Diisopropylethylamine → 1-isobutyl-3-[2-[4-[3-[4-[[4-methyl-1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenoxy]propyl]-4,9-diazaspiro[5.5]undecan-9-yl]-2-oxo-ethyl]urea

HRID 2284874노트

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HRID 2284874 반응식
C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.[CH2:50]1[C:55]2([CH2:60][CH2:59][N:58]([C:61](=[O:71])[CH2:62][NH:63][C:64]([NH:66][CH2:67][CH:68]([CH3:70])[CH3:69])=[O:65])[CH2:57][CH2:56]2)[CH2:54][NH:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C.C[O-].[Na+]>CO.C(#N)C>[CH2:67]([NH:66][C:64]([NH:63][CH2:62][C:61]([N:58]1[CH2:59][CH2:60][C:55]2([CH2:50][CH2:51][CH2:52][N:53]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:36][CH:37]=3)[CH2:54]2)[CH2:56][CH2:57]1)=[O:71])=[O:65])[CH:68]([CH3:69])[CH3:70]

참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 10942334Sodium MethoxideHCID 1180213681-[2-(3,8-Diazaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-3-isobutyl-ureaHCID 118045083[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate

생성물 1

HCID 917550101-isobutyl-3-[2-[4-[3-[4-[[4-methyl-1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenoxy]propyl]-4,9-diazaspiro[5.5]undecan-9-yl]-2-oxo-ethyl]urea

시약·촉매·용매 2

HCID 887Methanol용매HCID 6342Acetonitrile용매

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온도
80 °C

실험 절차

To a 0.25 L round bottom flask add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate (7.2 g, crude), 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (12.28 mmol), acetonitrile (100 mL), and diisopropylethylamine (40.92 mmol). Heat at 80° C. for 16 hours then concentrate under reduced pressure. Add methanol (50 mL) and sodium methoxide (20.46 mmol, 30% solution in MeOH) and stir at room temperature for 1 hour. Quench by adding a small piece of dry ice. Concentrate under reduced pressure. Purify by reverse phase flash chromatography (400 g C18 cartridge) eluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions. Concentrate under reduced pressure to yield the title compound as a formic acid salt containing small impurities. Dissolve the salt in 7N ammonia in methanol (20 mL) then concentrate to form the free base. Purify the free base by flash chromatography (330 g silica gel cartridge) eluting with 5% 7N ammonia in methanol/dichloromethane. Concentrate the product fractions under reduced pressure to yield the title compound (1.75 g, 22.81%): MS (m/z): 746.6 (M+H). H1 NMR (400.31 MHz, CD3OD): δ 7.28 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.97 (t, J=8.8 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 4.15 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.91 (d, J=1.6 Hz, 2H), 3.87-3.80 (m, 2H), 3.65 (dd, J=11.6, 5.6 Hz, 1H), 3.57-3.38 (m, 5H), 3.31 (bm, 2H), 2.90 (d, J=6.8 Hz, 2H), 2.46-2.13 (m, 8H), 1.88 (pentet, J=6.8 Hz, 2H), 1.68 (septet, J=6.8 Hz, 1H), 1.61-1.28 (m, 8H), 0.86 (d, J=6.8, 6H).

후처리

  1. concentrationthen concentrate under reduced pressure
  2. customQuench
  3. additionby adding a small piece of dry ice
  4. concentrationConcentrate under reduced pressure
  5. customPurify by reverse phase flash chromatography (400 g C18 cartridge)
  6. washeluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions
  7. concentrationConcentrate under reduced pressure

출처 및 근거

ORD 기록
ord-39b171cea227465ab2ecd92a108618da
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09145437B2

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