2-Methylpropyl isocyanate → 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 1625944Notes

Reaction equation

HRID 1625944 reaction equation
[CH2:1]([N:5]=[C:6]=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.Cl.C([O:13][C@@H:14]1[C@@H:55]([O:56]C(=O)C)[C@H:54]([O:60]C(=O)C)[C@@H:53]([CH2:64][O:65]C(=O)C)[O:52][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=1)(=O)C.C(N(C(C)C)CC)(C)C>ClCCl>[C@@H:15]1([O:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][C:35]5([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH:46][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:40][CH2:39]5)[CH2:34]4)=[CH:25][C:24]=3[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=2)[O:52][C@H:53]([CH2:64][OH:65])[C@@H:54]([OH:60])[C@H:55]([OH:56])[C@H:14]1[OH:13]

Participants

5

Reactant 3

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 46.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Add isobutyl isocyanate (77 mg, 0.78 mmol) to a solution 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 (350 mg, 0.39 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane (1.0 mL). After 30 min at room temperature, concentrate to dryness under the reduced pressure. Treat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature, remove the solvent under the reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 29% B for 4 min, 29-44% B for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B—acetonitrile to yield the title compound as solid (134 mg, 0.18 mmol). MS (m/z): 755.2 (M+1), 753.2 (M−1).

Workup

  1. concentrationconcentrate to dryness under the reduced pressure
  2. additionTreat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature
  3. customremove the solvent under the reduced pressure
  4. customPurify the resulting residue by preparative HPLC method
  5. waithigh pH, 29% B for 4 min
  6. wait29-44% B for 5 min @ 85 mL/min using

Sources & evidence

ORD record
ord-127fbe4d2b834204b242e21ec46d1df9
Source dataset
uspto-grants-2014_07
Patent number
US08785404B2

Reaction notes

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