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

HRID 1095788Notes

Reaction equation

[H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1Cl>CS(C)=O>[CH:18]1([CH2:17][O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6](=[O:21])[CH:5]=[C:4]3[NH:3][C:28]2[C:27]([Cl:30])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:22])[CH2:19][CH2:20]1

Participants

Conditions

Temperature: 32 °C

Procedure

Sodium hydride (60%, 14 g, 350 mmol) was added (caution: H2 gas evolution) to a solution of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (18 g, 69 mmol) and DMSO (200 mL) under N2. After 1 h at room temperature, 3,4,5-trichloropyridine (12.6 g, 69 mmol) was added portionwise with external cooling (internal temperature kept below 30° C.), and the reaction was warmed at 32° C. overnight. The reaction was quenched with water (40 mL) and adjusted to pH=6, with saturated potassium phosphate (KH2PO4). The resulting solids were collected by filtration, purified by silica gel chromatography (100:1; dichloromethane/methanol), and then triturated with ethyl acetate (300 mL) to give 22 g of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-quinolin-2(1H)-one as a straw yellow solid. MS (ESI): 406.1.

Workup

temperaturewith external cooling (internal temperature kept below 30° C.)
customThe reaction was quenched with water (40 mL)
filtrationThe resulting solids were collected by filtration
custompurified by silica gel chromatography (100:1; dichloromethane/methanol)
customtriturated with ethyl acetate (300 mL)

Sources & evidence

ORD record: ord-d21807e1fb2f4248b0b08191483240d9
Source dataset: uspto-grants-2012_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08138205B2

Reaction notes

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