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 386779Notes

Reaction equation

HRID 386779 reaction equation
[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]

Participants

7

Reactant 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-pyrimidinamine2×HCID 597645801,1-Dimethylethyl 4-[4-amino-2-methyl-5-(1-methylethoxy)phenyl]-1-piperidinecarboxylate

Product 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

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
150 °C

Procedure

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 (Intermediate 2, 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.) are dissolved in anhydrous THF (6 mL). N2 is bubbled through the reaction mixture for 5 minutes and then the reaction vessel is sealed and heated with microwave irradiation to 150° C. for 20 min. The reaction is filtered and the filtrate concentrated under vacuum. After concentration, the crude product is 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) is dissolved in CH2Cl2 (3 mL) and treated with TFA (3 mL). After 45 min., the reaction is concentrated under vacuum. 1 N HCl in Et2O (5 mL×2) is added causing the product HCl salt to precipitate. The solvent is 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 (66) is 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+).

Workup

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

Sources & evidence

ORD record
ord-6da029ed9c6a41639da5748f10f2f7d8
Source dataset
uspto-grants-2013_02
Patent number
US08372858B2

Reaction notes

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