2-Hydroxy-p-toluic acid → Benzoic acid, 2-hydroxy-4-methyl-, methyl ester

Temperature

60 °C

Iodomethane (22.6 mL, 362 mmol, 1.1 equiv) was added to a suspension of 4-methylsalicylic acid (50.0 g, 329 mmol, 1 equiv) and lithium carbonate (26.8 g, 362 mmol, 1.1 equiv) in dimethylformamide (450 mL) at 23° C. The reaction flask was heated in an oil bath at 60° C. After 3.5 h, the warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (800 mL). The organic layers were combined. The combined solution was washed sequentially with water (2×500 mL) then saturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. A small sample of the product (˜50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes) and was characterized by 1H NMR, 13C NMR, IR, and HRMS. The balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification. TLC: (2% ethyl acetate-hexanes) Rf=0.15 (CAM); 1H NMR (500 MHz, CDCl3) δ: 10.70 (s, 1H), 7.70 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 6.69 (d, 1H, J=7.7 Hz), 3.92 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 170.5, 161.5, 147.0, 129.6, 120.4, 117.7, 109.8, 52.0, 21.8; FTIR (neat), cm−1: 3186 (m), 2956 (m), 1672 (s), 1623 (m), 1579 (m), 1504 (m), 1441 (s), 1338 (s), 1298 (s), 1250 (s), 1215 (s), 1157 (s), 1096 (s), 906 (s), 780 (s); HRMS (ESI): Calcd for (C9H10O3+H)+ 167.0703, found 167.0698.

1. customthe warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL)
2. customThe layers were separated
3. extractionThe aqueous layer was extracted with ethyl acetate (800 mL)
4. washThe combined solution was washed sequentially with water (2×500 mL)
5. dry with materialsaturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate
6. filtrationThe dried solution was filtered
7. concentrationthe filtrate was concentrated
8. customA small sample of the product (˜50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes)
9. customThe balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification

ORD record

ord-21bb1a820fe542bab570bcb3f7e9f075

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09102697B2