Cesium carbonate → 1,1-Dimethylethyl 4-(4-((5-chloro-4-((2-((1-methylethyl)sulfonyl)phenyl)amino)-2-pyrimidinyl)amino)-2-methyl-5-(1-methylethoxy)phenyl)-1-piperidinecarboxylate

HRID 2046958Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2046958
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH2:24])=[CH:16][C:15]=2[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[C:30]([Cl:46])=[CH:29][N:28]=1.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([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:22])[CH3:23])[C:17]([NH:24][C:27]3[N:32]=[C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[S:40]([CH:43]([CH3:44])[CH3:45])(=[O:42])=[O:41])[C:30]([Cl:46])=[CH:29][N:28]=3)=[CH:16][C:15]=2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 597643782,5-dichloro-N-(2-((1-methylethyl)sulfonyl)phenyl)-4-pyrimidinamineHCID 597645801,1-Dimethylethyl 4-[4-amino-2-methyl-5-(1-methylethoxy)phenyl]-1-piperidinecarboxylate

Produkt 1

HCID 668769521,1-Dimethylethyl 4-(4-((5-chloro-4-((2-((1-methylethyl)sulfonyl)phenyl)amino)-2-pyrimidinyl)amino)-2-methyl-5-(1-methylethoxy)phenyl)-1-piperidinecarboxylate

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
150 °C

Versuchsvorschrift

Steps 4 and 5: 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.488 mmol) from the previous step, (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (169 mg, 0.488 mmol, 1 equiv.), xantphos (28 mg, 0.049 mmol, 0.1 equiv.), palladium acetate (5.5 mg, 0.024 mmol, 0.05 equiv.), and Cs2CO3 (477 mg, 1.46 mmol, 3 equiv.) were dissolved in anhydrous THF (6 mL). N2 is bubbled through the reaction mixture for 5 minutes and the reaction vessel was sealed and heated with microwave irradiation to 150° C. for 20 minutes. The reaction was filtered and the filtrate concentrated under vacuum. After concentration, the crude product was purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow film: ESMS m/z 658.3 (M+H+). This product (105 mg, 0.160 mmol) was dissolved in CH2Cl2 (3 mL) and treated with TFA (3 mL). After 45 minutes, the reaction was concentrated under vacuum. 1 N HCl in Et2O (5 mL×2) was added causing the product HCl salt to precipitate. The solvent was removed by decantation. The resulting 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine was dried under high vacuum, generating an off-white powder: 1H NMR (400 MHz, DMSO-d6+trace D2O) δ 8.32 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56-4.48 (m, 1H), 3.49-3.32 (m, 3H), 3.10-2.91 (m, 3H), 2.09 (s, 3H), 1.89-1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M+H+).

Aufarbeitung

  1. customN2 is bubbled through the reaction mixture for 5 minutes
  2. customthe reaction vessel was sealed
  3. filtrationThe reaction was filtered
  4. concentrationthe filtrate concentrated under vacuum
  5. concentrationAfter concentration
  6. customthe crude product was purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-767dd4911aff495b8e1717150a9e2e24
Quelldatensatz
uspto-grants-2013_11
Patentnummer
US08592432B2

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