Toluene → Pyrrolidine Cholesterol Phosphoramidite

HRID 2403016Notes

Reaction equation

HRID 2403016 reaction equation
[CH3:1][CH:2]([CH:9]1[C:25]2([CH3:26])[CH:12]([CH:13]3[CH:22]([CH2:23][CH2:24]2)[C:21]2(C)[C:16]([CH2:17]C(OC(=O)NCCCCCC([N:38]4[CH2:42][CH:41](O)[CH:40](C(C5C=CC=CC=5)OC(C5C=CC(OC)=CC=5)C5C=CC(OC)=CC=5)[CH2:39]4)=O)C[CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C1(C)C=CC=CC=1.[C:77]([CH2:79][CH2:80][O:81][P:82]([N:90](C(C)C)C(C)C)N(C(C)C)C(C)C)#N.C(OCC)(=[O:99])C>C(#N)C.ClCCl.CCCCCC>[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[P:82]([O:81][C@H:80]1[CH2:79][CH2:77][C@@:21]2([CH3:20])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:17]1)([NH2:90])[OH:99]

Participants

7

Reactant 4

HCID 1140TolueneHCID 8857Ethyl AcetateHCID 1281532-Cyanoethyl tetraisopropylphosphorodiamiditeHCID 131728221(6-{3-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl Ester

Product 1

HCID 68638832Pyrrolidine Cholesterol PhosphoramiditeYield 84%

Reagents, catalysts & solvents 2

HCID 8058HexaneSolventHCID 21877088Acetonitrile methylene chlorideSolvent

Procedure

Compound 66 (0.15 g, 0.158 mmol) was coevaporated with toluene (5 mL). To the residue N,N-tetraisopropylammonium tetrazolide (0.0089 g, 0.079 mmol) was added and the mixture was dried over P2O5 in a vacuum oven for overnight at 40° C. The reaction mixture was dissolved in the mixture of anhydrous acetonitrile/dichloromethane (2;1, 1 mL) and 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite (0.0714 g, 0.0781 mL, 0.237 mmol) was added. The reaction mixture was stirred at ambient temperature for overnight. The completion of the reaction was ascertained by TLC (1;1 ethyl acetate:hexane). The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (10 mL) and washed with 5% NaHCO3 (4 mL) and brine (4 mL). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting mixture was chromatographed (50:49:1, EtOAc:Hexane:triethlyamine) to afford 67 as white foam (0.152 g, 84%).

Workup

  1. dry with materialthe mixture was dried over P2O5 in a vacuum oven for overnight at 40° C
  2. additionwas added
  3. customThe solvent was removed under reduced pressure
  4. dissolutionthe residue was dissolved in ethyl acetate (10 mL)
  5. washwashed with 5% NaHCO3 (4 mL) and brine (4 mL)
  6. dry with materialThe ethyl acetate layer was dried over anhydrous Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customThe resulting mixture was chromatographed (50:49:1, EtOAc:Hexane:triethlyamine)

Sources & evidence

ORD record
ord-9fa83ee6ff604e4fa531bbab2a3393cd
Source dataset
uspto-grants-2014_08
Patent number
US08796436B2

Reaction notes

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