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

HRID 2046965Notes

Reaction equation

HRID 2046965 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-pyrimidinamineHCID 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, was added Pd/C (10% on carbon, 100 mg). The mixture was hydrogenated under 1 atm of hydrogen gas. After 4 hours, the mixture was filtered and concentrated. The obtained aniline, as yellow solid, was 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 (770 mg, 2.2 mmol), cesium carbonate (1.3 g, 4 mmol), and xantphos (115 mg, 0.2 mmol) in THF (20 mL), was added palladium acetate (22 mg, 5% mmol) in a microwave tube. The mixture was purged with N2 for 3 min. The sealed tube was heated at 150° C. for 20 min under microwave irradiation. The mixture was cooled, filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 65% ethyl acetate in hexanes) to afford a yellow solid. The solid was treated with DCM/TFA (1/1, 10 mL) for 1 hour followed by concentration under vacuum. Final purification using preparative RP LC-MS afforded 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one 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 was filtered
  2. concentrationconcentrated
  3. customThe obtained aniline, as yellow solid, was used for next step without additional purification
  4. customThe mixture was purged with N2 for 3 min
  5. temperatureThe mixture was cooled
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was 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-d9f0305006ac439289f7c02f482b081f
Source dataset
uspto-grants-2013_11
Patent number
US08592432B2

Reaction notes

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