Trifluoroacetic acid → (3-{2-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentylcarbamoyl]-acetylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

HRID 1766831Notes

Reaction equation

HRID 1766831 reaction equation
C(OC(=O)N[C@@H:8]([CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])[C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O.[C:43]([O:47][C:48](=[O:84])[NH:49][C:50]1[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[C:52]([NH:60][C:61](=[O:83])[CH2:62][C:63](=[O:82])[NH:64][C@@H](CNCC2C=CC(C)=CC=2C)[C@@H](O)CCC)[CH:51]=1)([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:43]([O:47][C:48](=[O:84])[NH:49][C:50]1[CH:55]=[C:54]([C:56]([F:58])([F:59])[F:57])[CH:53]=[C:52]([NH:60][C:61](=[O:83])[CH2:62][C:63](=[O:82])[NH:64][C@@H:8]([CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:51]=1)([CH3:46])([CH3:44])[CH3:45]

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11215504[3-(2-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl esterHCID 69287833(1S,2S)-(1-([benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamic acid tert-butyl ester

Product 1

HCID 69287464(3-{2-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentylcarbamoyl]-acetylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl esterYield 75%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The compound (1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamic acid tert-butyl ester (515 mg, 1.06 mmol) was dissolved in CH2Cl2 (12 mL) and treated with TFA (4 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in benzene and concentrated in vacuo; this procedure was repeated. The resultant amine was dissolved in 15 mL of 2:1 CH2Cl2/DMF. The resultant solution was charged sequentially with N-(3-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid (400 mg, 1.1 mmol, see examples 8 and 1), N,N-diisopropylethylamine (0.96 mL, 5.5 mmol) and HATU (504 mg, 1.3 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide (3-{2-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentylcarbamoyl]-acetylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (577 mg, 75% yield). MS found: (M+Na)+=751.4.

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe residue was dissolved in benzene
  3. concentrationconcentrated in vacuo
  4. dissolutionThe resultant amine was dissolved in 15 mL of 2:1 CH2Cl2/DMF
  5. stirringThe mixture was stirred for 12 h at RT
  6. concentrationconcentrated in vacuo
  7. custompartitioned between EtOAc and sat. NH4Cl
  8. extractionThe aqueous phase was extracted with EtOAc (1×)
  9. washThe combined organic extracts were washed with sat. NaHCO3 and brine
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-44833054b6fd44c89565ba7f72b014bb
Source dataset
uspto-grants-2007_06
Patent number
US07230133B2

Reaction notes

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