Potassium Carbonate → 2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid

HRID 1525872Notes

Reaction equation

HRID 1525872 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][CH:42]=[N:43]6)=[CH:38][CH:37]=5)=[CH:3][C:4]=4[F:27])[C:9]([OH:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 712708922-(4-Bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid

Product 1

HCID 712709422-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acidYield 67.1%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.408 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.449 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 mmol) and 2M aq potassium carbonate (1.224 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The reaction mixture was diluted with methanol (10 mL), treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH) followed by lyophilization from water afforded the title compound as a white solid (134 mg, 63%). MS(ES)+ m/e 490.3 [M+H]+.

Workup

  1. customThe reaction vessel was purged with nitrogen
  2. customsealed
  3. customthe mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min
  4. additionThe reaction mixture was diluted with methanol (10 mL)
  5. additiontreated with Silicycle Si-thiol (20 mg)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-a213c37c0a1d48e992486844d38c0640
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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