Lithium Hydroxide → 2-(Benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide

HRID 350991Notes

Reaction equation

HRID 350991 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](O)=[O:25])=[CH:20][C:15]=2[O:14][CH2:13]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH-].[Li+].[OH-].[Na+]>CN(C)C=O.CO.O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([NH:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=3[F:11])=[O:25])=[CH:20][C:15]=2[O:14][CH2:13]1

Participants

11

Reactant 7

HCID 3939Lithium HydroxideHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27368792-(1,3-Benzodioxol-5-yloxy)pyridine-3-carboxylic acidHCID 27960291-Hydroxybenzotriazole hydrateHCID 220584394-(Aminomethyl)-3-fluorophenol hydrochloride

Product 1

HCID 226101182-(Benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamideYield 55.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield.

Workup

  1. customThe reaction was quenched into dilute aqueous hydrochloric acid
  2. extractionextracted with diethyl ether
  3. washThe pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine
  4. customto afford 12.2 g crude
  5. filtrationThe precipitate was filtered off
  6. extractionextracted with ethyl acetate (2×200 ml)
  7. washThe pooled organics were washed with 2N sodium carbonate
  8. dry with materialbrine and dried (MgSO4)

Sources & evidence

ORD record
ord-311e0376969643bf92d8f8168e0c26f9
Source dataset
uspto-grants-2007_02
Patent number
US07183293B2

Reaction notes

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