Tetrahydrofuran → HCID 117748799, compound

HRID 1775875Notes

Reaction equation

HRID 1775875 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]([C:57]3[S:58][C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:60][CH:61]=3)=[O:56])[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[S:58][C:57]([C:55]([NH:54][C@@H:41]([CH2:40][C:37]2[CH:38]=[CH:39][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:35][CH:36]=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:56])=[CH:61][CH:60]=1)([CH3:63])([CH3:64])[CH3:65]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 151402Sodium Carbonate DecahydrateHCID 27343604-Hydroxyphenylboronic acidHCID 117748798HCID 117748798, compound

Product 1

HCID 117748799HCID 117748799, compoundYield 91%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (224.6 mg, 1.6 mmol), sodium carbonate decahydrate (96.0 mg, 1.6 mmol), tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninate (500.0 mg, 1.6 mmol), Pd(dppf)Cl2 (58.5 mg, 0.08 mmol), THF (2.0 mL), CH3CN (2.0 ml) and water (1.0 mL). The solution was degassed using N2 bubbling for 10 min. The reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was dried under reduced pressure to remove the solvent and diluted in DCM (20 mL). 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 462.3 mg (91%) of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-36 as a solid. LCMS-ESI (m/z) calculated for C35H40N4O5S: 628.3. found 629.3 [M+H]+, tR=3.447 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 9.12 (s, 2H), 8.55 (t, J=16.2 Hz, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.1 Hz, 2H), 7.69 (t, J=7.5 Hz, 3H), 7.50 (dd, J=15.4, 8.3 Hz, 2H), 7.00-6.85 (m, 2H), 6.75 (t, J=9.9 Hz, 1H), 4.80 (td, J=9.7, 4.7 Hz, 1H), 4.15 (p, J=7.2 Hz, 1H), 3.10 (ddd, J=39.3, 19.4, 11.8 Hz, 2H), 1.40 (d, J=6.6 Hz, 9H), 1.31 (s, 9H), 1.23 (t, J=11.1 Hz, 3H).

Workup

  1. customThe solution was degassed
  2. customfor 10 min
  3. customThe reaction mixture was dried under reduced pressure
  4. customto remove the solvent
  5. additiondiluted in DCM (20 mL)
  6. extractionThe mixture was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL)
  7. dry with materialThe combined organics were dried over MgSO4
  8. customevaporated
  9. customThe final compound was purified by column chromatography (40% DCM in hexane)

Sources & evidence

ORD record
ord-f5a1be934ef74bc3b1594e95d09b2014
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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