Ammonium Chloride → (2S,3aR,7aS)-Ethyl 1-((S)-1-phenylethyl)octahydro-1H-indole-2-carboxylate

Temperature

20 °C

1.18 L of Anhydrous tetrahydrofuran was added to 2 L reactor, reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. With mixing, 60.4 g of sodium t-butoxide (0.628 mol, 1.2 equiv.) was added and the mixture was cooled to below 10° C. temperature. During this period, the solids were dissolved to form an slightly hazy solution. To this mixture, a solution of 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (14, 0.524 mol, 1.0 equiv. based on HCl salt 10) in 297 mL of anhydrous tetrahydrofuran was added over a period of NLT 30 min, while maintaining the temperature below 10° C. The reaction mixture was warmed to 20±3° C. and mixed for NLT 3 h under nitrogen atmosphere. The reaction was then quenched using a solution of 50.3 g of ammonium chloride (0.942, 1.8 equiv.) in 267 mL of water, slowly. The phases were allowed to separate and the upper tetrahydrofuran layer was separated and concentrated on a rotary evaporator at NMT 50 temperature to an orange colored product residue. The lower aqueous layer was extracted with 2×495 mL of heptanes. The heptanes extracts were combined with the concentrated product residue and washed with 2×495 mL of 3.5 M aqueous sodium chloride solution. The heptanes extract was dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator at NMT 70° C. temperature under vacuum. The resulting oil was further dried overnight under high vacuum to afford 124.3 g of crude (2S,3aR,7aS)-ethyl 1-((S)-1-phenylethyl)octahydro-1H-indole-2-carboxylate (15) as a major isomer (de: >97%), which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 28.59 min; LC-MS (m/z): 302.2 (M+H)+.

1. customwhich is equipped with mechanical stirrer
2. additionWith mixing
3. temperaturethe mixture was cooled to below 10° C. temperature
4. waitDuring this period
5. dissolutionthe solids were dissolved
6. customto form an slightly hazy solution
7. temperaturewhile maintaining the temperature below 10° C
8. additionmixed for NLT 3 h under nitrogen atmosphere
9. customThe reaction was then quenched
10. customto separate
11. customthe upper tetrahydrofuran layer was separated
12. concentrationconcentrated on a rotary evaporator at NMT 50 temperature to an orange colored product residue
13. extractionThe lower aqueous layer was extracted with 2×495 mL of heptanes
14. washwashed with 2×495 mL of 3.5 M aqueous sodium chloride solution
15. extractionThe heptanes extract
16. customwas dried
17. filtrationfiltered
18. concentrationconcentrated on a rotary evaporator at NMT 70° C. temperature under vacuum
19. customThe resulting oil was further dried overnight under high vacuum

ORD record

ord-bbf888b5581948f6b78f376a3884be56

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08288565B2