Lithium hydroxide, monohydrate → AM-103 free acid

HRID 2366094Notes

Reaction equation

HRID 2366094 reaction equation
C([O:3][C:4](=[O:46])[C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=3)=[CH:32][CH:31]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)C.O[Li].O>C1COCC1.CO.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=3)=[CH:34][CH:35]=1)[C:7]([CH2:6][C:5]([CH3:45])([CH3:44])[C:4]([OH:46])=[O:3])=[C:15]2[S:16][C:17]([CH3:20])([CH3:19])[CH3:18]

Participants

4

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 162262693-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester

Product 1

HCID 16224456AM-103 free acidYield 94.1%

Reagents, catalysts & solvents 1

HCID 21892291Methanol tetrahydrofuran waterSolvent

Conditions

Temperature
55 °C

Procedure

3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid ethyl ester (693 g, 1.086 mol) was added to a reactor containing 6.91 L of THF/MeOH/water in a 2:1:1 ratio and stirred. LiOH.H2O (54.75 g, 1.3 mol) was added to the reactor and the mixture was heated to between 50 to 60° C. and stirred overnight (about 12 hours). TLC analysis (EtOAc/Petroleum ether, 1/5) showed the reaction had reached completion. The THF/MeOH/water solvent mixture was removed in vacuo and about 6 liters of water was added. The organic impurities were removed with extraction using EtOAc in 1.5 liter batches. The pH of the aqueous layer was adjusted to a pH of between 2 and 3 using 3N HCl. The compound was extracted twice with dichloromethane in 6 liter batches. Following a water wash and a brine wash, the organic layer was dried over Na2SO4. The solid was filtered and the organic layer was concentrated in vacuo to afford 623 g of desired product in 94% yield.

Workup

  1. stirringstirred overnight (about 12 hours)
  2. customThe THF/MeOH/water solvent mixture was removed in vacuo and about 6 liters of water
  3. additionwas added
  4. customThe organic impurities were removed with extraction
  5. extractionThe compound was extracted twice with dichloromethane in 6 liter batches
  6. washwash
  7. washa brine wash
  8. dry with materialthe organic layer was dried over Na2SO4
  9. filtrationThe solid was filtered
  10. concentrationthe organic layer was concentrated in vacuo

Sources & evidence

ORD record
ord-fa578f0353774f919dd10a60a34b6219
Source dataset
uspto-grants-2014_04
Patent number
US08697730B2

Reaction notes

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