反应详情

温度

40 °C

Example 1, 2nd Alternative Preparation, Step 1a: To a hydrogenator were charged ethyl (7R,8S)-8-((S)-1-phenyl-ethylamino)-1,4-dioxa-spiro [4.5]decane-7-carboxylate 4-toluenesulfonate salt 1A (1417 g, 2.8 moles, c.f.: WO2004098516, prepared analogous to U.S. Pat. No. 6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40° C. until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ˜2 L until most ethanol was removed (<0.5%) and residual moisture content was <1,000 ppm. Batch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate. The mixture was heated to 80° C. until clear, then cooled 65°-70° C. Seed crystals of 1 (5 g) were added and the batch was cooled to 50° C. over 2 hours, then further cooled to 20° C. over 4 hours and held for ˜10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vacuum at ˜35° C. until volatiles were reduced below ˜1% (LOD). Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300 MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H,), 3.20-3.13 (m, 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm×150 mm i.d., 3.5 μm particle size, 0.05% NH40H (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).

1. customExample 1, 2nd Alternative Preparation, Step 1a
2. custom: WO2004098516, prepared analogous to U.S
3. customwas consumed (HPLC)
4. temperatureThe suspension was cooled
5. custompurged with nitrogen gas
6. customthe catalyst was removed by filtration while inerted
7. washThe spent catalyst was washed with ethanol (4.3 L)
8. concentrationconcentrated under vacuum to a volume of 2-3 L
9. temperaturewhile maintaining the batch between 40°-60° C
10. additionIsopropyl acetate (5 L) was charged
11. concentrationthe mixture was concentrated to a volume of ˜2 L until most ethanol
12. customwas removed (<0.5%) and residual moisture content
13. additionBatch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate
14. temperatureThe mixture was heated to 80° C. until clear,
15. temperaturethen cooled 65°-70° C
16. additionwere added
17. temperaturethe batch was cooled to 50° C. over 2 hours
18. temperaturefurther cooled to 20° C. over 4 hours
19. filtrationThe resulting slurry was filtered
20. washthe cake was washed with isopropyl acetate (2 L)
21. customThe product was dried under vacuum at ˜35° C. until volatiles