Potassium Hydroxide → 1-Methyl-5-[4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamido]-1h-indole-2-carboxylic acid potassium salt

HRID 1455834Notes

Reaction equation

HRID 1455834 reaction equation
[OH-].[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O:34]CC)=[O:33].[K+].CN1C2C(=CC(NC(C3C(C4C=CC=CC=4)=CC=C(C(F)(F)F)C=3)=O)=CC=2)C=C1C([O-])=O>O.CC(O)C>[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33]

Participants

6

Reactant 3

HCID 14797Potassium HydroxideHCID 22262720Ethyl 1-methyl-5-{[4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl]amino}-1H-indole-2-carboxylateHCID 689529151-methyl-5-[4-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt

Product 1

HCID 689528711-Methyl-5-[4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamido]-1h-indole-2-carboxylic acid potassium saltYield 93.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
2.5 °C

Procedure

A solution of potassium hydroxide (54.1 g) in water (600 mL) was added over 15 minutes to a suspension of ethyl 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate (300 g), from the previous step, in propan-2-ol (4500 mL) at 60° C. and the resulting mixture was heated to reflux for an hour. The solution was seeded with product (1-methyl-5-[4-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt) and the mixture granulated at 60-70° C. for two hours. The mixture was slowly cooled to 0-5° C. and the product potassium salt collected by filtration, washing with a chilled 90/10 mixture of propan-2-ol and demineralized water (510 mL total volume). The product solids were dried, yielding 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt 2.6 hydrate (287.4 g, 85% correcting for water content of 9.1% by weight). Anhydrous Mol wt of parent acid (calc) 438.41, MS: 439.3 (MH+), 437.3 (M−). 1H NMR (DMSO-d6): δ 3.99 (s, 3H), 6.53 (s, 1H), 7.12-7.76 (complex, 11H), 10.05 (broad), HPLC retention time 9.30 minutes. The preferred solid form of the product is characterized by the pXRD (powder X-ray diffraction) pattern shown in FIG. 7.

Workup

  1. temperaturethe resulting mixture was heated
  2. temperatureto reflux for an hour
  3. filtrationthe product potassium salt collected by filtration
  4. washwashing with
  5. temperaturea chilled
  6. addition90/10 mixture of propan-2-ol and demineralized water (510 mL total volume)
  7. customThe product solids were dried

Sources & evidence

ORD record
ord-16076f99123649c195a69b9d6b3fc19b
Source dataset
uspto-grants-2009_01
Patent number
US07482368B2

Reaction notes

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