Lithium Hydroxide → HCID 9802192, compound

HRID 900529Notes

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-9f89eac4f44b4ec18d2673f44ac0fa99
Source dataset: uspto-grants-2008_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07358386B2

Reaction notes

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