Cesium carbonate → 3-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523286Notes

Reaction equation

HRID 523286 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:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29](=[O:35])[N:28]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:27]2=[O:52].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:28]2[C:27](=[O:52])[C:26]4[C:31](=[CH:32][CH:33]=[C:24]([F:23])[CH:25]=4)[N:30]([CH3:34])[C:29]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 1317355636-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 865828003-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 42.1%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °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), 6-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 13] (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 (1 mL) was heated at 60° C. overnight, then at 90° C. for 4 h. The cooled mixture was concentrated and the residue was purified twice by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give a mixture of four atropisomers of 3-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (129 mg, 39% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min; sample preparation: 15.4 mg/mL in MeOH; injection: 0.5 mL. The third peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (33 mg). 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 10.44 (br. s., 1H), 8.29 (dd, J=8.1, 6.4 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56-7.49 (m, 1H), 7.36 (dd, J=15.2, 7.3 Hz, 2H), 7.22 (d, J=6.8 Hz, 1H), 7.04-6.92 (m, 3H), 3.65 (s, 3H), 1.84 (s, 3H), 1.63 (s, 6H).

Workup

  1. concentrationThe cooled mixture was concentrated
  2. customthe residue was purified twice by column chromatography on silica gel (40 g)
  3. washeluting with EtOAc-hexanes (gradient from 50-100%)
  4. customto give

Sources & evidence

ORD record
ord-86ca63c94acd4d18a01003b73c391f0d
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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