Potassium Carbonate → 4-Cyclopropyl-9-(1-(4-(quinolin-7-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

HRID 1525863Notes

Reaction equation

HRID 1525863 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:24][CH2:23][C:13]3([O:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=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:20]1([N:15]2[CH2:14][C:13]3([CH2:23][CH2:24][N:10]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:42]=[C:41]6[C:36]([CH:37]=[CH:38][CH:39]=[N:40]6)=[CH:35][CH:34]=5)=[CH:3][CH:4]=4)[CH3:9])[CH2:11][CH2:12]3)[O:18][CH2:17][C:16]2=[O:19])[CH2:22][CH2:21]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 712708649-(1-(4-Bromophenyl)ethyl)-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

Product 1

HCID 712708024-Cyclopropyl-9-(1-(4-(quinolin-7-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-oneYield 19.8%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 9-[1-(4-bromophenyl)ethyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.297 mmol) in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.329 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.015 mmol) and 2M aq potassium carbonate (0.892 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 150° C. for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (4-10% methanol/dichloromethane) and then by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜11 with 30% w/v ammonium hydroxide solution. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization of the resulting semi-solid from water yielded the title compound as a white solid (26 mg, 18%). MS(ES)+ m/e 442.1 [M+H]+.

Workup

  1. customThe reaction vessel was purged with nitrogen
  2. customsealed
  3. customthe mixture was irradiated in a Biotage Initiator Microwave at 150° C. for 20 min
  4. additionThe resulting black mixture was diluted with water (50 mL)
  5. extractionextracted three times with dichloromethane
  6. additionThe combined organic layers were treated with Silicycle Si-thiol (20 mg)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe resulting crude product was purified by silica gel chromatography (4-10% methanol/dichloromethane)
  11. additionFractions containing the desired product
  12. concentrationThis mixture was concentrated to a minimal volume in vacuo
  13. extractionwas then extracted three times with dichloromethane
  14. dry with materialThe combined organic layers were dried over sodium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c722b3c977b34e749e2d78602b6fb019
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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