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Preparation method of pentethyl quinamidine optical isomer

A technology for optical isomers and penhyclidine is applied in the field of stereoselective synthesis of penhyclidine optical isomers, which can solve the problems of time-consuming and labor-intensive and unfavorable for large-scale synthesis

Inactive Publication Date: 2011-02-09
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the limitations of separation and purification methods, this method is time-consuming and laborious, which is not conducive to large-scale synthesis
So far, there is no report on the stereoselective synthesis of penehyclidine optical isomers from optically pure raw materials, so there is an urgent need to develop a stereoselective synthesis method of penehyclidine optical isomers

Method used

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  • Preparation method of pentethyl quinamidine optical isomer
  • Preparation method of pentethyl quinamidine optical isomer
  • Preparation method of pentethyl quinamidine optical isomer

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0020] Embodiment 1, the preparation of (2S, 5S)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (IIa)

[0021] Add 20 g (0.13 mol) of S-mandelic acid into 200 mL of n-pentane, add 21.2 mL of pivalaldehyde (content 80%, 0.16 mol, purchased from Fluka Company), then add 0.5 mL of trifluoromethanesulfonic acid, and reflux for 6 hours , Remove the generated water with a water separator. Cool to room temperature, add 100mL 8% sodium bicarbonate solution, distill off n-pentane under reduced pressure, filter to obtain (2S,5S)-2-tert-butyl-5-phenyl-1,3-dioxane-4 - Ketone (IIa), yield 27.1g, melting point 100-102°C, yield 95%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.81, H 7.39. 1 H-NMR: δ (ppm, CDCl 3 ), 1.10 (s, 9H), 5.25 (s, 1H), 5.38 (s, 1H), 7.47 (m, 5H).

Embodiment 2

[0022] Embodiment 2, the preparation of (2R, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (IIb)

[0023] With reference to the method of Example 1, using (R)-mandelic acid as raw material, synthesize (2R, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (IIb), Melting point 100-102°C, yield 97%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.83 H 7.30. 1 H-NMR: δ (ppm, CDCl 3 ), 1.12 (s, 9H), 5.23 (s, 1H), 5.36 (s, 1H), 7.49 (m, 5H).

Embodiment 3

[0024] Example 3, Preparation of (2S, 5R)-2-tert-butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-dioxan-4-one (IIIa)

[0025] Dissolve 10 g (45 mmol) of (2S, 5S)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one in 70 mL of dry tetrahydrofuran, cool to -78°C, add 60 mL of di( Lithium trimethylsilyl)amide (solution in tetrahydrofuran, 1.0M). 65mmol of cyclopentanone was added dropwise under stirring, the reaction was stirred for 2 hours, and 15mL of saturated sodium hydrogen phosphate solution and 200mL of saturated ammonium chloride solution were added dropwise. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried, and the solvent was evaporated to obtain (2S, 5R)-2-tert-butyl-5-phenyl-5-(cyclopentyl-1- Hydroxy)-1,3-dioxan-4-one (IIIa), yield 10.5 g, yield 74%. 1 H-NMR: δ (ppm, CDCl 3 ), 0.88 (s, 9H), 1.52-2.06 (m, 8H), 5.52 (s, 1H), 7.31 (m, 3H), 7.78 (dd, J=1.5, 8.3Hz, 2H).

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Abstract

The present invention relates to a method for preparing penehycloidine hydrochloride, namely, 3-(2'-hydroxy-2'-cyclopentyl-2'-phenyloxethyl) quinuclidinane optical isomer. Said method includes the following steps: using optical pure (S) or (R)-amygdalic acid as chiral template raw material, stereoselectively synthesizing key intermediate (S) or (R)-alpha-phenyl-alpha-cyclopentyl-1,2-oxirane, thenmaking it be reacted with (3S) or (3R)-quinuclidinol to correspondently obtain four optical isomers of objective compound. The optical purity of said objective compound is above 98%.

Description

technical field [0001] The invention relates to a method for stereoselectively synthesizing penehyclidine optical isomers. Background technique [0002] Penehyclidine Hydrochloride [Penehyclidine Hydrochloride, i.e. 3-(2'-hydroxyl-2'-cyclopentyl-2'-phenylethoxy)quinuclidine hydrochloride, its structure is as shown in formula (I) Shown] belongs to ethyl cycloalkane amino ether compounds, it is a new type of structure selective anticholinergic drugs (Lin Yongjin et al. Academy of Military Medical Sciences Journal, 1987, 11, 356.), has been successfully used clinically for the treatment of organophosphorus pesticides In terms of poisoning, etc., it has high antitoxic potency, long-lasting effect and less adverse effects (Zeng Fanzhong et al. Chinese Journal of Internal Medicine. 1993, 32, 838; Qiao Jianzhong et al. Chinese Journal of Pharmaceutical Sciences. 2003, 38, 942.). In the evaluation study of anticholinergic effect, compared with the tool drug QNB (3-Quinuclidine benz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D453/00
Inventor 仲伯华韩翔宇刘河陈兰福刘克良
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A