Hydrochloric Acid → methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate

HRID 1509667노트

반응식

HRID 1509667 반응식
[CH3:1][C:2]1([CH3:42])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31](OC(C)(C)C)=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)[O:3]1.Cl.[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])C(O)=O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.C(O)C>[CH3:54][CH:53]([CH3:55])[C@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[C:31](=[O:32])[N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24]1[NH:25][C:21]2[CH:20]=[CH:19][C:18]3[C:38](=[CH:39][CH:40]=[C:41]4[C:12]5[CH:11]=[CH:10][C:9]([B:4]6[O:3][C:2]([CH3:42])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]6)=[CH:14][C:13]=5[CH2:15][O:16][C:17]4=3)[C:22]=2[N:23]=1

참가 물질

8

반응물 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 86688819tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

생성물 1

HCID 86690048methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate수율 73.5%

시약·촉매·용매 2

HCID 702Ethanol용매HCID 8857Ethyl Acetate용매

실험 절차

A solution of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) was heated to 60° C. for 2 hours. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The resulting crude material was dissolved in dimethylformamide (17 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (455 mg, 2.6 mmol), HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). The reaction was stirred at room temperature for one hour then diluted with ethyl acetate. The organics were washed with water (×2) and brine, dried with magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography to yield Intermediate methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate (780 mg, 72% yield over 2 steps).

후처리

  1. concentrationThe reaction was concentrated
  2. dissolutionredissolved in a minimal amount of methanol
  3. additionAn equal volume of dichloromethane was added
  4. concentrationthe solution was again concentrated
  5. additionDichloromethane was added to the resulting residue
  6. concentrationconcentrated off two more times
  7. dissolutionThe resulting crude material was dissolved in dimethylformamide (17 mL)
  8. washThe organics were washed with water (×2) and brine
  9. dry with materialdried with magnesium sulfate
  10. concentrationconcentrated
  11. customThe resulting residue was purified by flash column chromatography

출처 및 근거

ORD 기록
ord-c8ea68bb8d7c4e6bb3f76406b714b7f3
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09221833B2

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