Sodium hydride → 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

HRID 2381060Notes

Reaction equation

HRID 2381060 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:20])[CH:3]=1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:31])[C:29]=1Cl.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[NH:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:1][C:29]2[C:28]([Cl:31])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:23])[CH2:19][CH2:18][CH2:17][CH2:16]1

Participants

6

Reactant 4

HCID 24758Sodium hydride2×HCID 516951Monobasic potassium phosphateHCID 37865313,4,5-Trichloropyridine2×HCID 667812934-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one

Product 1

HCID 248519098-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (340 mg, 1.24 mmol) was added in 3 portions over 5 min to a mixture of sodium hydride (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at rt under N2. After 5 min, 3,4,5-trichloropyridine (271 mg, 1.49 mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol) was added followed by more 3,4,5-trichloropyridine (250 mg, 1.37 mmol). After an additional 4 h, the reaction was poured into 1M KH2PO4 (75 mL) and stirred for 5 min. The solids were filtered, washed with water (25 mL), and then purified by reverse-phase HPLC (3:7→1:0; acetonitrile:water). In some cases, additional purification by silica gel chromatography (1:0→9:1; dichlormethane:methanol) was needed to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7.

Workup

  1. waitAfter 19 h
  2. waitAfter an additional 4 h
  3. filtrationThe solids were filtered
  4. washwashed with water (25 mL)
  5. custompurified by reverse-phase HPLC (3:7→1:0; acetonitrile:water)
  6. customIn some cases, additional purification by silica gel chromatography (1:0→9:1; dichlormethane:methanol)

Sources & evidence

ORD record
ord-1ebcccc2bfd243209403b0581fad3821
Source dataset
uspto-grants-2012_09
Patent number
US08258154B2

Reaction notes

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