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Tetrahydrofuran → tert-butyl ((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate

HRID 1775883
Notes
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Reaction equation

HRID 1775883 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:54][C:55](=[O:66])[C:56]3[CH:61]=[CH:60][C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=3)[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH3:46])=[O:43])=[CH:36][CH:35]=2)=[N:32][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:62]([C:59]1[CH:58]=[CH:57][C:56]([C:55]([NH:54][C@@H:41]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:31]3[N:30]=[CH:29][C:28]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[CH:33][N:32]=3)=[CH:39][CH:38]=2)[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[CH3:46])=[O:43])=[O:66])=[CH:61][CH:60]=1)([CH3:63])([CH3:64])[CH3:65]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 151402Sodium Carbonate DecahydrateHCID 27343604-Hydroxyphenylboronic acidHCID 117748658tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate

Product 1

HCID 117749025
tert-butyl ((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
Yield 83%

Reagents, catalysts & solvents 3

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (317.23 mg, 2.30 mmol), sodium carbonate decahydrate (138.0 mg, 2.3 mmol), tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoyl)-D-alaninate INT-32 (700.0 mg, 1.15 mmol), Pd(dppf)Cl2 (87.8 mg, 0.12 mmol), THF (10 mL), CH3CN (10 ml) and water (5 mL). The solution was degassed using N2 bubbling for 10 min. The reaction mixture was heated to 80° C. for 2 hours. The mixture was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 595.0 mg (83%) of tert-butyl ((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-45 as solid. LCMS-ESI (m/z) calculated for C37H42N4O5: 622.3. found 623.3 [M+H]+, tR=3.635 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 9.11 (s, 2H), 8.50 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 4.85 (td, J=9.9, 4.6 Hz, 1H), 4.17 (p, J=7.1 Hz, 1H), 3.24-3.00 (m, 2H), 1.46-1.34 (m, 9H), 1.32-1.19 (m, 12H).

Workup

  1. customThe solution was degassed
  2. customfor 10 min
  3. extractionThe mixture was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL)
  4. dry with materialThe combined organics were dried over MgSO4
  5. customevaporated
  6. customThe final compound was purified by column chromatography (40% DCM in hexane)

Sources & evidence

ORD record
ord-ad1a9db0afd34504a13809fcae0527d9
Source dataset
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09260427B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes