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

HRID 2271855Notes

Reaction equation

HRID 2271855 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]([F: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]([F: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 667160792-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 86692976HCID 86692976, compound

Product 1

HCID 682986854-(4-(6-(3-Aminopiperidin-1-yl)pyridin-3-ylamino)-3-(methylsulfonyl)quinolin-6-yl)-2-chloro-6-fluorophenolYield 22.9%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
140 °C

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-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.145 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). The reaction mixture was degassed using N2 and heated at 140° C. for 30 min. The reaction mixture was cooled to rt and to purification by preperatory 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 (15 mg, 19%) as a brown-yellow solid: 1H NMR (300 MHz, MeOD) δ 9.07 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.27 (dd, J=8.8, 1.9 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (dd, J=9.3, 2.7 Hz, 1H), 7.28 (m, 1H), 7.09 (m, 2H), 4.56 (q, J=10.4, 9.4 Hz, 1H), 4.09 (d, J=13.3 Hz, 1H), 3.47 (s, 3H), 3.39 (d, 8.1 Hz, 2H), 2.21 (s, 1H), 2.01 (m, 1H), 1.75 (m, 2H); ESI MS m/z 542, [C26H25ClFN5O3S+H]+; HPLC 99.6% (AUC), tR=9.90 min.

Workup

  1. customThe reaction mixture was degassed
  2. temperatureThe reaction mixture was cooled to rt and to purification by preperatory HPLC
  3. additionThe crude mixture was then treated with TFA
  4. dissolutionThis residue was then dissolved in MeOH (2 mL)
  5. additiontreated with a 2.0 M HCl solution in diethyl ether

Sources & evidence

ORD record
ord-4e08f76a1cb24d209d9d9f7e84de0bc5
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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