반응 #2507849

반응 방정식

Sulfamic acid

3′-Amino-2′-hydroxybiphenyl-3-carboxylic acid

1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol

Hydrochloric acid

hydrochloric acid

sodium nitrite

→

Eltrombopag

수율 95.4%

용매

water

methanol

triethylamine

water

반응 조건

후처리

1. 1
   workup.STIRRINGThe resulting red solution was stirred for thirty minutes
2. 2
   온도The solution was then cooled to 0-5° C.
3. 3
   기타did not rise above 10° C
4. 4
   workup.STIRRINGThe reaction mixture was stirred for one hour at 5-10° C
5. 5
   workup.STIRRINGthe resulting mixture was stirred for additionally one hour at the same temperature
6. 6
   온도The reaction mixture was warmed to room temperature
7. 7
   workup.STIRRINGthe resulting mixture was stirred for additionally two hours at room temperature
8. 8
   workup.STIRRINGwith stirring over twenty minutes
9. 9
   기타A solid precipitated
10. 10
    여과was collected by filtration
11. 11
    세척washed with of mixture MeOH:water (1:1, 100 mL)
12. 12
    기타dried at 40° C./0 bar in vacuum oven for about 18 hours

실험 절차

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%)

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