Tris(hydroxymethyl)aminomethane → 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

HRID 2189428Notes

Reaction equation

HRID 2189428 reaction equation
[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:53](OC1C=CC([N+]([O-])=O)=CC=1)=[O:54].[CH2:65]([OH:72])[C:66]([NH2:71])([CH2:69][OH:70])[CH2:67][OH:68]>ClCCl.O.CO>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:53]([NH:71][C:66]([CH2:69][OH:70])([CH2:67][OH:68])[CH2:65][OH:72])=[O:54])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]

Participants

8

Reactant 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 8471TriethylamineHCID 821294-Nitrophenyl chloroformateHCID 689452653-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

Product 1

HCID 689425653-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleYield 48.5%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (60 mg) in dichloromethane (3 mL) were added triethylamine (0.016 mL) and 4-nitrophenyl chloroformate (21 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added tris(hydroxymethyl)aminomethane (35 mg) and methanol (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-6/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (36 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.018 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (22 mg).

Workup

  1. stirringthe mixture was stirred at room temperature for 3 hours
  2. extractionthe resulting mixture was extracted with ethyl acetate
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customThe solvent was removed under reduced pressure
  6. customthe residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-6/1)

Sources & evidence

ORD record
ord-73d5e24f3db1466ea51f213be55d2f1c
Source dataset
uspto-grants-2012_12
Patent number
US08324176B2

Reaction notes

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