Ammonia → 1-(2-{2-[(3E)-4-(4-{[3-(beta-D-glucopyranosyloxy)-5-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-3-methylphenyl)but-3-en-1-yl]-2,9-diazaspiro[5.5]undec-9-yl}-2-oxoethyl)-3-(2-methylpropyl)urea

HRID 1625945Notes

Reaction equation

HRID 1625945 reaction equation
Cl.Cl.C([O:6][C@@H:7]1[C@@H:48]([O:49]C(=O)C)[C@H:47]([O:53]C(=O)C)[C@@H:46]([CH2:57][O:58]C(=O)C)[O:45][C@H:8]1[O:9][C:10]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][C:28]4([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH2:39])[CH2:33][CH2:32]4)[CH2:27]3)=[CH:18][C:17]=2[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=1)(=O)C.C(N(C(C)C)CC)(C)C.[CH2:71]([N:75]=[C:76]=[O:77])[CH:72]([CH3:74])[CH3:73].N>ClCCl.C(#N)C>[C@@H:8]1([O:9][C:10]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][C:28]5([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH:39][C:76]([NH:75][CH2:71][CH:72]([CH3:74])[CH3:73])=[O:77])[CH2:33][CH2:32]5)[CH2:27]4)=[CH:18][C:17]=3[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=2)[O:45][C@H:46]([CH2:57][OH:58])[C@@H:47]([OH:53])[C@H:48]([OH:49])[C@H:7]1[OH:6]

Participants

7

Reactant 4

HCID 222Ammonia3×HCID 612812-Methylpropyl isocyanateHCID 81531DiisopropylethylamineHCID 867625414-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride

Product 1

HCID 734385681-(2-{2-[(3E)-4-(4-{[3-(beta-D-glucopyranosyloxy)-5-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-3-methylphenyl)but-3-en-1-yl]-2,9-diazaspiro[5.5]undec-9-yl}-2-oxoethyl)-3-(2-methylpropyl)ureaYield 68%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
5 °C

Procedure

A mixture of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (11.70 g; 13.04 mmoles) in dichloromethane (33 mL) and diisopropylethylamine (13.65 mL; 78.27 mmoles) is stirred for 10 minutes to dissolve. The mixture is cooled to 5° C. and isobutyl isocyanate (2.59 g, 26.09 mmoles) is added dropwise over 5 minutes. When the addition is complete the cooling bath was removed. After 15 minutes, the mixture is concentrated under reduced pressure. The residue is treated with ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) and stirred at ambient temperature for 1.5 hours. Further ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added and the reaction is stirred overnight. The mixture is warmed to 40° C. and ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added. The mixture is stirred for 160 minutes, and then concentrated. The residue is purified by reverse phase (C18) flash column chromatography eluting with 20:80 to 80:20 10 mM ammonium bicarbonate in water:acetonitrile to give the title compound (6.686 g, 68% yield). Mass spectrum (m/z): 755.5 (M+1).

Workup

  1. dissolutionto dissolve
  2. additionWhen the addition
  3. customwas removed
  4. waitAfter 15 minutes
  5. concentrationthe mixture is concentrated under reduced pressure
  6. stirringstirred at ambient temperature for 1.5 hours
  7. stirringthe reaction is stirred overnight
  8. temperatureThe mixture is warmed to 40° C.
  9. stirringThe mixture is stirred for 160 minutes
  10. concentrationconcentrated
  11. customThe residue is purified by reverse phase (C18) flash column chromatography
  12. washeluting with 20:80 to 80:20 10 mM ammonium bicarbonate in water

Sources & evidence

ORD record
ord-97bd5c3dc0cc4a68970b0d39007f05cd
Source dataset
uspto-grants-2014_07
Patent number
US08785404B2

Reaction notes

Loading…