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Novel synthesis method for levorgyration demethyl phencynonate

A technology of methylphencyclononate and benzyl, which is applied in the field of synthesizing L-demethylphencyclononate, which can solve problems such as explosive, not environmentally friendly, and complicated operation

Inactive Publication Date: 2013-07-31
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] There are following deficiencies in the above-mentioned synthetic route of the prior art: 1) when preparing (R)-alpha-phenyl-alpha-cyclopentyl-alpha-glycolic acid methyl ester, use highly toxic, volatile, Explosive diazomethane is unsafe and not environmentally friendly; 2) the synthesis of the intermediate N-methyl-3-azabicyclo-[3.3.1]-nonan-9-one requires two pours of acid-base, and Acetic anhydride is further reacted to process the by-products generated in the reaction, and high vacuum distillation is required, which is complicated to operate; 3) during demethylation, highly toxic trichloroethanol chloroformate and a class of solvent benzene are used, which is not conducive to environmental protection; 4) The last step requires the use of zinc powder and acetic acid. The reaction produces zinc sludge, which is costly for the treatment of industrial wastes. At the same time, the reaction produces zinc acetate, which may easily lead to excessive heavy metal residues in the product, requiring careful post-treatment

Method used

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  • Novel synthesis method for levorgyration demethyl phencynonate
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  • Novel synthesis method for levorgyration demethyl phencynonate

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specific Embodiment approach

[0094] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention.

[0095] The present invention provides general and / or specific descriptions of the materials and test methods used in the tests. Although many materials and operating methods used to realize the object of the present invention are well known in the art, such as commercially available or can be synthesized by those of ordinary skill in the art according to the present invention or prior art teachings, the present invention Still described in as much detail as possible here.

Embodiment 1

[0097] 1. Preparation of (2R, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one

[0098] N 2 Under protection, put 60 g (0.39 mol) of R-mandelic acid into 600 mL of n-pentane, stir for half an hour, add 2.64 mL of trifluoromethanesulfonic acid, and then add 64.56 mL of pivalaldehyde (80% content, purchased from Fluka Company) , Reflux for 23 hours after the addition, and remove the generated water with a water separator. Cool to room temperature, add 8% sodium bicarbonate solution to adjust pH=8-9, filter, wash with water and n-pentane, and dry by IR to obtain (2R,5R)-2-tert-butyl-5-phenyl-1, 3-dioxan-4-one (II), yield 76.35g, melting point 141-143°C, yield 93%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.81, H 7.39 .1H-NMR: δ (ppm, CDCl3), 1.10 (s, 9H), 5.25 (s, 1H), 5.38 (s, 1H), 7.47 (m, 5H). 1H-NMR: δ (ppm, CDCl3), 1.12 (s, 9H), 5.23 (s, 1H), 5.36 (s, 1H), 7.49 (m, 5H). Developing system: PE:EtOAc=20:1; Rf value: 0.65 for the product...

Embodiment 2

[0120] 1. Preparation of (2R, 5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one

[0121] N 2 Under protection, put 60 g (0.39 mol) of R-mandelic acid into 600 mL of n-hexane, stir for half an hour, then add 2.64 mL of trifluoromethanesulfonic acid (note: heterogeneous phase, attention should be paid to stirring effect), and then add pivalaldehyde 64.56 mL (content 80%, purchased from Fluka Company), refluxed for 23 hours after the addition, and removed the generated water with a water separator. Cool to room temperature, add 8% sodium bicarbonate solution to adjust pH=8-9, filter, wash with water and n-hexane, and dry to obtain (2R,5R)-2-tert-butyl-5-phenyl-1,3- Dioxan-4-one, yield 75.55g, melting point 141-143°C, yield 92%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.81, H 7.39. 1H-NMR: δ (ppm, CDCl3), 1.10 (s, 9H), 5.25 (s, 1H), 5.38 (s, 1H), 7.47 (m, 5H). 1H-NMR: δ (ppm, CDCl3), 1.12 (s, 9H), 5.23 (s, 1H), 5.36 (s, 1H), 7.49 (m, 5H). ...

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Abstract

The invention relates to a novel synthesis method for levorgyration demethyl phencynonate. More specifically, the invention relates to a synthesis method for levorgyration demethyl phencynonate or salt thereof represented by formula I. The method comprises the following steps: (i) carrying out ester interchange between (R)-alpha-phenyl-alpha-cyclopentyl-alpha-methyl glycolate and N-benzyl-3-azabicyclo-[3.3.1]-nonyl-9-alcohol in an appropriate solution and in presence of an appropriate reagent so as to obtain (R)-alpha-cyclopentyl-alpha-phenyl-glycollic aicd-9-[N-(benzyl)-3-azabicyclo (3.3.1)nonyl] ester; (ii) performing catalytic hydrogenation on (R)-alpha-cyclopentyl-alpha-phenyl-glycollic aicd-9-[N-(benzyl)-3-azabicyclo (3.3.1)nonyl] ester in an appropriate solution and in presence of an appropriate catalyst so as to remove benzyl and obtain the compound represented by formula I; (iii) in presence of an acid, reacting the compound to form a salt so as to obtain the salt of the compound. The invention also relates to a preparation method for key intermediates used in the above-mentioned method. The methods have excellent characteristics as described in the specification.

Description

technical field [0001] The present invention relates to a kind of L-desmethylphencyclononyl ester or its salt, that is, L-alpha-cyclopentyl-alpha-phenyl-glycolic acid-9-[3-azabicyclo(3.3.1)nonyl]ester or A new method for the synthesis of its salt. Background technique [0002] Desmethylphencyclononyl hydrochloride is the general name of (R) α-cyclopentyl-α-phenyl-glycolic acid-9-[3-azabicyclo(3.3.1)nonyl]hydrochloride, its The structure looks like this: [0003] [0004] L-desmethylphencyclonate is a metabolite of L-phencyclononate, and it is a new structurally-new M4 receptor antagonist with receptor selectivity. Its selectivity index (M4 / M1>100, M4 / M2>100, M4 / M3 > 10, M4 / M5 > 10) are superior to M4 receptor selective antagonists reported in the literature (eg see references 1-5). Because of its strong activity (IC 50 4.4×10 -9 M), low toxicity (mouse LD 50 490mg / Kg), has entered preclinical research as a candidate drug for the treatment of Parkinson's ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/22C07C69/732C07C67/10
Inventor 何新华仲伯华张凭
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A