Cesium carbonate → 4-(4-(6-(3-Aminopiperidin-1-yl)pyridin-3-ylamino)-3-(methylsulfonyl)quinolin-6-yl)-2,6-dichlorophenol

HRID 2271856Notes

Reaction equation

HRID 2271856 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:29][CH:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:18][CH:19]=2)[CH2:24]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 667151272,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 86692976HCID 86692976, compound

Product 1

HCID 667158884-(4-(6-(3-Aminopiperidin-1-yl)pyridin-3-ylamino)-3-(methylsulfonyl)quinolin-6-yl)-2,6-dichlorophenolYield 12.1%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Procedure

To a suspension of tert-butyl 1-(5-(6-bromo-3-(methylsulfonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (70 mg, 0.121 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.142 mmol) and Pd(dppf)Cl2 (9 mg, 0.012 mmol) in dioxane (4 mL) was added Cs2CO3 (182 μL, 2.0 M solution in H2O). N2 gas was bubbled through the reaction mixture, the vessel was sealed and the mixture was then heated microwave irradiation conditions to 140° C. for 30 min. The solution was allowed to cool to rt, then directly subjected to purification by preparatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HCl solution in diethyl ether to afford the product (8.2 mg, 10%) as an orange solid: 1H NMR (500 MHz, MeOD) δ 9.03 (s, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.24 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.74 (dd, J=9.2, 2.7 Hz, 1H), 7.22 (s, 2H), 7.11 (d, J=9.2 Hz, 1H), 4.60 (s, 1H), 4.05 (d, J=13.5 Hz, 1H), 3.45 (s, 3H), 3.26 (m, 3H), 2.19 (d, J=11.1 Hz, 1H), 1.94 (d, J=11.0 Hz, 1H), 1.71 (m, 2H); ESI MS m/z 558, [C26H25Cl2N5O3S+H]+; HPLC 98.9% (AUC), tR=10.14 min.

Workup

  1. customN2 gas was bubbled through the reaction mixture
  2. customthe vessel was sealed
  3. temperaturethe mixture was then heated
  4. custommicrowave irradiation conditions to 140° C. for 30 min
  5. customdirectly subjected to purification by preparatory HPLC
  6. additionThe crude mixture was then treated with TFA
  7. dissolutionThis residue was then dissolved in MeOH (2 mL)
  8. additiontreated with a 2.0 M HCl solution in diethyl ether

Sources & evidence

ORD record
ord-188498f70c034dcaa3da13930601e338
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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