ethyl (1R,2S,5R)-2-((3S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate → (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid

HRID 2242325Notes

Reaction equation

HRID 2242325 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([O:30]CC)=[O:29])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([OH:30])=[O:29])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

3

Reactant 1

HCID 24948375ethyl (1R,2S,5R)-2-((3S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate

Product 1

HCID 24948561(1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acidYield 840.6%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Conditions

Temperature
55 °C

Procedure

Example 1, Alternative Step 9f: The aminoester 6 (9.76 g, 2.12 mmol) was dissolved in 2N HCl (80 mL), then heated to ˜55° C. under inert atmosphere. The reaction was stirred for 20 h, then cooled to room temperature. The reaction solution was washed twice with toluene (25 mL portions), neutralized to pH 6-7 by the addition of KOH pellets, then extracted eight times with methylene chloride (100 mL portions). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to 50 mL total volume. The concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring. The resulting white slurry was stirred at ambient temperature for Ih, then cooled to 0° C. and stirred for 1 h. The product was filtered, and washed twice with methyl tert-butyl ether (25 mL portions). Water from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL). The product was dried under reduced pressure to provide (1R,2S,5R)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylic acid 7, (7.69 g, 84% yield) as a white foam. 1H-NMR: (400 MHz, 50° C., CDCl3) δ 7.44-7.32 (m, 5H), 6.10 (broad s, 1H), 5.19 (app s, 2H), 4.42 (dd, J=15.6, 7.8 Hz, 1H), 4.29-4.23 (m, 1H), 3.68-3.60 (m, 2H), 3.33-3.27 (m, 2H), 3.20 (broad s, 1H), 2.99 (broad s, 1H), 2.51 (s, 3H), 2.49-2.45 (m, 3H), 2.33-2.31 (m, 1H), 2.00 (ddd, J=9.0, 8.6, 3.9 1H), 1.95-1.78 (m, 2H), 1.36-1.21 (m, 6H). LCMS: m/z 432.20 [Calc: C23H34N3O5 432.25].

Workup

  1. temperaturecooled to room temperature
  2. washThe reaction solution was washed twice with toluene (25 mL portions)
  3. additionneutralized to pH 6-7 by the addition of KOH pellets
  4. extractionextracted eight times with methylene chloride (100 mL portions)
  5. dry with materialThe combined extracts were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure to 50 mL total volume
  8. additionThe concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring
  9. stirringThe resulting white slurry was stirred at ambient temperature for Ih
  10. temperaturecooled to 0° C.
  11. stirringstirred for 1 h
  12. filtrationThe product was filtered
  13. washwashed twice with methyl tert-butyl ether (25 mL portions)
  14. customWater from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL)
  15. customThe product was dried under reduced pressure

Sources & evidence

ORD record
ord-caf6fb14802d4be9b598fd2fc6e39984
Source dataset
uspto-grants-2010_03
Patent number
US07671062B2

Reaction notes

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