Hydrochloric Acid → HCID 178433880, compound

HRID 910331Notes

Reaction equation

HRID 910331 reaction equation
[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].S(=O)(=O)(O)[NH2:24].[CH3:28][C:29]1[CH:30]=[C:31]([N:36]2[C:40]([OH:41])=[CH:39][C:38]([CH3:42])=[N:37]2)[CH:32]=[CH:33][C:34]=1[CH3:35]>O.C(N(CC)CC)C.CO>[CH3:35][C:34]1[CH:33]=[CH:32][C:31]([N:36]2[N:37]=[C:38]([CH3:42])/[C:39](=[N:24]/[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=4)[C:3]=3[OH:17])/[C:40]2=[O:41])=[CH:30][C:29]=1[CH3:28]

Participants

9

Reactant 5

HCID 313Hydrochloric Acid2×HCID 5987Sulfamic AcidHCID 114923323-(3-Amino-2-hydroxyphenyl)benzoic acidHCID 23668193Sodium NitriteHCID 178429255HCID 178429255, compound

Product 1

HCID 178433880HCID 178433880, compoundYield 95.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 8471TriethylamineSolvent

Procedure

3′-Amino-2′-hydroxybiphenyl-3-carboxylic acid (“BPCA”) Form I (90 g, 392.6 mmol), was added slowly with stirring at room temperature to a solvent mixture of tech. methanol (1.8 L) and 4 M hydrochloric acid (0.245 L, 981.5 mmol) in 3 L reactor. The resulting red solution was stirred for thirty minutes. The solution was then cooled to 0-5° C. and a cold solution of sodium nitrite (27 g, 391.3 mmol) in 90 mL of water was added over twenty minutes such that the reaction mixture temperature did not rise above 10° C. The reaction mixture was stirred for one hour at 5-10° C. Sulfamic acid (4 g, 41.2 mmol) in 90 mL of water was added at 5° C. and the resulting mixture was stirred for additionally one hour at the same temperature. The reaction mixture was warmed to room temperature and triethylamine (ca 104 mL) was added to adjust pH 7-8. 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol (“pyrazole”) form I (72 g, 357.8 mmol), was added in one portion to the reaction mixture and the resulting mixture was stirred for additionally two hours at room temperature. Hydrochloric acid (4M, ca 140 mL) was slowly added with stirring over twenty minutes to adjust pH to 1.8. A solid precipitated and was collected by filtration, washed with of mixture MeOH:water (1:1, 100 mL) and dried at 40° C./0 bar in vacuum oven for about 18 hours giving 151 g of crude orange to brown crystals of Eltrombopag crude (XRPD: form III with small percentage (less than 10%) of form I. (HPLC: 98.5%, Yield=95.4%)

Workup

  1. stirringThe resulting red solution was stirred for thirty minutes
  2. temperatureThe solution was then cooled to 0-5° C.
  3. customdid not rise above 10° C
  4. stirringThe reaction mixture was stirred for one hour at 5-10° C
  5. stirringthe resulting mixture was stirred for additionally one hour at the same temperature
  6. temperatureThe reaction mixture was warmed to room temperature
  7. stirringthe resulting mixture was stirred for additionally two hours at room temperature
  8. stirringwith stirring over twenty minutes
  9. customA solid precipitated
  10. filtrationwas collected by filtration
  11. washwashed with of mixture MeOH:water (1:1, 100 mL)
  12. customdried at 40° C./0 bar in vacuum oven for about 18 hours

Sources & evidence

ORD record
ord-e836008021224355bf21c4f1801f77ca
Source dataset
uspto-grants-2011_09
Patent number
US08022093B2

Reaction notes

Loading…