Dimethyl Sulfoxide → ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)-D-alanine

HRID 1775854Notes

Reaction equation

HRID 1775854 reaction equation
[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=4)=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[C:14]([NH:16][C@@H:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH3:18])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1.CS(C)=O>C(Cl)Cl.O>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=4)=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[C:14]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 1140TolueneHCID 6422Trifluoroacetic acidHCID 117748654tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl) pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate

Product 1

HCID 89633681((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)-D-alanineYield 57%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Prepared using General Procedure 8. To a stirred solution of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)-D-alaninate (375 mg, 0.495 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was azetroped with toluene (2×30 mL) to give a viscous oily solid. DMSO (5 mL) was added and the solution was sonicated. To this solution was added water (60 mL) and the mixture was sonicated for 5 mins then stirred at room temperature for 20 mins. The white solid was isolated by filtration and washed with additional water (20 mL) and isohexanes (30 mL). The material was dried under vacuum, suspended in ACN (20 mL), then diluted with diethyl ether (30 mL) and stirred for 20 mins. The suspension was filtered and the wet solid was dried under vacuum to give 189.3 mg (55%) of ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine Compound 327 as a white powder. LCMS-ESI (m/z) calculated for C38H46N4O5S: 670.3. found 671.0 [M+H]+, tR=13.32 min (Method 10). The chiral purity was calculated at >99% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.16 (s, 2H), 8.56 (d, J=8.8 Hz, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.35-8.26 (m, 2H), 7.84-7.76 (m, 2H), 7.70 (d, J=3.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.13-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H), 4.86-4.77 (m, 1H), 4.29-4.18 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.20-3.10 (m, 1H), 3.08-2.94 (m, 1H), 1.80-1.68 (m, 2H), 1.51-1.22 (m, 20H), 0.94-0.83 (m, 3H).

Workup

  1. customPrepared
  2. customto give a viscous oily solid
  3. customthe solution was sonicated
  4. customthe mixture was sonicated for 5 mins
  5. stirringthen stirred at room temperature for 20 mins
  6. customThe white solid was isolated by filtration
  7. washwashed with additional water (20 mL) and isohexanes (30 mL)
  8. customThe material was dried under vacuum
  9. additiondiluted with diethyl ether (30 mL)
  10. stirringstirred for 20 mins
  11. filtrationThe suspension was filtered
  12. customthe wet solid was dried under vacuum

Sources & evidence

ORD record
ord-58609a9a2bfd4fe29bc62b1b22a305ac
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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