Acetic Acid → BI 207127

HRID 1907895Notes

Reaction equation

HRID 1907895 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CCCC)=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:28][CH2:27][CH2:26]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.CO.[OH-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:26][CH2:27][CH2:28]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 176Acetic Acid2×HCID 887MethanolHCID 14798Sodium HydroxideHCID 86665161HCID 86665161, compound

Product 1

HCID 56948249BI 207127Yield 101.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
66.5 °C

Procedure

To the suspension of (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VII (489.0 g, 91.9 Wt %, 633.3 mmol) in THF (1298 g) and MeOH (387 g) was added 50% NaOH (82.7 g, 949.9 mmol), followed by rinse with water (978 g). The mixture was stirred between 65-68° C. for about 1 h for complete hydrolysis. The resulting solution was cooled to 35° C., and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g). The solution was heated to 60±4° C., and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated. The resulting suspension was stirred at 60±4° C. for 0.5 h. Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60±4° C. for additional 0.5 h. The batch was cooled to 26±4° C. over 1 h and held for 1 h. The batch was filtered, rinsed with a premixed solution of water (1956 g) and MeOH (773.6 g), dried at 50° C. under vacuum to give (E)-3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylic acid (1) (419.0 g, 95% yield) with ≧99.0 A % (240 nm) and 94.1 Wt % by HPLC.

Workup

  1. washby rinse with water (978 g)
  2. temperatureThe resulting solution was cooled to 35° C.
  3. filtrationfiltered through
  4. filtrationan in-line filter (0.5 micron)
  5. washrinsed with a pre-mixed solution of water (978 g) and MeOH (387 g)
  6. temperatureThe solution was heated to 60±4° C.
  7. stirringwas well agitated
  8. stirringThe resulting suspension was stirred at 60±4° C. for 0.5 h
  9. stirringbatch was stirred at 60±4° C. for additional 0.5 h
  10. temperatureThe batch was cooled to 26±4° C. over 1 h
  11. waitheld for 1 h
  12. filtrationThe batch was filtered
  13. washrinsed with a premixed solution of water (1956 g) and MeOH (773.6 g)
  14. customdried at 50° C. under vacuum

Sources & evidence

ORD record
ord-7203ce5e25fd46b7b3fa1d270c848bcf
Source dataset
uspto-grants-2013_12
Patent number
US08598183B2

Reaction notes

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