Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate → tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R)-7-(cyclopropylsulfanyl)-14-hydroxy-4,17,20-trimethyl-3,12-dioxo-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}-4-fluoroisoquinolin-1-yl)carbamate

HRID 708816Notes

Reaction equation

HRID 708816 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([S:83][CH:84]2[CH2:86][CH2:85]2)=[C:33]([CH2:35][N:36]([CH3:82])[C:37]([CH:39]([NH:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[C:62]([N:66]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[N:61][CH:60]=[C:59]3[F:81])[C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([CH2:47][CH:48]([OH:53])[CH2:49][C:50]([OH:52])=O)=[C:42]([CH3:54])[CH:41]=2)=[O:38])[CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl.CN(C=O)C>[C:77]([O:76][C:74]([N:66]([C:62]1[C:63]2[C:58](=[CH:57][C:56]([NH:55][C@H:39]3[C:37](=[O:38])[N:36]([CH3:82])[CH2:35][C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][C:32]=4[S:83][CH:84]4[CH2:85][CH2:86]4)[NH:28][C:50](=[O:52])[CH2:49][CH:48]([OH:53])[CH2:47][C:43]4[C:42]([CH3:54])=[CH:41][C:40]3=[CH:45][C:44]=4[CH3:46])=[CH:65][CH:64]=2)[C:59]([F:81])=[CH:60][N:61]=1)[C:67](=[O:68])[O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:75])([CH3:78])([CH3:79])[CH3:80]

Participants

6

Reactant 2

HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 1180928014-{4-[({[5-Amino-2-(cyclopropylsulfanyl)phenyl]methyl}(methyl)carbamoyl)[(1-{bis[(tert-butoxy)carbonyl]amino}-4-fluoroisoquinolin-6-yl)amino]methyl]-2,6-dimethylphenyl}-3-hydroxybutanoic acid

Product 1

HCID 118098686tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R)-7-(cyclopropylsulfanyl)-14-hydroxy-4,17,20-trimethyl-3,12-dioxo-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}-4-fluoroisoquinolin-1-yl)carbamateYield 32.6%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of BOP (234 mg, 0.529 mmol), TEA (0.074 mL, 0.529 mmol) and DMAP (129 mg, 1.058 mmol) in dichloromethane (10 mL) and DMF (10 mL) was added 2E in dichloromethane (10 mL) via a syringe pump over 10.0 h. The reaction was continued at rt for 4 h, quenched by water and extracted by EtOAc (×3). The combined organics were washed by brine, dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 10 min using a 4 g silica gel cartridge) to give a mixture of diastereoisomers (92 mg, 43% yield). The diastereoisomers were separated to give 2F (30 mg, 0.037 mmol, 32.6% yield) using a R,R-Welko-O 1 column (21.1 mm×250 mm, 10 micron, Regis Technologies, Inc.). MS (ESI) m/z: 814.7 (M+H)+.

Workup

  1. customquenched by water
  2. extractionextracted by EtOAc (×3)
  3. washThe combined organics were washed by brine
  4. dry with materialdried with Na2SO4
  5. concentrationconcentrated
  6. customThe crude product was purified by flash chromatography (loading in chloroform
  7. wait0% to 100% ethyl acetate in hexane over 10 min using
  8. customa 4 g silica gel cartridge) to give
  9. additiona mixture of diastereoisomers (92 mg, 43% yield)
  10. customThe diastereoisomers were separated

Sources & evidence

ORD record
ord-8920ab6ed5a841ef8b4361aa3c6bce93
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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