (3S)-3-AMINO-3-(6-METHOXYPERIDIN-3-YL) PROPANOATE (3-2) Into a 7 mL vial were charged chloro (1, 5-CYCLOOCTADIENE) rhodium (I) dimer { [Rh (cod) CI] 2} (14.2 mg, 0.029 mmol) and (R, S)-t-Bu Josiphos (31.3 mg, 0.058 mmol) under a nitrogen atmosphere. Degassed methanol (1 mL) was then added and the catalytic complex was stirred for 45 min at room temperature. In a separate 2-mL vial, the enamine ester 3-1 (0.1 g, 0.5 mmol) was dissolved in 0.9 mL distilled 2,2, 2-trifluoroethanol. To the same vial 0.1 RNL of the prepared catalyst solution was added resulting in 1 mol% catalyst loading and a 2,2, 2- trifluoroethanol/methanol mixture of 90/10. The hydrogenation vial was then sealed and transferred into the hydrogenation bomb under nitrogen. After degassing three times with hydrogen, the enamine ester was hydrogenated under 90-psig-hydrogen gas at 50 C for 13.5 h. Assay yield was determined by HPLC to be 88% and optical purity to be 89% ee. 1H-NMR (400 MHz, CDCl3) : 8 1.81 (bs, 2H), 2.64 (m, 2H), 3.68 (s, 3H), 3.91 (s, 3H), 4.4 (dd, 1H), 6.72 (d, 1H), 7.62 (dd, 1H), and 8. 11 (s, 1H) ppm.
The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.
Reference:
Patent; MERCK & CO. INC.; WO2004/85378; (2004); A1;,
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