Water → 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-1,3-propanediol

HRID 1749661Notes

Reaction equation

HRID 1749661 reaction equation
[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:4]=2[N:3]=1.O.[CH2:33]([OH:40])[C:34]([NH2:39])([CH2:37][OH:38])[CH2:35][OH:36]>CO>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:4]=2[N:3]=1.[NH2:39][C:34]([CH2:37][OH:38])([CH2:35][OH:36])[CH2:33][OH:40]

Participants

5

Reactant 3

HCID 962WaterHCID 6503Tris(hydroxymethyl)aminomethaneHCID 56949517Gsk-2636771

Product 1

HCID 669766662-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-1,3-propanediolYield 93.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid (40.0 g, 92 mmol) was suspended in Methanol (1.6 L) in a 3 L rounded-bottom flask. The resulting slurry was heated to 60° C. mixing on a buchii rotary evaporator water bath and tris(hydroxymethyl)aminomethane (3M solution in water) (0.031 L, 92 mmol) was added in four aliquots over 15 minutes followed by the addition of seed crystals as produced by method analogous to Example 86, Batch 2, above (108 mg). This slurry was stirred (flask rotated on buchii rotovap) at 60° C. for 3 hours, then cooled (˜1° C./min) to 20° C. (room temperature), then finally magnetically stirred at 20° C. (room temperature) for 8 hours. The resulting white solid was isolated by vacuum filtration, dried under vacuum at 60° C. for 8 hours to provide 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid-2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) (47.76 g, 86 mmol, 93% yield) as a white solid. Both proton NMR and LCMS are consistent with the proposed structure. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=7.83 Hz, 1H) 7.37 (d, J=2.27 Hz, 1H) 7.17-7.33 (m, 2H) 6.33 (d, J=7.83 Hz, 1H) 5.59 (s, 2H) 3.66-3.80 (m, 4H) 2.98-3.15 (m, 4H) 2.50-2.58 (m, 10H) 2.43 (s, 3H); LCMS m/z MH+=434.3.

Workup

  1. additionwas added in four aliquots over 15 minutes
  2. additionfollowed by the addition of seed crystals
  3. customas produced by method analogous to Example 86, Batch 2, above (108 mg)
  4. temperaturecooled (˜1° C./min) to 20° C. (room temperature)
  5. stirringfinally magnetically stirred at 20° C. (room temperature) for 8 hours
  6. customThe resulting white solid was isolated by vacuum filtration
  7. customdried under vacuum at 60° C. for 8 hours

Sources & evidence

ORD record
ord-faaa60e87d9a45cf968aa2d2780c506a
Source dataset
uspto-grants-2015_10
Patent number
US09156797B2

Reaction notes

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