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Process for preparing phencynonate optical isomer

An optical isomer, optical technology, used in organic chemistry and other directions

Active Publication Date: 2008-09-24
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is no report on the synthesis of phencyclononate optical isomers from optically pure raw materials

Method used

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  • Process for preparing phencynonate optical isomer
  • Process for preparing phencynonate optical isomer
  • Process for preparing phencynonate optical isomer

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0024] Embodiment 1, the preparation of (2R, 5S)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (IIa)

[0025] Dissolve 20 g (0.13 mol) of R-mandelic acid in 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, install The water tank was refluxed for 6 hours, and the water was removed by the water separator. Cool to room temperature, add 100 mL of 8% sodium bicarbonate solution, distill off n-pentane under reduced pressure, and filter to obtain (2R,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

[0026] Embodiment 2, the preparation of (2S, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (IIb)

[0027] With reference to the method of Example 1, using (S)-mandelic acid as raw material, synthesize (2R, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-ketone (IIb) , melting point 100-102°C, yield 97%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.83H 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

[0028] Example 3, Preparation of (2R, 5R)-2-tert-butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-dioxan-4-one (IIIa)

[0029] Dissolve 10 g (45 mmol) of (2R,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). 65 mmol of cyclopentanone was added dropwise under stirring, and the reaction was stirred for 2 hours, and 15 mL of saturated sodium hydrogen phosphate solution and 200 mL 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 (2R, 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 the process of preparing 2'-phenyl-2'-glycolic acid-9alpha-[N-methyl-3-azadicyclo (3, 3, 1) nona] ester optical isomers. The process includes stereo selective synthes is of key intermediate (R) or (S)-alpha-phenyl-alpha-cyclopentyl-alpha-glycolate with optically pure R or S amygdalic acid as chiral template material; and further condesnation with 9alpha-N-methyl-3-azadicyclo(3, 3, 1)nona alcohol to obtain the destination product. The final product has optical purity over 98 %.

Description

technical field [0001] The present invention relates to a kind of stereoselective synthesis (R) and (S)-2'-phenyl-2'-cyclopentyl-2'-hydroxyacetic acid-9α-[N-methyl-3-azabicyclo( 3,3,1) Nonyl] ester (also known as phencyclic nonyl ester) optical isomer method. Background technique [0002] Phencynonate hydrochloride, 2′-cyclopentyl-2′-phenyl-2′-hydroxyacetic acid-9α-[N-methyl-3-azabicyclo(3.3.1)nonyl]ester salt Acid acid, its structure is as follows formula I) [0003] [0004] It is a selective anticholinergic drug, clinically used to prevent and treat various motion sickness such as motion sickness and seasickness. CN1089838A and US6028198 disclose the purposes of phencyclonyl hydrochloride as anti-motion sickness (motion sickness, boat, machine etc.) medicine; CN97125424.9, GB2297255 and ES 549796A disclose the preparation method of phencyclonyl hydrochloride; WO02067933 discloses hydrochloric acid The use of phencyclonate for treating Parkinson's disease / syndrome an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/02C07D221/22C07D471/08C07D487/02C07C59/06
Inventor 仲伯华刘河韩翔宇刘克良谢剑炜
Owner BEIJING SIHUAN PHARMA