Ammonia → ((1S,2S,4S)-2-Hydroxy-4-hydroxymethyl-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester

HRID 500013Notes

Reaction equation

HRID 500013 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][O:20]CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH2:11][C@H:10]([CH2:9][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)[CH:29]([CH3:31])[CH3:30])[C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:17])[CH3:18])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 222AmmoniaHCID 25517Ammonium ChlorideHCID 5360545SodiumHCID 67304985(2R,3S,5S)-5-((1S,3S)-3-Benzyloxymethyl-1-hydroxy-4-methyl-pentyl)-3-isopropyl-2-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 11678270((1S,2S,4S)-2-Hydroxy-4-hydroxymethyl-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 1 g of the pyrrolidine 8 in 17 mL of THF is cooled to −78° C. and 17 mL of ammonia condensed into the flask. To the mixture is added 0.44 g of Sodium and the resulting dark-coloured mixture stirred over night at −78° C. To the mixture is added 2.6 g of ammonium chloride. The mixture is allowed to warm to r.t. (ammonia evaporates off and unreacted sodium is dissolved) before addition of 40 mL of toluene and 1.9 g of acetic acid. After 10 min 25 mL of water is added and the phases are separated. The aqueous phase is back-extracted with 25 mL of toluene, then the combined organic phases are washed four times with 1:1 water-brine before drying over sodium sulfate and evaporating in vacuum. Purification of the crude oily product (0.86 g) on silica gel, eluting with ethyl acetate-heptane affords e.g. 0.71 g of pure 9a. 1H-NMR (CDCl3, 300K): 6.8 (2H), 6.7 (1H), 4.7 (1H), 4.1 (2H), 3.8 (3H), 3.5-3.7 (5H), 3.4-3.5 (1H), 3.4 (3H), 2.7-2.8 (1H), 2.4-2.5 (3H), 2.0-2.2 (2H), 1.5-1.8 (8H), 1.4 (9H), 0.8-0.9 (12H).

Workup

  1. temperatureto warm to r.t.
  2. custom(ammonia evaporates off and unreacted sodium is dissolved)
  3. additionbefore addition of 40 mL of toluene and 1.9 g of acetic acid
  4. additionAfter 10 min 25 mL of water is added
  5. customthe phases are separated
  6. extractionThe aqueous phase is back-extracted with 25 mL of toluene
  7. washthe combined organic phases are washed four times with 1:1 water-brine
  8. dry with materialbefore drying over sodium sulfate
  9. customevaporating in vacuum
  10. customPurification of the crude oily product (0.86 g) on silica gel
  11. washeluting with ethyl acetate-heptane

Sources & evidence

ORD record
ord-ba426b96a45a45928f1a4cce984be0b9
Source dataset
uspto-grants-2010_08
Patent number
US07767831B2

Reaction notes

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