Pyrazinamide → (2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide

HRID 525288

반응식

HRID 525288 반응식
[N:1]1[CH:6]=[CH:5]N=C[C:2]=1[C:7](N)=[O:8].[C:10]1([CH2:16][C@H:17]([NH:21][C:22]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:23])[C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C[C@]12[C@H]3C[C@H](C3(C)C)C[C@H]1[O:34][B:35]([C@@H:37]([NH2:42])[CH2:38][CH:39]([CH3:41])[CH3:40])O2.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:8]1[CH2:7][CH2:2][NH:1][CH2:6][CH2:5][O:34][B:35]1[C@@H:37]([NH:42][C:18](=[O:20])[C@@H:17]([NH:21][C:22]([C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:23])[CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:38][CH:39]([CH3:41])[CH3:40]

참가 물질

6

반응물 4

HCID 1046PyrazinamideHCID 81531DiisopropylethylamineHCID 15042559N-(Pyrazinylcarbonyl)-L-phenylalanineHCID 46911940(R)-BoroLeu-(+)-Pinanediol hydrochloride

생성물 1

HCID 53327095(2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide수율 93%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
-25.5 °C

실험 절차

Preparation of N-[(1S)-1[[[(1R)-1-[3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-benzyl]2-pyrazine carboxamide. A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, thermocouple, nitrogen inlet/outlet and cooling bath is charged with 11 g (99.9 mmol) of (S)-3-phenyl-2-[(pyrazine-2-carbonyl)-amino]-propionic acid, 15.5.0 g (40.6 mmol) of 0-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mL of N,N-dimethylformamide (DMF). The pale yellow reaction solution is cooled to −35° C. where 12.6 g (17 mL, 97.3 mmol) of N,N-di-isopropyl ethyl amine is added dropwise over six minutes at −34° C. to −35° C. The resulting solution is then stirred overnight at −40 to −11° C. The reaction mixture is quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. After transferring into a reparatory funnel the layers are separated. The organic phase is then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL). The product solution is dried over magnesium sulfate then filtered. The filtrate is evaporated to dryness in vacuo to give 19.57 g (37.7 mmol, 93%) of the title compound as a light brown foam with an HPLC purity of 92 A %. 1H NMR (d6-DMSO, 400 MHz) δ 9.15 (d, 1H, J=1.44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H), 1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).

후처리

  1. temperaturethermocouple, nitrogen inlet/outlet and cooling bath
  2. additionis added dropwise over six minutes at −34° C. to −35° C
  3. customThe reaction mixture is quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture
  4. customAfter transferring into a reparatory funnel
  5. customthe layers are separated
  6. washThe organic phase is then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL)
  7. dry with materialThe product solution is dried over magnesium sulfate
  8. filtrationthen filtered
  9. customThe filtrate is evaporated to dryness in vacuo

출처 및 근거

ORD 기록
ord-59c0f91ca03241f896602778bb232a5c
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09340559B2

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