Cesium carbonate → HCID 59746472, compound

HRID 2090821Notes

Reaction equation

HRID 2090821 reaction equation
[CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])([CH3:3])C.O[N:11]1[C:15]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.BrC1C=[C:35]2[C:40](=[CH:41]C=1)[CH2:39][NH:38][CH2:37][CH2:36]2.[C:43](=[O:46])([O-])[O-].[Cs+].[Cs+].CN1CCNCC1.BrC1C=C2C(=CC=1)CN(C(=O)[CH2:68][O:69][CH2:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][N:72]1[S:77]([C:80]1[C:85]([CH3:86])=[CH:84][C:83]([O:87][CH3:88])=[CH:82][C:81]=1[CH3:89])(=[O:79])=[O:78])CC2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>ClCCl.O1CCOCC1.[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:88][O:87][C:83]1[CH:82]=[C:81]([CH3:89])[C:80]([S:77]([N:72]2[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]2[CH2:70][O:69][CH2:68][C:43]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][N:11]([CH3:15])[CH2:3][CH2:1]4)[CH:9]=3)[CH2:39]2)=[O:46])(=[O:78])=[O:79])=[C:85]([CH3:86])[CH:84]=1

Participants

12

Reactant 8

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 158851836-Bromo-1,2,3,4-tetrahydroisoquinolineHCID 59746549HCID 59746549, compound

Product 1

HCID 59746472HCID 59746472, compoundYield 80%

Reagents, catalysts & solvents 3

HCID 86621119HCID 86621119, compoundCatalystHCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
23 °C

Procedure

To a solution of the acid structural unit S27 (1.5 g) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 23° C. It was then cooled to 0° C., and 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.2 eq., dissolved in dichloromethane) was added dropwise. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. The mixture was diluted with dichloromethane (100 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in dichloromethane). Yield: 80% Step (ii): Cesium carbonate (2.5 eq.) was added to a solution of N-methylpiperazine (3.6 mmol) and 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)piperidin-2-yl)methoxy)ethanone (3 mmol) in dioxane (20 ml), and the resulting solution was degassed for 30 min. with argon. Xanthphos (2 mmol), followed by palladium tris(dibenzylideneacetone)dipalladium (0.15 mmol) were then added, under argon, and the mixture was heated for 16 h at 120° C. The progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was filtered and washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was taken up in dichloromethane and washed with water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography (4% methanol in dichloromethane). Yield: 10%; MS, m/z 585.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. temperatureIt was then cooled to 0° C.
  3. stirringThe reaction mixture was stirred for 16 h at 25° C. until the reaction
  4. extractionextracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by column chromatography (5% ethyl acetate in dichloromethane)
  8. customthe resulting solution was degassed for 30 min. with argon
  9. additionwere then added, under argon
  10. temperaturethe mixture was heated for 16 h at 120° C
  11. filtrationThe reaction mixture was filtered
  12. washwashed with ethyl acetate
  13. concentrationthe filtrate was concentrated in vacuo
  14. washwashed with water and saturated sodium chloride solution
  15. dry with materialThe organic phase was dried (Na2SO4)
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo
  18. customThe product was purified by column chromatography (4% methanol in dichloromethane)

Sources & evidence

ORD record
ord-aff59d96b5f742e8a8492ec99d71a0c7
Source dataset
uspto-grants-2013_05
Patent number
US08435978B2

Reaction notes

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