Morpholine → (R)-1-(4-Fluorophenyl)-4a-methoxymethyl-6-(5-morpholin-4-ylpyridine-3-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene

HRID 1907292Notes

Reaction equation

HRID 1907292 reaction equation
Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[NH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:86]3[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 66779670(R)-6-(5-Bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene

Product 1

HCID 56848975(R)-1-(4-Fluorophenyl)-4a-methoxymethyl-6-(5-morpholin-4-ylpyridine-3-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.15 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.035 g), tris(dibenzylideneacetone)dipalladium (0.026 g), sodium tert-butoxide (0.049 g), morpholine and tetrahydrofuran was heated at 100° C. in a microwave reactor for 30 minutes. The mixture was filtered through Celite, and the pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume), to afford a yellow oil. The yellow oil was purified by preparative reverse-phase HPLC, eluting with a mixture of methanol and water containing 0.1% formic acid (9:20 to 4:3 by volume) to afford the title compound as a white solid (0.097 g). LCMS (Method C): 540 (M+H)+, Retention time 10.6 minutes.

Workup

  1. filtrationThe mixture was filtered through Celite
  2. washthe pad was washed with ethyl acetate
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. customthe residue was purified by column chromatography on silica gel
  5. washeluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume)
  6. customto afford a yellow oil
  7. customThe yellow oil was purified by preparative reverse-phase HPLC
  8. washeluting with a mixture of methanol and water containing 0.1% formic acid (9:20 to 4:3 by volume)

Sources & evidence

ORD record
ord-b18699b2bafc4fe488f9fb54e6e9f8c7
Source dataset
uspto-grants-2013_12
Patent number
US08598154B2

Reaction notes

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