Methanesulfonic Acid → benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate

HRID 2242329Notes

Reaction equation

HRID 2242329 reaction equation
C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]1=[O:36])=O)(C)(C)C.[CH3:37]S(O)(=O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)C.C(O)(=O)C.C(N(CC)CC)C>[C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:18])[CH3:19])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:21]1=[O:36])(=[O:5])[CH3:37]

Participants

9

Reactant 4

HCID 6395Methanesulfonic AcidHCID 7918Acetic AnhydrideHCID 14798Sodium HydroxideHCID 86618127benzyl {(S)-1-[(1S,2R,4R)-2-tert-butoxycarbonylamino-4-(isopropyl-methyl-amino)-cyclo-hexyl]-2-oxo-pyrrolidin-3-yl}-carbamate

Product 1

HCID 44185160benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 1140TolueneSolvent2×HCID 3776IsopropanolSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
60 °C

Procedure

Example 1, Alternative Preparation, Step 5: The tert-Butyl carbamate 9 (50 g) was dissolved in Toluene (500 mL) and i-PrOH (150 mL). The resulting solution was then heated to 60° C. Methanesulfonic acid (19.6 mL) was added below 65° C. Upon reaction completion (HPLC), the mixture was cooled to RT and triethylamine (69.4 mL) added slowly below 25° C. Acetic anhydride was then added below 25° C. After 1 h acetic acid (250 mL) was added below 25° C. The toluene phase was discarded and 2-methyl-THF (500 mL) was added to the aqueous phase. The mixture was stirred vigorously and basified with NaOH (25% aqueous solution) to pH 12. The aqueous phase was discarded and the organic layer was washed with brine (250 mL). The organic layer was concentrated under reduced pressure and continuously replaced with i-PrOH. The solution was cooled and filtered to provide benzyl {(S)-1-[(1S,2R,4R)-2-acetylamino-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamate 10 in i-PrOH solution which was used directly in the hydrogenation.

Workup

  1. customExample 1, Alternative Preparation, Step 5
  2. customUpon reaction completion (HPLC)
  3. temperaturethe mixture was cooled to RT
  4. washthe organic layer was washed with brine (250 mL)
  5. concentrationThe organic layer was concentrated under reduced pressure
  6. temperatureThe solution was cooled
  7. filtrationfiltered

Sources & evidence

ORD record
ord-02984adb9dd341c1b9e446115eaa0b01
Source dataset
uspto-grants-2010_03
Patent number
US07671062B2

Reaction notes

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