Cesium carbonate → HCID 86580854, compound

HRID 523299Notes

Reaction equation

HRID 523299 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].[CH3:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:44](=[O:45])[CH:43]=[C:42]2[S:46][CH:47]=[CH:48][N:41]2[C:40]1=[O:49].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:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:44](=[O:45])[CH:43]=[C:42]4[S:46][CH:47]=[CH:48][N:41]4[C:40]2=[O:49])[C:24]=1[CH3:23])=[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 123693342HCID 123693342, compound2×

Product 1

HCID 86580854HCID 86580854, compoundYield 33.9%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (0.139 g, 0.364 mmol), 6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione [Intermediate 36] (0.127 g, 0.331 mmol) and Cs2CO3 (0.215 g, 0.661 mmol) in THF (3.0 mL) and water (0.75 mL) was bubbled with argon for 3 min, then was treated with PdCl2(dppf) DCM adduct (0.013 g, 0.017 mmol). The mixture was bubbled with argon for 30 sec more and the reaction vessel was sealed. The mixture was stirred at 50° C. for 5 h. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers was extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (90%, then 100%), to give 3-chloro-4-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a tan solid (62.7 mg, 32% 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 (60:40) at 85 mL/min; sample preparation: 9 mg/mL in MeOH-DMSO; injection: 2 mL. The third peak eluted from the column provided one single atropisomer of 3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 38]. Mass spectrum m/z 559 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.27 (br. s., 1H), 8.14 (s, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.69 (dd, J=4.6, 0.7 Hz, 1H), 7.59 (br. s., 1H), 7.54-7.49 (m, 1H), 7.47-7.43 (m, 1H), 7.26 (dd, J=7.4, 1.2 Hz, 1H), 7.03 (d, J=4.6 Hz, 1H), 6.99 (dd, J=8.6, 1.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.98 (s, 1H), 1.70 (s, 3H), 1.45-1.42 (m, 6H).

Workup

  1. customwas bubbled with argon for 3 min
  2. customThe mixture was bubbled with argon for 30 sec more
  3. customthe reaction vessel was sealed
  4. additionThe cooled mixture was diluted with EtOAc
  5. washwashed sequentially with water and brine
  6. extractionThe combined aqueous layers was extracted with EtOAc
  7. customthe combined organic layers were dried
  8. concentrationconcentrated
  9. customThe residue was purified by column chromatography on silica gel (80 g)
  10. washeluting with EtOAc-hexanes (90%

Sources & evidence

ORD record
ord-9cc40f075dd84195941908d5d5e6fcc0
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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