| 77% |
Stage #1: at 65℃; for 7 h;
Stage #2: With sodium hydroxide In water |
Oxime 13a (20.0 g; 107 mmol) was added to a 500 mL Parr vessel along with 2.0 g of 5percent dry Pd/C. Amide 12a (21.4 g; 107 mmol) was dissolved in acetic acid (220 mL) and charged to the Parr bottle. The vessel was purged with N2 and H2 and the mixture hydrogenated at 45 psig by heating at 65° C. for 7 h. After this time, the reaction mixture was cooled to room temperature, filtered to remove Pd, and the cake was washed with acetic acid. The filtrate was neutralized with 50percent aqueous NaOH. CH2Cl2 (500 mL) was added, followed by more 50percent aqueous NaOH until the pH of the aqueous phase was 13. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with CH2Cl2 (3.x.350 mL), and the combined organics were washed with H2O (2.x.250 mL). The washes were back-extracted with CH2Cl2 (250 mL), and the combined organics were concentrated in vacuo. The residue was dissolved in hot CH3CN and the resulting solution was filtered and cooled. The solids that formed were isolated by filtration to afford 27.7 g (83 mmol; 77percent) of pyrrole 14a. |
| 70% |
With zinc In methanol; acetic acid at 65 - 70℃; |
190 g, 0.949 mol B1 (MW: 200.28) was dissolved in 500 mL methanol and 130 g, 1.988 molZinc powder (MW: 65.38), protected by argon and heated to 65-70 ° C with stirring, and 180 g of 0.962 mol of B2 (MW: 187.19)Acetic acid solution (250mL acetic acid), the reaction was continued at 65-70 after the completion of the dropwise addition reaction, TLC showed that the control material B1The reaction was completed, filtered off excess zinc, the filtrate was concentrated under reduced pressure to remove the methanol inside, the remaining concentrate was added water, stirredSolution, dropping 50percent sodium hydroxide solution, adjusting the pH of the solution was 10-14, adding methyl tert-butyl ether, stirring 0.5h,Still stratified, the lower aqueous phase was extracted three times with methyl tert-butyl ether, methyl tert-butyl ether combined, dried over anhydrous sodium sulfate,Filtration, the filtrate was concentrated under reduced pressure to a large number of solid precipitation, filtration, to obtain a light yellow solid cake that crude product B3, the filter cake and thenWith methyl tert-butyl ether and n-hexane (volume ratio of 3: 1) mixed beating purification, the purified product was dried in vacuoWhite solid powder, pure B3 (226 g, molar yield: 70percent). |
| 53% |
Stage #1: at 20 - 75℃; for 1 h;
Stage #2: With sodium hydroxide In water |
Amide 12a (68.5 g; 342 mmol) was added to a 1000 mL 3-neck round-bottomed flask along with acetic acid (175 mL). The resulting solution was heated to 65° C. and Zn ( quantity of 75.2 g; 1150 mmol) was added to the flask. Once at 65° C., a solution of oxime 13a ( quantity of 66.9 g; 357 mmol) was added. This process was continued until all the zinc and oxime were added. There was a 10-15° C. exotherm between additions; however, the reaction temperature was brought back to 65° C. before the next addition. After the last addition, the reaction mixture was heated to 75° C. and allowed to stir for 1 h. The reaction vessel was then cooled to room temperature and the slurry was filtered through a coarse frit to remove the unreacted zinc. The filtrate was then transferred to a 2000 mL 3-neck round-bottomed flask equipped with an N2 inlet and overhead stirrer. H2O (300 mL) was added to the flask and the solution was basified with 50percent NaOH solution. Once the pH of the reaction solution reached 9.0, zinc salts started to form; excess NaOH was added until all zinc salts dissolved. The reaction mixture was then split into two batches and each batch was extracted with CH2Cl2 (3.x.250 mL). The organic layers from both batches were combined and washed with brine (300 mL). The organics were concentrated and recrystallized from acetonitrile. The product, pyrrole 14a, was isolated as off white crystals (60.6 g; 181 mmol; 53percent). TLC conditions: 86:12:2 CH2Cl2/MeOH/NH4OH. IR (NaBr) 3333, 3284, 3005, 1687, 1601, 1531, 1502, 1434, 1326, 1286 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1 H), 6.43 (s, 1 H), 3.45 (q, J=5.4 Hz, 2 H), 2.62 (t, J=5.9 Hz, 2 H), 2.55 (q, J=7.0 Hz, 4 H), 2.47 (s, 3 H), 2.46 (s, 3 H), 1.55 (s, 9 H), 1.01 (t, J=7.1 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ 165.7, 161.0, 134.5, 125.7,118.8, 118.3, 80.9, 51.5, 46.5, 36.7, 28.5, 13.4, 11.8, 11.7; HRMS (ES): found, m/z 338.2447 (M+H+); C18H31N3O3+H requires 338.2443. |
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