反应 #2507849

反应方程式

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

收率 95.4%

溶剂

water

methanol

triethylamine

water

反应条件

后处理

1. 1
   workup.STIRRINGThe resulting red solution was stirred for thirty minutes
2. 2
   温度The solution was then cooled to 0-5° C.
3. 3
   其他did 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
   温度The 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
   其他A solid precipitated
10. 10
    过滤was collected by filtration
11. 11
    洗涤washed with of mixture MeOH:water (1:1, 100 mL)
12. 12
    其他dried at 40° C./0 bar in vacuum oven for about 18 hours

实验过程

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%)

来源