Trimethylsilyl triflate → (S)-1-[(2S,3R)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285381노트

반응식

HRID 2285381 반응식
[Cl:1][C:2]([Cl:45])([Cl:44])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:43])[C@@H:14]([NH:35][C:36](OC(C)(C)C)=[O:37])[C@H:15]([O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:16])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:67]([O:71][C:72]([NH:74][C@@H:75]([CH:79]([CH3:81])[CH3:80])C(O)=O)=[O:73])([CH3:70])([CH3:69])[CH3:68].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C>[Cl:44][C:2]([Cl:1])([Cl:45])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:43])[C@@H:14]([NH:35][C:36](=[O:37])[C@@H:75]([NH:74][C:72]([O:71][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:73])[CH:79]([CH3:81])[CH3:80])[C@H:15]([O:17][Si:18]([C:31]([CH3:34])([CH3:32])[CH3:33])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:16])[NH:8]1)=[O:6]

참가 물질

8

반응물 5

HCID 65367Trimethylsilyl triflateHCID 81531Diisopropylethylamine2회HCID 83693Boc-L-ValineHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86709671(S)-1-[(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

생성물 1

HCID 86709670(S)-1-[(2S,3R)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester수율 46%

시약·촉매·용매 2

HCID 6342Acetonitrile용매HCID 6344Dichloromethane용매

실험 절차

(S)-1-[(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.95 g, 2.79 mmol) was dissolved in dichloromethane (10 mL), under an atmosphere of nitrogen and cooled using an ice bath before adding trimethylsilyl trifluoromethanesulfonate (379 μL, 4.19 mmol). The reaction mixture was stirred for 1 h before adding N,N-diisopropylethylamine (1.95 mL, 11.2 mmol) and removing all volatiles. The residue was redissolved, along with (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (728 mg, 3.35 mmol) in anhydrous acetonitrile (10 mL). The solution was cooled using an ice bath, before adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.49 g, 3.91 mmol) and N,N-diisopropylethylamine (1.95 mL, 11.2 mmol). The reaction mixture was allowed to slowly warm to room temperature and left to stir overnight. The solvent was evaporated and the remaining residue was purified by silica gel chromatography using a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (1.02 g, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J=6.9 Hz, 6H), 1.12 (d, J=6.3 Hz, 3H), 1.49 (s, 9H), 1.21-1.25 (m, 1H), 1.74-1.94 (m, 2H), 2.12-2.24 (m, 1H), 2.66-2.86 (m, 2H), 3.48 (d, J=11.1 Hz, 1H), 4.06-4.29 (m, 4H), 4.76 (ABq, Δδ=0.24, JAB=11.8 Hz, 2H), 5.16 (d, J=9.3 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.34-7.47 (m, 6H), 7.57-7.65 (m, 2H), 7.66-7.74 (m, 2H). LCMS (m/z) 801.2 [M+H], Tr=4.31 min.

후처리

  1. temperaturecooled
  2. customremoving all volatiles
  3. temperatureThe solution was cooled
  4. waitleft
  5. stirringto stir overnight
  6. customThe solvent was evaporated
  7. customthe remaining residue was purified by silica gel chromatography

출처 및 근거

ORD 기록
ord-7db753a94e0a4b7ba9f3fa7efbb8b537
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09145441B2

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