Cesium carbonate → 3-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523287Notes

Reaction equation

HRID 523287 reaction equation
Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:52])[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](B4OC(C)(C)C(C)(C)O4)[C:37]=3[CH3:51])[C:30](=[O:35])[N:31]2[CH3:34])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.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>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:29]2[C:28](=[O:52])[C:27]4[C:32](=[CH:33][C:24]([F:23])=[CH:25][CH:26]=4)[N:31]([CH3:34])[C:30]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 1177612874-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2×HCID 1239217227-fluoro-1-methyl-3-(2-methyl-3-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione2×

Product 1

HCID 865828013-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 53.5%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (200 mg, 0.524 mmol), 7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 15] (215 mg, 0.524 mmol), Cs2CO3 (512 mg, 1.57 mmol) and PdCl2(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (0.50 mL) was heated at 90° C. for 4 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 0-40%), to provide a mixture of four atropisomers of 3-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (164 mg, 53% yield). The material was separated by chiral super-critical fluid chromatography as follows: column: Lux Cel2 (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (62:19:19) at 85 mL/min; sample preparation: 30 mg/mL in MeOH; injection: 0.5 mL. The material isolated from the third peak eluting from the column was again separated by chiral super-critical fluid chromatography as follows: column. CHIRALPAK® AS (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (68:16:16) at 85 mL/min; sample preparation: 11.4 mg/mL in MeOH; injection: 3.5 mL. The first peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (25 mg, 15% yield). The isomeric purity was determined to be greater than 98%. Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.31 (dd, J=8.6, 6.2 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.38 (ddd, J=14.1, 7.8, 1.0 Hz, 2H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 7.06-6.95 (m, 3H), 3.67 (s, 4H), 1.86 (s, 3H), 1.65 (s, 6H).

Workup

  1. concentrationThe cooled mixture was concentrated
  2. customthe residue was purified by column chromatography on silica gel (220 g)
  3. washeluting with EtOAc-hexanes (gradient from 0-40%)
  4. customto provide

Sources & evidence

ORD record
ord-fbd5b2f239aa4fb1a313a9313e616e2d
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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