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

HRID 2242324Notes

Reaction equation

HRID 2242324 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:20](=O)[CH2:19][C@H:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([NH:33][CH3:34])([CH3:32])[CH3:31].[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl.CCCCCC.CO.CS(C)=O>[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:33]([CH:30]([CH3:32])[CH3:31])[CH3:34])[CH2:19][C@H:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 14798Sodium HydroxideHCID 78485N-MethylisopropylamineHCID 4311764Sodium borohydrideHCID 24948374ethyl (1R,2S)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate

Product 1

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

Reagents, catalysts & solvents 4

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8058HexaneSolvent

Procedure

Example 1, Alternative Step 9e: Cyclohexanone 5 (22.5 g, 0.06M, 1 eq), DMSO (30 mL) and Ti(O-iPr)4 (33.7 mL, 0.11M, 2.04 eq) were placed in a round bottom flask. N-isopropyl-N-methylamine (11.6 mL, 0.11M, 2.0 eq) was then added in one portion. The mixture was left to stir for 30 mins at room temperature before being cooled to <3° C. in ice/water. MeOH (30 mL) was then added followed by the portionwise addition of NaBH4 (4.33 g, 0.11M, 2.04 eq)—temperature kept <8° C. 30 mins after the addition was completed the reaction mass was diluted with methylene chloride (300 mL) and then NaOH (1N, 40 mL). The resulting slurry was filtered through Celite, and the cake washed with methylene chloride (100 mL). The resulting liquor was concentrated under reduced pressure and the residue dissolved in EtOAc (500 mL). This solution was extracted with 1N HCl (2×400 mL), the combined aqueous layers were then basified with Na2CO3. Extraction with EtOAc (4×250 mL) provided a clear and colorless organic phase which was dried over Na2SO4 and concentrated to give a white powder (24.6 g, 96%, 7:1 d.r.). This material was then slurried overnight in hexane (670 mL). The solid was isolated by filtration and dried under reduced pressure to give ethyl (1R,2S,5R)-2-((3S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 as a while solid (20.9 g, 81%, 24:1 d.r.). 1H-NMR: (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.55 (d, J 4.5, 1H), 5.10 (s, 2H), 4.42 (q, J 4.5, 1H), 4.23-4.12 (m, 1H), 4.08 (dq, J 10.5, 7.0, 1H), 4.02 (dq, J 10.5, 7.0, 1H), 3.84 (t, J 9.0, 1H), 3.46-3.36 (m, 1H), 3.04 (septet, J 6.5, 1H), 2.86-2.80 (m, 1H), 2.63-2.48 (m, 2H), 2.17 (s, 3H, Me), 2.10-1.63 (m, 7H), 1.22 (t, J 7.0, 3H), 1.00 (d, J 6.5, 3H), 0.97 (d, J 6.5, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.01M NH4OAc (MeOH:water 20:80) to 0.01M NH4OAc (MeOH:water:MeCN 20:5:75) 10 to 100% 15 min gradient. 8.23 (Compound 6), 8.88 (5-epi-Compound 6). HRMS: 460.2798 [Calc: C25H38N3O5 460.2811].

Workup

  1. waitThe mixture was left
  2. customkept <8° C
  3. addition30 mins after the addition
  4. filtrationThe resulting slurry was filtered through Celite
  5. washthe cake washed with methylene chloride (100 mL)
  6. concentrationThe resulting liquor was concentrated under reduced pressure
  7. dissolutionthe residue dissolved in EtOAc (500 mL)
  8. extractionThis solution was extracted with 1N HCl (2×400 mL)
  9. extractionExtraction with EtOAc (4×250 mL)
  10. customprovided a clear and colorless organic phase which
  11. dry with materialwas dried over Na2SO4
  12. concentrationconcentrated
  13. customto give a white powder (24.6 g, 96%, 7:1 d.r.)
  14. customThe solid was isolated by filtration
  15. customdried under reduced pressure

Sources & evidence

ORD record
ord-97372ad79f3c463c9d30296f7fabf5fb
Source dataset
uspto-grants-2010_03
Patent number
US07671062B2

Reaction notes

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