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)-N-methylacetamide

HRID 1525886Notes

Reaction equation

HRID 1525886 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=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:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][C:4]=4[F:28])[C:9]([NH:11][CH3:12])=[O:10])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 71270936HCID 71270936, compound

Product 1

HCID 71270997(+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-methylacetamideYield 25%

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)-N-methylacetamide (0.366 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.403 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.099 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 extracted with dichloromethane four times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The material was triturated with hexanes and the hexane solution was discarded. Purification of the residue by chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a beige solid in >98% ee (50 mg, 25% yield). MS(ES)+ m/e 503.1 [M+H]+. αD=+34 deg (c=0.04, 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. extractionextracted with dichloromethane four times
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe material was triturated with hexanes
  10. customPurification of the residue by chiral HPLC (Chromegachiral CC4, methanol)

Sources & evidence

ORD record
ord-cebb6bc630f1446f882578aaea3a7c88
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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