Ethanol → Alvimopan dihydrate

HRID 1647765Notes

Reaction equation

HRID 1647765 reaction equation
CC(C)C[O:4][C:5](=[O:34])[CH2:6][NH:7][C:8](=[O:33])[C@H:9]([CH2:17][N:18]1[CH2:23][CH2:22][C@:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)([CH3:24])[C@@H:20]([CH3:32])[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([OH:38])C.[OH-:39].[Na+]>O>[OH2:4].[OH2:38].[OH:31][C:27]1[CH:26]=[C:25]([C@:21]2([CH3:24])[CH2:22][CH2:23][N:18]([CH2:17][C@H:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([NH:7][CH2:6][C:5]([OH:34])=[O:4])=[O:33])[CH2:19][C@@H:20]2[CH3:32])[CH:30]=[CH:29][CH:28]=1.[OH2:39].[OH:31][C:27]1[CH:26]=[C:25]([C@:21]2([CH3:24])[CH2:22][CH2:23][N:18]([CH2:17][C@H:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([OH:33])=[O:38])[CH2:19][C@@H:20]2[CH3:32])[CH:30]=[CH:29][CH:28]=1

Participants

6

Reactant 3

HCID 702EthanolHCID 14798Sodium HydroxideHCID 9871231HCID 9871231, compound

Product 2

HCID 5488547Alvimopan dihydrateHCID 675427611-Piperidinepropanoic acid, 4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-, hydrate (1:1), (αS,3R,4R)-

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A solution of a compound of Example 1 (12.5 g, 0.026 mol, 1.0 equiv) in 315 mL of 3A ethanol was charged to round bottom flask. Water (74.0 mL) was added to the mixture. Aqueous solution of sodium hydroxide ((1.0 M) 0.077 mol, 3.0 equiv) was added dropwise over 10-15 minutes at 25°-30° C. The solution was stirred and then filtered. The pH of the solution was adjusted from 12.50 to 6.00 by addition of concentrated hydrochloric acid. The solution was seeded and (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl]amino]acetic acid began to precipitate within 10-15 minutes. The crystallization was stirred at 25° C. for two hours and then (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl] amino]acetic acid was filtered under slight suction to a wet cake. The crystals were slurried with 60 mL of water and filtered to a hard cake under suction. The crystals were dried to the dihydrate overnight (16 hours) under open air at 33% relative humidity at 25° C. by pulling air over the product in the filter funnel under slight suction. The title compound was isolated in 85% yield (10.2 g), from (αS,3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl -α-(phenylmethyl)-1-piperidine propanoic acid monohydrate, as white crystals with a sharp melting point of 208° C. The sample was analyzed using x-ray powder diffraction.

Workup

  1. filtrationfiltered
  2. additionThe pH of the solution was adjusted from 12.50 to 6.00 by addition of concentrated hydrochloric acid
  3. customto precipitate within 10-15 minutes
  4. customThe crystallization
  5. stirringwas stirred at 25° C. for two hours
  6. filtration(2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl] amino]acetic acid was filtered under slight suction to a wet cake
  7. filtrationfiltered to a hard cake under suction
  8. dry with materialThe crystals were dried to the dihydrate overnight (16 hours) under open air at 33% relative humidity at 25° C.

Sources & evidence

ORD record
ord-37827006c8484f13ab7dccc62746fef7
Source dataset
uspto-grants-1995_07
Patent number
US05434171

Reaction notes

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