Hydrochloric Acid → (1S,2S,5R,6S)-2-[[(2S)-2-Aminopropanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid dihydrate

HRID 2037302Notes

Reaction equation

HRID 2037302 reaction equation
[OH2:1].C([O:6]C([NH:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:20][CH2:19]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12])=O)(C)(C)C.Cl.[OH-].[Na+]>C(O)C>[OH2:6].[OH2:1].[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:19][CH2:20]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 14798Sodium HydroxideHCID 86691269(1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid

Product 1

HCID 71695829(1S,2S,5R,6S)-2-[[(2S)-2-Aminopropanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid dihydrateYield 81.6%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
25 °C

Procedure

Charge water (32 mL, 8 volumes) and (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (3.99 g, 10.4 mmol) to a reactor followed by concentrated HCl (1.80 mL, 2.0 equivalents) and then heat the reaction to 45-55° C. until the reaction complete (monitor by HPLC). Cool the reaction mixture to 20-30° C. and adjust the pH to approximately 3.6 with 5 N NaOH. Add absolute ethanol (15 mL, 3.75 volumes) over at least 30 minutes between 20-30° C. to the resulting slurry. Allow the resulting slurry to granulate between 20-30° C. for at least 12 hours. Cool the mixture between −5-5° C. and allow it to granulate for at least 60 minutes. Filter the resulting solids and wash the cake with 30% absolute ethanol in water (2×9 mL, 2.25 volumes). Dry the solids under reduced pressure at 35° C. for at least 12 hours, and then allow the resulting solids to stay on the balance until no additional weight change for at least 2 hours to provide the title compound as a white solid (2.71 g, 8.51 mmol, 81.6%). 1H NMR (D2O, 400 MHz): δ 3.90 (q, J=7.2, 1H), 2.56 (dd, J=6.5, 2.9, 1H), 1.74-1.66 (m, 2H), 1.62-1.54 (m, 2H), 1.39 (d, J=7.1, 3H), 0.61-0.56 (m, 1H), 0.55-0.49 (m, 1H), 0.40-0.30 (m, 2H).

Workup

  1. temperatureheat
  2. customthe reaction to 45-55° C. until the reaction complete (monitor by HPLC)
  3. waitto granulate between 20-30° C. for at least 12 hours
  4. temperatureCool the mixture between −5-5° C.
  5. waitto granulate for at least 60 minutes
  6. filtrationFilter the resulting solids
  7. washwash the cake with 30% absolute ethanol in water (2×9 mL, 2.25 volumes)
  8. customDry the solids under reduced pressure at 35° C. for at least 12 hours
  9. waitto stay on the balance until no additional weight change for at least 2 hours

Sources & evidence

ORD record
ord-6dd622919d9e48629f8a3e88fc6e0113
Source dataset
uspto-grants-2013_11
Patent number
US08575214B2

Reaction notes

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