Water → 2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one

HRID 1056353Notes

Reaction equation

HRID 1056353 reaction equation
[CH3:1][CH:2]1[C:6]2[NH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28](I)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28]([C:8]3[NH:7][C:6]4[CH:2]([CH3:1])[NH:3][C:4](=[O:19])[C:5]=4[CH:9]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21]

Participants

9

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 897821382-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-oneHCID 897833126-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one

Product 1

HCID 897836172-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-oneYield 106%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

A glass microwave reaction vessel was charged with 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (472a, 500 mg, 1.91 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (681 mg, 1.91 mmol) in 1,4-dioxane (6.0 mL)/water (1.5 mL) followed by K3PO4 (1215 mg, 5.72 mmol), Xphos (91 mg, 0.191 mmol, Sigma-Aldrich) and Pd2dba3 (87 mg, 0.095 mmol, Strem). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 105° C. for 45 min. The mixture was cooled to RT and EtOAc (50 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (40 mL×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The reaction was repeated on a 1000 mg scale and the residues were combined and purified with silica gel chromatography (eluted with 1-4% MeOH in DCM) to give 2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472b, 740 mg, 36% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 366 (M+1). This material was subjected to chiral SFC to give two eluents: the first eluent was Example 450 (530 mg); the second eluent was (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) (110 mg) as a tan solid. The SFC conditions were: [AS-H (Sum, 21 mm×25 cm, S/N=1071) with 45% organic modifier: 55% carbon dioxide, organic modifier: MeOH with 20 mM ammonia. Flow rate=50 mL/min]. The analytical data for (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) was: MS (ESI, pos. ion) m/z: 366.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (1H, br. s.), 7.79-7.97 (2H, m), 7.61 (1H, s), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.95 (1H, s), 4.53 (1H, q, J=6.6 Hz), 3.48 (3H, s), 1.51 (9H, s), 1.37 (3H, d, J=6.7 Hz).

Workup

  1. customA glass microwave reaction vessel
  2. temperatureThe mixture was cooled to RT
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (40 mL×2)
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified with silica gel chromatography (eluted with 1-4% MeOH in DCM)

Sources & evidence

ORD record
ord-9eb40d36807944e7a791099893c4a1c9
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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