4-Chlorobenzoic Acid → 4-Chloro-2-methylbenzoic acid

Temperatur

-50 °C

In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at 0° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g).

1. customIn a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2
2. temperatureThe solution was cooled to −90° C.
3. temperatureto maintain the temperature at −90° C
4. stirringThe reaction mixture was stirred at −90° C. for 1 h
5. temperatureto warm-up to −80° C.
6. additionCH3l (80 mL, 1.28 moles) was added very slowly
7. stirringThe reaction mixture was stirred for 10 min at 0° C.
8. customquenched slowly with H2O (600 mL)
9. temperatureto warm-up to room temperature
10. customThe aqueous layer was separated
11. washwashed with Et2O (2×500 mL)
12. temperaturewhile cooling in an ice bath
13. temperaturecooling
14. customcrystallization of the desired product
15. dry with materialThe crude product was dried under vacuum and over anhydrous P2O5
16. customre-crystallized from hot toluene (700 mL)

ORD-Eintrag

ord-c1ce83ec94da48adbb69de23b85a3d02

Quelldatensatz

uspto-grants-2004_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06794404B2