Lithium hydroxide, monohydrate → (S)-2-((2R,6R)-2,6-Dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetic acid

Temperature

5 °C

Lithium hydroxide hydrate (8.51 g, 203 mmol) in H2O (270 mL) was added dropwise to a stirred solution of (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl-amino)acetate (27.7 g, 101 mmol) in THF (405 mL) over 65 min, while maintaining an internal temperature<5° C. The reaction mixture was stirred in an ice bath for 40 min and then in a water bath at RT for 5 h. The reaction mixture was partially concentrated to remove the THF and then partitioned between water (250 mL) and DCM (250 mL). The aqueous layer was adjusted to pH=2 with 1 N HCl (205 mL), and then extracted with isopropyl acetate (7×250 mL). The combined extracts were washed with brine (1×600 mL), dried (MgSO4), filtered and concentrated. The resulting viscous oil was treated with toluene (100 mL) and ether (75 mL), evaporated and dried in vacuo to afford Cap-2 (25.8 g, with 0.33 eq. of toluene) as a white foam. Chiral SFC purity>99.9% (Chiralpak AD-H (25×0.46 cm, 5 μm) 5% EtOH in CO2, 3 mL/min, 35° C., 220 nm, 100 bar). HPLC purity 95.6% (Column: Sunfire C8 75×4.6 mm ID; 2.5 μm; 40° C.; Mobile Phase: A=Water w/0.1% Formic Acid; B═CH3CN w/0.1% Formic Acid). LC/MS (ES+) 228.1 (M+H−H2O)+. By 1H-NMR the material contained about 0.33 eq. of toluene. 1H-NMR (400 MHz, CDCl3) δ 5.29 (d, J=8.6 Hz, 1H), 4.46-4.25 (m, 2H), 3.82 (dd, J=9.7, 5.9 Hz, 1H), 3.74 (s, 3H), 2.46-2.30 (m, 1H), 1.76-1.55 (m, 2H), 1.51-1.35 (m, 1H), 1.29 (d, J=6.8 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.18-1.06 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 174.1, 156.7, 68.3, 64.4, 57.5, 52.2, 35.8, 32.6, 30.3, 21.6, 16.7.

1. waitin a water bath at RT for 5 h
2. concentrationThe reaction mixture was partially concentrated
3. customto remove the THF
4. custompartitioned between water (250 mL) and DCM (250 mL)
5. extractionextracted with isopropyl acetate (7×250 mL)
6. washThe combined extracts were washed with brine (1×600 mL)
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated
10. additionThe resulting viscous oil was treated with toluene (100 mL) and ether (75 mL)
11. customevaporated
12. customdried in vacuo

ORD record

ord-d057a35b7f44447cad02e06ff2976eca

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08552047B2