Ammonium Chloride → 2-[1-(6-Tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl ester

HRID 1789909Notes

Reaction equation

HRID 1789909 reaction equation
[Cu](C#N)C#N.[CH:6]([Mg]Br)([CH3:8])[CH3:7].[CH2:11]([O:13][C:14](=[O:36])[C:15](=[CH:21][C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12].[Cl-].[NH4+]>O1CCCC1.N>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH:21]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:26][CH:27]=1)[CH:6]([CH3:8])[CH3:7])[C:14]([O:13][CH2:11][CH3:12])=[O:36])[CH3:20]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 543379912-(6-Tert-butoxycarbonylaminopyridin-3-ylmethylene)-malonic acid diethyl esterHCID 178418260HCID 178418260, compoundHCID 178418365HCID 178418365, compound

Product 1

HCID 543263812-[1-(6-Tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl esterYield 67.1%

Reagents, catalysts & solvents 2

HCID 222AmmoniaSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred solution of copper cyanide (3.58 g, 40 mmol) in tetrahydrofurane (50 mL) at −15° C. a solution of isopropylmagnesium bromide (40 mL, 2 M, 80 mmol) in tetrahydrofurane was added under argon over 15 min. After additional 15 min stirring a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (3.78 g, 10.4 mmol) in tetrahydrofurane (50 ml) was added dropwise over 15 min. After stirring for 16 h the mixture was allowed to warm up to room temperature. Then a solution of ammonium chloride (5%) in aqueous ammonia solution (5%) was added with vigorous stirring, allowing access of air. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with aqueous ammonia solution (5%) and brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 1.7% methanol in dichloromethane) to give crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl ester (2.85 g, 25%).

Workup

  1. additionwas added dropwise over 15 min
  2. extractionThe mixture was extracted twice with ethyl acetate
  3. washThe combined organic layers were washed successively with aqueous ammonia solution (5%) and brine
  4. dry with materialdried over magnesium sulphate
  5. customThe solvent was removed under reduced pressure
  6. customthe residue was purified by column chromatography (silica gel, 1.7% methanol in dichloromethane)

Sources & evidence

ORD record
ord-ddd52b858b564021a8ec19389258f48a
Source dataset
uspto-grants-2006_07
Patent number
US07071175B1

Reaction notes

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