1-Hydroxybenzotriazole → 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

HRID 724312ノート

反応式

HRID 724312 の反応式
Cl.[OH:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10].[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17]([NH:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH2:3][OH:2])=[O:18]

参加物

7

反応物 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2724654rac-((1R,2R)-2-aminocyclohexyl)methanol hydrochlorideHCID 113918232-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid

生成物 1

HCID 695861635-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide収率 70.9%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒2 回HCID 8471Triethylamine溶媒

実験手順

A solution of trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed by reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (216 mg) as a colourless oil.

後処理

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue was partitioned between ethyl acetate (25 ml) and water (25 ml)
  3. customThe organic phase was removed
  4. washwashed with sat. sodium bicarbonate solution (25 ml)
  5. dry with materialThe organic layer was dried over MgSO4
  6. customthe solvent was removed by reduced pressure
  7. customThe residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70

出典と根拠

ORDレコード
ord-176fdaa5bdf246deae9ab68ec9c61659
出典データセット
uspto-grants-2006_11
特許番号
US07141586B2

反応ノート

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