Trifluoroacetic acid → (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acid

HRID 1775858Notes

Reaction equation

HRID 1775858 reaction equation
[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([O:23]C(C)(C)C)=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([OH:23])=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 117740760(S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)pyrrolidine-2-carboxylate

Product 1

HCID 89633696(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acidYield 41.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

Prepared using General Procedure 8. To a stirred solution of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350 mg, 0.465 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with toluene (10 mL) and solvent removed. The residue was dissolved in EA (50 mL), THF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL). The aqueous layer was removed and acetic acid (5 mL) was added. The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed and residual acetic acid was removed under high vacuum overnight. The material was dissolved in DCM (5 mL) and ACN (5 mL) was added. The material was stirred under a flow of air for 1 hour and the suspension was filtered and the solid washed with additional ACN (5 mL) and iso-hexanes (20 mL) to give 134 mg (41%) of (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound 328 as a yellow powder. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.3 [M+H]+, tR=10.59 min (Method 10). The chiral purity was calculated at >93% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz, 1H), 8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H), 7.57-7.48 (m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H), 4.94-4.86 (m, 1H), 4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.86-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H), 0.93-0.85 (m, 3H).

Workup

  1. customPrepared
  2. customremoved
  3. dissolutionThe residue was dissolved in EA (50 mL)
  4. washTHF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL)
  5. customThe aqueous layer was removed
  6. additionacetic acid (5 mL) was added
  7. washThe organic layer was washed with brine (50 mL)
  8. dry with materialdried over MgSO4
  9. customThe solvent was removed
  10. customresidual acetic acid was removed under high vacuum overnight
  11. dissolutionThe material was dissolved in DCM (5 mL)
  12. additionACN (5 mL) was added
  13. stirringThe material was stirred under a flow of air for 1 hour
  14. filtrationthe suspension was filtered
  15. washthe solid washed with additional ACN (5 mL) and iso-hexanes (20 mL)

Sources & evidence

ORD record
ord-f6111b8ecd594b80872b7009a173dca1
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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