Cesium carbonate → 6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide

HRID 523294Notes

Reaction equation

HRID 523294 reaction equation
Br[C:2]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([NH2:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][C@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:8][C:9]=1[NH:10]2.[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=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:15][C:14]1[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([N:30]3[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]3=[O:35])[C:37]=2[CH3:51])=[C:3]2[C:11](=[C:12]([C:16]([NH2:18])=[O:17])[CH:13]=1)[NH:10][C:9]1[CH2:8][C@@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6][CH2:5][C:4]2=1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 117761028(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide2×HCID 1239796828-Fluoro-1-methyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]quinazoline-2,4-dione2×

Product 1

HCID 865806916-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamideYield 50%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of (S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide [Intermediate 31] (100 mg, 0.259 mmol), 8-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 2] (112 mg, 0.272 mmol), Cs2CO3 (169 mg, 0.519 mmol) and PdCl2(dppf) DCM adduct (16.9 mg, 0.021 mmol) in THF (4.3 mL) and water (1.1 mL) was heated at 50° C. for 17.5 h. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 50-80%). The impure product was further purified by preparative HPLC to give 6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (mixture of four atropisomers) (76 mg, 50% yield). Mass spectrum m/z 589 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.13 (br. s., 1H), 7.94 (d, J=7.9 Hz, 1H), 7.76-7.68 (m, 2H), 7.46 (br. s., 1H), 7.40-7.28 (m, 3H), 7.22-7.16 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.64 (m, 3H), 2.95-2.82 (m, 1H), 2.40 (d, J=16.3 Hz, 1H), 1.94-1.70 (m, 3H), 1.70-1.61 (m, 3H), 1.58-1.48 (m, 1H), 1.16-1.02 (m, 7H).

Workup

  1. washwashed sequentially with water and brine
  2. customdried
  3. concentrationconcentrated
  4. customThe residue was purified by column chromatography on silica gel (24 g)
  5. washeluting with EtOAc-hexanes (gradient from 50-80%)
  6. customThe impure product was further purified by preparative HPLC

Sources & evidence

ORD record
ord-ef47fb92d3404ad5b06f1cdb09d7f74b
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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