1,2-Dichloroethane → Tert-butyl (2R,5S)-2-[(R)-hydroxy(phenyl)methyl]-5-(4-{[10-(pyridin-2-ylmethyl)-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl]carbonyl}benzyl)pyrrolidine-1-carboxylate

HRID 1804653Notes

Reaction equation

HRID 1804653 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]([OH:28])=O)=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@H]([C@H]2CC[C@@H](CC3C=CC(C(N4CCC(C5N=CSC=5)CC4)=O)=CC=3)[NH:40]2)O)C=CC=CC=1.[CH:64]1[CH:69]=[N:68][C:67]2N(O)N=N[C:66]=2[CH:65]=1.[CH2:74](Cl)[CH2:75]Cl.C[CH2:79][N:80]([CH:84]([CH3:86])[CH3:85])[CH:81]([CH3:83])[CH3:82]>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:40]3[CH:83]4[CH2:74][CH2:75][CH:85]3[CH:84]3[N:80]([CH2:79][C:67]5[CH:66]=[CH:65][CH:64]=[CH:69][N:68]=5)[CH:81]4[CH2:82][CH2:86]3)=[O:28])=[CH:29][CH:30]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 50997280(R)-phenyl[(2R,5S)-5-(4-{[4-(1,3-thiazol-4-yl)-piperidin-1-yl]carbonyl}benzyl)pyrrolidine-2-yl]methanolHCID 670587074-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid

Product 1

HCID 67986715Tert-butyl (2R,5S)-2-[(R)-hydroxy(phenyl)methyl]-5-(4-{[10-(pyridin-2-ylmethyl)-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl]carbonyl}benzyl)pyrrolidine-1-carboxylateYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 4-{((2s,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}benzoic acid (50 mg, 0.13 mmol) and the title compound from Step B above (37 mg, 0.13 mmol) in 1.5 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.24 mL, 0.13 mmol) followed by EDC (46 mg, 0.26 mmol) and DIEA (17 μL, 0.13 mmol). The resulting mixture was stirred at RT under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (1000 uM) eluting with 5% MeOH in dichloromethane to afforded the product (32 mg, 42%). ESI-MS calculated for C38H46N4O4: Exact Mass: 622.35. Found 623.38 (MH)+ and 645.33 (MNa)+.

Workup

  1. washThe mixture was washed with water
  2. extractionextracted with dichloromethane (2×5 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuum
  6. customThe residue was purified by preparative TLC plate (1000 uM)
  7. washeluting with 5% MeOH in dichloromethane

Sources & evidence

ORD record
ord-9238bad517944318bc5e049652450a52
Source dataset
uspto-grants-2013_01
Patent number
US08354403B2

Reaction notes

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