Cesium carbonate → 6-(5-Chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one

HRID 386767Notes

Reaction equation

HRID 386767 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][C:18]([N+:27]([O-])=O)=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:20]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[H][H].Cl[C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])[C:37]([Cl:53])=[CH:36][N:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.C1COCC1.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:53][C:37]1[C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[N:39][C:34]([NH:27][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:15]3=[O:30])=[CH:20][C:19]=2[O:23][CH:24]([CH3:25])[CH3:26])=[N:35][CH:36]=1

Participants

11

Reactant 6

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 21863450Trifluoroacetic acid methylene chlorideHCID 597643782,5-dichloro-N-(2-((1-methylethyl)sulfonyl)phenyl)-4-pyrimidinamine2×HCID 597644074-(5-Isopropoxy-6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl esterHCID 178418361HCID 178418361, compound

Product 1

HCID 248164386-(5-Chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 4-(5-isopropoxy-6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester from the previous step (850 mg, 2 mmol) in methanol, is added Pd/C (10% on carbon, 100 mg). The mixture is hydrogenated under 1 atm of hydrogen gas. After 4 hours, the mixture is filtered and concentrated. The obtained aniline, as yellow solid, is used for next step without additional purification. To a mixture of the crude product (2 mmol) from previous step, (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (Intermediate 2, 770 mg, 2.2 mmol), cesium carbonate (1.3 g, 4 mmol), and xantphos (115 mg, 0.2 mmol) in THF (20 mL), is added palladium acetate (22 mg, 5% mmol) in a microwave tube. The mixture is purged with N2 for 3 min. The sealed tube is heated at 150° C. for 20 min under microwave irradiation. The mixture is cooled, filtered and concentrated. The residue is purified by silica gel flash column chromatography (eluent: 65% ethyl acetate in hexanes) to afford a yellow solid. The solid is treated with DCM/TFA (1/1, 10 mL) for 1 hour followed by concentration under vacuum. Final purification using preparative RP LC-MS affords 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (178) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 10.13 (s, 1H), 9.60-9.50 (br, 1H), 9.34-9.21 (br, 1H), 8.46 (d, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.91 (dd, 1H), 7.71 (m, 1H), 7.34 (t, 1H), 7.03 (s, 1H), 4.30 (m, 1H), 4.53 (m, 1H), 4.33 (s, 2H), 3.62 (m, 2H), 3.21-3.09 (m, 3H), 2.31-2.21 (m, 2H), 2.09-2.05 (m, 2H), 1.41 (d, 6H), 2.30 (d, 6H); ESMS m/z 599.2 (M+H+).

Workup

  1. filtrationthe mixture is filtered
  2. concentrationconcentrated
  3. customThe obtained aniline, as yellow solid, is used for next step without additional purification
  4. customThe mixture is purged with N2 for 3 min
  5. temperatureThe mixture is cooled
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is purified by silica gel flash column chromatography (eluent: 65% ethyl acetate in hexanes)
  9. customto afford a yellow solid
  10. concentrationfollowed by concentration under vacuum
  11. customFinal purification

Sources & evidence

ORD record
ord-48567d7aba024d8d9b9513a3c75e276c
Source dataset
uspto-grants-2013_02
Patent number
US08372858B2

Reaction notes

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