1-Hydroxybenzotriazole → Tert-butyl(2S,5R)-2-{4-[(3-cyclopropyl-1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl)carbonyl]-benzyl}-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate

HRID 1804656Notes

Reaction equation

HRID 1804656 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([C:26]([C:25]4[CH:29]=[CH:30][C:22]([CH2:21][C@@H:9]5[CH2:10][CH2:11][C@H:12]([C@H:13]([OH:20])[C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:8]5[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:23][CH:24]=4)=[O:27])[CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 670587074-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acidHCID 670606873-Cyclopropyl-2-oxa-8-azaspiro[4.5]decan-1-one

Product 1

HCID 67972721Tert-butyl(2S,5R)-2-{4-[(3-cyclopropyl-1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl)carbonyl]-benzyl}-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylateYield 58.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 0.16 g (0.39 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 2 ml anhydrous DMF at ambient temperature was added 0.14 g (0.58 mmol) 3-cyclopropyl-2-oxa-8-azaspiro[4.5]decan-1-one from the above, followed by 0.12 g (0.58 mmol) EDCl, 0.08 g (0.58 mmol) HOBt, and 0.34 ml (1.94 mmol) N,N-diisopropylethylamine. The solution was stirred for 2 h at ambient temperature. The solution was poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were extracted with brine (20 ml). It was dried over magnesium sulfate and concentrated. The residue was purified using a Biotage Horizon® system (50-100% ethyl acetate/hexanes mixture) to give 0.135 g of the title compounds as a mixture of diastereomers in a 50:50 ratio. The two diastereomers were separated by chiral HPLC employing a Daicel CHIRALPAK® OD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is colorless solid (0.030 g, 16%). LC/MS 589.3 (M+1). The second eluting diastereomer was designated as Isomer 2 and is a colorless solid (0.025 g, 13%). LC/MS 589.3 (M+1).

Workup

  1. extractionextracted with ethyl acetate (2×20 ml)
  2. extractionThe combined organic layers were extracted with brine (20 ml)
  3. dry with materialIt was dried over magnesium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified

Sources & evidence

ORD record
ord-32e6d63966ef4d068a24324bf8c4b27b
Source dataset
uspto-grants-2013_01
Patent number
US08354403B2

Reaction notes

Loading…