Morpholine → HCID 86710011, compound

HRID 1855303Notes

Reaction equation

HRID 1855303 reaction equation
FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:36]4[C:37]([F:42])=[N:38][CH:39]=[CH:40][CH:41]=4)=[CH:16][C:17]=3[C:18]32[C:24]2=[N:25][CH:26]=[CH:27][N:23]2[C:22]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21]3)=[C:9]([F:43])[CH:8]=1)(=O)=O.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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].O>[F:43][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:36]4[C:37]([F:42])=[N:38][CH:39]=[CH:40][CH:41]=4)=[CH:14][CH:13]=3)[C:18]3([C:24]4=[N:25][CH:26]=[CH:27][N:23]4[C:22]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:21]3)[C:19]=2[CH:20]=[C:7]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH:8]=1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 2733832Lithium HexamethyldisilazideHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 86710010HCID 86710010, compound

Product 1

HCID 86710011HCID 86710011, compoundYield 40.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Procedure

A microwave vial was charged with 5-(tert-butoxycarbonylamino)-5′-fluoro-2′-(2-fluoropyridin-3-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-7′-yl trifluoromethanesulfonate (300 mg, 0.462 mmol), Pd2dba3 (21.15 mg, 0.023 mmol), biphenyl-2-yldi-tert-butylphosphine (16.54 mg, 0.055 mmol) and morpholine (141 mg, 1.617 mmol) and capped under argon gas. LiHMDS (1 M in THF) (1.155 mL, 1.155 mmol) was added and the mixture was microwaved at 90° C. for 10 min. Twenty five ml of water was added, and the aqueous layer was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The crude material (product) was purified via silica gel column chromatography (RediSep 40 g column) using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford tert-butyl 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-5-ylcarbamate (110 mg, 0.188 mmol, 40.6% yield) as an off white solid. This material was treated with TFA (0.323 ml, 4.19 mmol) in DCM (2 ml) and stirred at RT for one hour. The solution was concentrated, neutralized with sodium barcabonate solution and extracted with DCM. The organic extracts were combined, dried, filtered and concentrated. The crude product (racemic concentrate) was purified via silica gel column chromatography using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM, then the racemates were separated using chiral SFC to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example no. 9A) and (R)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example no. 9B).

Workup

  1. customcapped under argon gas
  2. customthe mixture was microwaved at 90° C. for 10 min
  3. extractionthe aqueous layer was extracted with EtOAc
  4. customthe combined organic layers were dried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material (product) was purified via silica gel column chromatography (RediSep 40 g column)

Sources & evidence

ORD record
ord-7f4172074de24aed8ca044970e7faeb1
Source dataset
uspto-grants-2015_02
Patent number
US08962859B2

Reaction notes

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