Lithium Hydroxide → HCID 9802192, compound

HRID 2216450Notes

Reaction equation

[Li+].[OH-].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C@H:28]([CH2:33][CH3:34])[C:29]([O:31]C)=[O:30])[CH2:23][CH2:22]2.CCOC(C)=O.CCCCCC>O.CO.C1COCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C@H:28]([CH2:33][CH3:34])[C:29]([OH:31])=[O:30])[CH2:23][CH2:22]2

Participants

Conditions

Temperature: 60 °C

Procedure

To a solution of LiOH (90.4 g, 3.76 mol) in 1.3 L water and 1.3 L MeOH, was added a solution of the ester prepared in Example 11 (325 g, 0.75 mol) in 3.9 L THF at rt. The solution turned cloudy. This mixture was heated at 60° C. (pot temperature) for 4 hours, and TLC (50% EtOAc/hexane) analysis showed ca. 50% conversion. A solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed ca. 85% reaction. Again, a solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed very little starting ester left. After the reaction mixture was cooled to rt, THF and MeOH were removed at a reduced pressure. The residue was diluted with water until the solids dissolved (a total of 60 L of water used). Conc. HCl solution was slowly added to this aqueous solution until pH 2.0–3.0. The solid was collected by filtration, and dried under house vacuum overnight. This solid was stirred with 15 L EtOAc and 2 L of 1N HCl solution for 30 minutes. The EtOAc layer was separated and washed with 1N HCl solution (2×1 L). The organic phase was then washed with water (4×2 L) until pH=5.0–6.0. Under Ar protection, the EtOAc solution was reduced to 2.5 L by normal pressure distillation, then cooled to rt without disturbance. White solid precipitated out. After further cooling in an ice water bath for 2 hours, the solid was filtrated and washed with 500 mL cold EtOAc. After drying under high vacuum at 35° C. to a constant weight, the final product (266 g, 81%, 98% ee,) was collected as a white crystal. 1H NMR (CDCl3) δ 7.82(d, 2H), 7.20(d, 2H), 7.05(d, 1H), 6.75(d, 1H), 6.70(dd, 1H), 4.20(t, 2H), 3.42(q, 1H), 2.95(t, 2H), 2.80(m, 2H), 2.50(m, 1H), 2.35(s, 3H), 2.32(s, 3H), 2.20(m, 1H), 1.90(m, 1H), 1.65(m, 1H), 1.45(m, 1H), 0.90(t, 3H). Chiral purity, 99% ee, [α]D=+16.11(CHCl3), mp 149.5–150.5° C.

Workup

customca. 85% reaction
waitAfter 2 hours
waitleft
temperatureAfter the reaction mixture was cooled to rt
customTHF and MeOH were removed at a reduced pressure
additionThe residue was diluted with water until the solids
dissolutiondissolved (a total of 60 L of water
additionConc. HCl solution was slowly added to this aqueous solution until pH 2.0–3.0
filtrationThe solid was collected by filtration
customdried under house vacuum overnight
customThe EtOAc layer was separated
washwashed with 1N HCl solution (2×1 L)
washThe organic phase was then washed with water (4×2 L) until pH=5.0–6.0
distillationUnder Ar protection, the EtOAc solution was reduced to 2.5 L by normal pressure distillation
temperaturecooled to rt without disturbance
customWhite solid precipitated out
temperatureAfter further cooling in an ice water bath for 2 hours
filtrationthe solid was filtrated
washwashed with 500 mL cold EtOAc
customAfter drying under high vacuum at 35° C. to a constant weight
customthe final product (266 g, 81%, 98% ee,) was collected as a white crystal

Sources & evidence

ORD record: ord-0b1964d5c12d4e57b33729eb134e92a1
Source dataset: uspto-grants-2006_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07112597B2

Reaction notes

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