Hydrochloric Acid → HCID 13732955, compound

Temperature

80 °C

A mixture of 10.44 g of 3-hydroxy-spiro[benzofuran-2(3H),1'-cycloheptane], 2.3 g of sodium hydride and 115 ml of dry dimethylformamide (DMF) was stirred under nitrogen and heated to 80° C. to pre-form the alkoxide, then cooled back to room temperature and treated with a solution of 11.63 g of distilled dimethylaminopropyl chloride in 115 ml of DMF. A sustained, mild exotherm was observed. After stirring overnight at room temperature under nitrogen, an additional 5.81 g of dimethylaminopropyl chloride in 115 ml of DMF was added. After 3 hours of further stirring at room temperature, the mixture was worked up by pouring it onto a mixture of 400 ml of crushed ice and 36 ml of concentrated hydrochloric acid, basifying with saturated sodium bicarbonate solution and extracting the product with ether (1×500 ml, 1 x 250 ml). The ether extracts were washed with 250 ml of saturated sodium bicarbonate solution and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded an oil weighing 13.1 g. This material was dissolved in 100 ml of ether and treated with a solution of 3.76 g of maleic acid in 250 ml of ether. The salt of the product separated out as an oil; seeding and scratching caused crystallization to occur. The salt was filtered, washed with ether and dried to afford 12.86 g of a solid, m.p. 82°-90° C. A GC analysis of this material showed it to be 94% product. Another 0.3 g of solid product had precipitated out of the filtrate from the crude salt; the solids were combined, suspended in water, and the free base was regenerated by addition of saturated sodium bicarbonate solution. Extraction with ether afforded 8.58 g of an oil. This material was purified by preparative HPLC, using two columns and 5% methanol/dichloromethane as a solvent. 6.89 g of a purified product was obtained as a mixture of solid and oil. The solid was filtered off, and the material from the filtrate was dissolved in ether and treated with a solution of 2.41 g of fumaric acid in a mixture of ether (200 ml) and ethanol (75 ml). The resultant solution was concentrated in vacuo to an oil. Trituration with 100 ml of ether and seeding caused solidification to occur. The solid was filtered, washed with ether and dried to afford 6.63 g of colorless solid, m.p. 111°-117° C. The crude salt was recrystallized by dissolving it in 30 ml of methanol, filtering, and diluting with ether until just faintly turbid (200 ml of ether). After seeding and stirring for 2 hours at room temperature, the recrystallized solid was filtered, washed with ether and dried to afford 4.16 g of crystalline solid, m.p. 119°-120° C.

1. temperaturecooled back to room temperature
2. stirringAfter stirring overnight at room temperature under nitrogen
3. stirringAfter 3 hours of further stirring at room temperature
4. additionby pouring it
5. extractionextracting the product with ether (1×500 ml, 1 x 250 ml)
6. washThe ether extracts were washed with 250 ml of saturated sodium bicarbonate solution
7. dry with materialdried overnight over anhydrous sodium sulfate
8. filtrationFiltration and concentration in vacuo
9. customafforded an oil
10. customThe salt of the product separated out as an oil
11. customcrystallization
12. filtrationThe salt was filtered
13. washwashed with ether
14. customdried

ORD record

ord-6a6a98eb3e7d4c0e930781ddfc44b927

Source dataset

uspto-grants-1986_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04623657