Sulfuric Acid → HCID 86686865, compound

Temperature

-20 °C

A 22 L multi-neck reactor equipped with a temperature probe, a nitrogen inlet, a cooling bath and an overhead mechanical stirrer was charged with methanol (2400 mL) and cooled to −20° C. Sulfuric acid (384 mL, 7.22 mol) was charged via an addition funnel over 1 hour. The temperature was maintained at about −25° C. and peaked at −18° C. for ˜5 minutes. Trimethyl orthoformate (906 mL, 8.3 mol) was added over 10 minutes followed by 5-chloro-2,3-dihydro-1H-inden-1-one (17) (600.00 g, 3.61 mol) as a solid. The internal temperature slightly increased by 2° C. Koser's reagent (1553 g, 3.97 mol) was dissolved in methanol (2400 mL) over 20 minutes which was added to the reaction vessel over 1 hour and 15 minutes. The addition was exothermic and the internal temperature was maintained at about −20° C. Upon completion of addition, the dark red solution was stirred at −20° C. for 1 hour, at which point HPLC analysis indicated complete conversion to the desired product. Water (7200 mL) was added in small portions. After the addition of a small amount of water (˜50 mL), the product suddenly precipitated. The agitation became slow and difficult. The mixture was stirred at 0˜10° C. for 1 hour and was filtered through a 3000 mL coarse fritted funnel. The filtration was complete in 2 hours and the cake was rinsed with water (7200 mL) until the pH of the filtrate reached about 5. The wet cake was added back to the reactor and heptane (3000 mL) was added. The mixture was stirred at −20° C. for 1 h and filtered. The cake was rinsed with heptanes (1200 mL) and conditioned for 30 minutes. The wet cake was dried under high vacuum for 3 days to completely remove heptane and reduce the water content to <2%. The material had purities of 99% (AUC by HPLC) and 93 wt % by wt % assay (622.88 g, 88%). 1H NMR (300 MHz, CDCl3, δ): 7.69 (m, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 4.18 (m, 1H), 3.63 (s, 3H), 3.47 (m, 1H) and 2.99 (m, 1H).

1. customA 22 L multi-neck reactor equipped with a temperature probe, a nitrogen inlet, a cooling bath and an overhead mechanical stirrer
2. temperatureThe temperature was maintained at about −25° C.
3. temperatureThe internal temperature slightly increased by 2° C
4. additionwas added to the reaction vessel over 1 hour and 15 minutes
5. additionThe addition
6. temperaturethe internal temperature was maintained at about −20° C
7. additionUpon completion of addition

ORD record

ord-a440ce2f27de4b928cca06cd1ba83a2f

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809356B2