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Triphenylphosphine → 5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide

HRID 63541
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HRID 63541 반응식
ClC1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26]CC=C)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=CC=1.[O:34]1[CH2:37][CH:36](CCO)[CH2:35]1.[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:46]=CC=C[CH:42]=1.CC(OC(/[N:66]=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:21]1([C:13]2[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH:36]3[CH2:35][O:34][CH2:37]3)=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:41]([CH3:46])=[CH:42][N:66]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
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참가 물질

7

반응물 4

HCID 11776Triphenylphosphine2회HCID 5363146Diisopropyl azodicarboxylate2회HCID 108443452-(Oxetan-3-yl)ethan-1-olHCID 866990012-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pent-4-en-1-yl)amino]-2H-indazole-3-carboxamide

생성물 1

HCID 717666615-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide
수율 59%

시약·촉매·용매 2

HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

To a stirred suspension of 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. LCMS analysis of the reaction after 2.5 hr showed the presence of starting material and further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (5) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2. found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).

후처리

  1. dissolutionThe suspension dissolved slowly
  2. customLCMS analysis of the reaction after 2.5 hr
  3. additionwere added
  4. stirringAfter stirring for 2 h
  5. washthe organics washed with water (10 mL), brine (10 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationThe organics were concentrated in vacuo
  8. customthe residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge)
  9. washeluting with acetic acid
  10. customDCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

출처 및 근거

ORD 기록
ord-6383373a85ef46b2ac94a48bb421955e
출처 데이터셋
uspto-grants-2016_09
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09447080B2

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