三乙胺 → N-(2-(Pyridin-3-ylmethyl)quinuclidin-3-yl)benzofuran-2-carboxamide

HRID 82425笔记

反应方程式

HRID 82425 反应方程式
C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([OH:29])=O.C(N(CC)CC)C.[NH2:37][C@H:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[C@@H:39]1[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][CH:39]2[CH:38]([NH:37][C:27]([C:19]3[O:18][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH:20]=3)=[O:29])[CH:43]3[CH2:42][CH2:41][N:40]2[CH2:45][CH2:44]3)[CH:48]=1

参与物

8

反应物 6

HCID 8471三乙胺2 次HCID 10331苯并呋喃-2-羧酸HCID 14798氢氧化钠HCID 75654氯磷酸二苯酯HCID 29414711Di-para-toluoyl-L-tartaric acidHCID 66669685(2R,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane

产物 1

HCID 22311391N-(2-(Pyridin-3-ylmethyl)quinuclidin-3-yl)benzofuran-2-carboxamide收率 50%

试剂、催化剂与溶剂 1

HCID 6344二氯甲烷溶剂2 次

实验过程

Diphenylchlorophosphate (96 μL, 124 mg, 0.46 mmol) was added drop-wise to a solution of the benzofuran-2-carboxylic acid (75 mg, 0.46 mmol) and triethylamine (64 μL, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL). After stirring at ambient temperature for 45 min, a solution of (2R,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.10 g, 0.46 mmol) (that derived from the di-p-toluoyl-L-tartaric acid salt) and triethylamine (64 μL, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL) was added. The reaction mixture was stirred overnight at ambient temperature, and then treated with 10% sodium hydroxide (1 mL). The biphasic mixture was separated, and the organic layer and a chloroform extract (2 mL) of the aqueous layer was concentrated by rotary evaporation. The residue was dissolved in methanol and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 82.5 mg (50% yield) of a white powder. The NMR spectrum was identical to that obtained for the 2S,3R isomer.

后处理

  1. additionwas added
  2. stirringThe reaction mixture was stirred overnight at ambient temperature
  3. customThe biphasic mixture was separated
  4. extractionthe organic layer and a chloroform extract (2 mL) of the aqueous layer
  5. concentrationwas concentrated by rotary evaporation
  6. dissolutionThe residue was dissolved in methanol
  7. custompurified by HPLC on a C18 silica gel column
  8. additioncontaining 0.05% trifluoroacetic acid
  9. customConcentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform

来源与证据

ORD记录
ord-42d0b9371d894374aa4383ac993a65ef
来源数据集
uspto-grants-2014_09
专利号
US08846715B2

反应笔记

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