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Potassium Carbonate → (+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-5-yl)phenyl)acetamide

HRID 1525909
Notes
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Reaction equation

HRID 1525909 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]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.[N:28]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.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:33]5[CH:34]=[CH:35][CH:36]=[C:37]6[C:32]=5[CH:31]=[CH:30][CH:29]=[N:28]6)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 5153389Quinolin-5-ylboronic acidHCID 71271075HCID 71271075, compound

Product 1

HCID 71270757(+)-2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-5-yl)phenyl)acetamideYield 21%

Reagents, catalysts & solvents 2

HCID 178418807
HCID 178418807, compound
Catalyst
HCID 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)acetamide (0.273 mmol) in dry 1,4-dioxane (1.5 mL) was treated with quinolin-5-ylboronic acid (0.300 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.014 mmol) and 2M aq potassium carbonate (0.818 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 resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-9% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >99% ee (30 mg, 21% yield). MS(ES)+ m/e 489.5 [M+H]+, αD=+38 deg (c=0.05, methanol).

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 resulting black mixture was diluted with water (50 mL) and brine (20 mL)
  5. extractionwas extracted with ethyl acetate three times
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by silica gel chromatography (0-9% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol)

Sources & evidence

ORD record
ord-6efe22cd6ec244dea6d8400d087c0941
Source dataset
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09084794B2

Reaction notes

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