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

HRID 1664659
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1664659
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
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Komponenten

11

Edukt 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 ester
HCID 178418361HCID 178418361, Verbindung

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 23938PalladiumKatalysatorHCID 167845palladium(II) acetateKatalysatorHCID 887MethanolLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
150 °C

Versuchsvorschrift

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+).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-e07f1705317a498fbd2700131f9c70b5
Quelldatensatz
uspto-grants-2011_10
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08039479B2

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