Tetrahydrofuran → HCID 117749093, compound

HRID 1775876Notes

Reaction equation

HRID 1775876 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:53][C:54]([C:56]3[S:57][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:59][CH:60]=3)=[O:55])[C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]3)=[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:61]([C:58]1[S:57][C:56]([C:54]([NH:53][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]([N:44]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]2)=[O:43])=[O:55])=[CH:60][CH:59]=1)([CH3:64])([CH3:62])[CH3:63]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 151402Sodium Carbonate DecahydrateHCID 27343604-Hydroxyphenylboronic acidHCID 117749079HCID 117749079, compound

Product 1

HCID 117749093HCID 117749093, compoundYield 76%

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 10 ml flask were added (4-hydroxyphenyl)boronic acid (60.7 mg, 0.44 mmol), sodium carbonate decahydrate (26.4 mg, 0.44 mmol), methyl (S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate INT-35 (130.0 mg, 0.44 mmol), Pd(dppf)Cl2 (16.09 mg, 0.022 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 (3×10 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (50% DCM in hexane) to afford 102.0 mg (76%) of methyl (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate INT-37 as a solid powder. LCMS-ESI (m/z) calculated for C34H36N4O5S: 612.3. found 613.3 [M+H]+, tR=3.138 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 9.13 (d, J=1.5 Hz, 2H), 8.77 (dd, J=11.4, 8.1 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 7.73 (d, J=3.8 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 6.99-6.84 (m, 3H), 4.88 (s, 1H), 3.72 (d, J=8.9 Hz, 1H), 3.62 (s, 1H), 3.59 (d, J=6.4 Hz, 1H), 3.50 (ddd, J=18.7, 12.0, 5.8 Hz, 1H), 3.36 (d, J=7.5 Hz, 1H), 3.27-3.16 (m, 1H), 3.18-2.97 (m, 3H), 2.15-1.95 (m, 2H), 1.88 (dd, J=12.5, 7.5 Hz, 1H), 1.32 (s, 9H).

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 (3×10 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 (50% DCM in hexane)

Sources & evidence

ORD record
ord-b7329134c7ef4f118914384b44a26513
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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