Sodium Hydroxide → 5-Bromo-2-methoxypyridine

Temperature

20 °C

Ethyl acetate (325 kg), sodium acetate (58 kg, 707 mol) and 2-methoxypyridine (68.7 kg, 630 mol) were mixed in a reactor vessel (inner volume 1000 L). To this solution was added dropwise bromine (122.3 kg, 765 mol) over 6.5 hr while keeping the inside temperature from exceeding 10° C. After the dropwise addition, the inside temperature was raised to 20° C. and the mixture was stirred for 5 hr. The ratio of reaction progress at this time point was 73%. Thereafter, the inside temperature was raised to 50° C. and the reaction was continued more for 5 hr. The ratio of reaction progress at this time point was 98%. The reaction mixture was cooled and water (70 kg) was added to the reaction mixture. While keeping the inside temperature from exceeding 5° C., the solution obtained by dissolving sodium hydroxide (46.1 kg) and sodium sulfite (17 kg) in water (200 kg) was added dropwise. The reaction mixture was stood still to allow partitioning. After confirming that the pH of the aqueous layer was not less than 8 and peroxide was absent, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (40 kg), and the extract and the above-mentioned organic layers were combined. The mixture was concentrated under reduced pressure to give crude 5-bromo-2-methoxypyridine (gross: 121.8 kg, net: 110.7 kg, yield 93%). The crude product was purified by distillation under reduced pressure to give 5-bromo-2-methoxypyridine (101.8 kg, yield 86%) having the following analytical data at a purity of not less than 99%.

1. customfrom exceeding 10° C
2. additionAfter the dropwise addition
3. customThe ratio of reaction progress at this time point
4. temperatureThereafter, the inside temperature was raised to 50° C.
5. waitthe reaction was continued more for 5 hr
6. customThe ratio of reaction progress at this time point
7. temperatureThe reaction mixture was cooled
8. customfrom exceeding 5° C.
9. customthe solution obtained
10. additionwas added dropwise
11. customto allow partitioning
12. customthe organic layer was separated
13. extractionThe aqueous layer was extracted with ethyl acetate (40 kg)
14. extractionthe extract
15. concentrationThe mixture was concentrated under reduced pressure
16. customto give crude 5-bromo-2-methoxypyridine (gross: 121.8 kg, net: 110.7 kg, yield 93%)
17. distillationThe crude product was purified by distillation under reduced pressure

ORD record

ord-1186bbf6a673438b960c37f23d44b6b0

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07524967B2