Triethylamine → 4-{5'-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3']bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester

HRID 1404307Notes

Reaction equation

HRID 1404307 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][N:40]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:40]=[CH:41][C:42]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[N:11]=[C:10]([C:18]5[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=5[F:25])[CH:9]=4)[CH:3]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 16217947Tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylateHCID 18407952Tripotassium phosphate trihydrateHCID 673643764-(5-Bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine

Product 1

HCID 673648404-{5'-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3']bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A slurry of 500 mg (1.21 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 516 mg (1.33 mmol) 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and 512 g (14.1 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 85 mg (0.12 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 16 μl triethylamine were added. The reaction mixture was stirred for 5 hours at 80° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethylacetate/methanol as eluent yielding 4-{5′-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3′]bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester as yellow oil; HPLC-MS: 2.69 min, [M+H] 597.

Workup

  1. customThe reaction mixture was partitioned between water and dichloromethane
  2. dry with materialThe organic phase was dried over sodium sulfate
  3. customevaporated
  4. customThe residue is chromatographed on a silica gel column with ethylacetate/methanol as eluent

Sources & evidence

ORD record
ord-79c51e78ef124dd8b8f6984b9818dabe
Source dataset
uspto-grants-2014_12
Patent number
US08912216B2

Reaction notes

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