Реакция #46945

Уравнение реакции

1-(2-hydroxy-5-methoxy-phenyl)-ethanone

1-(2-hydroxy-5-methoxy-phenyl)-ethanone

MeMgCl

MeMgCl

2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol

HCl

→

2-isopropyl-4-methoxyphenol

Растворители

water

THF

THF

THF

2-butanone

Условия реакции

Обработка

1. 1
   Другоеdid not exceed 25 degrees C
2. 2
   ТемператураThe reaction mixture was cooled
3. 3
   workup.ADDITIONwas added
4. 4
   Температураwhile maintaining the reaction temperature at 25° C
5. 5
   Фильтрацияfiltered through a bed of Celite
6. 6
   Другоеto remove
7. 7
   ПромывкаThe filter cake was rinsed with EtOAc
8. 8
   Другоеthe combined filtrate was separated
9. 9
   ПромывкаThe organic phase was washed with water
10. 10
    Концентрированиеconcentrated by distillation
11. 11
    Другоеto provide an oil
12. 12
    КонцентрированиеA 161.8 g aliquot of the solution was concentrated under vacuum

Методика

To a cooled solution of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone (10.0 kg) in 79.0 kg of THF was gradually added 46.4 kg of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours, at which point HPLC analysis showed more than 98% conversion of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone to 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (not shown in Scheme D). To the stirred solution was then added 10% palladium on carbon (1.02 kg, 50% water wet) suspended in 3.5 Kg of THF. The reaction mixture was cooled and placed under a hydrogen atmosphere at 5 psig, and concentrated HCl (19.5 kg) was added while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 44.4 kg water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated by distillation to provide an oil. This oil was dissolved in 2-butanone (20.4 kg) and the crude solution was employed directly in the next step. A 161.8 g aliquot of the solution was concentrated under vacuum to provide 49.5 g of 2-isopropyl-4-methoxyphenol as an oil, projecting to 10.4 kg crude contained product in the bulk 2-butanone solution. 1H nmr (DMSO) delta: 1.14 (d, 6H, J=6.9 Hz), 3.18 (septet, 1H, J=6.9 Hz), 3.65 (s, 3H), 6.56, (dd, 1H, J=8.6 Hz, 3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 6.69 (d, 1H, 8.6 Hz).

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