Showing posts with label WO 2013138200. Show all posts
Showing posts with label WO 2013138200. Show all posts

Monday, 15 December 2014

Green chemistry synthesis of the malaria drug amodiaquine and analogs thereof WO 2013138200 A1

An exemplary method for producing amodiaquine is:
Figure imgf000006_0001
[0013] In an aspect, analogs can be suitably prepared, such as by using a different secondary diamine. For example, an exemplary di-alkyl analog of amodiquine is a di- isopropyl analog that can be prepared using di-isopropyl amine instead of di-ethylamine, and such di-isopropyl analog is represented by the formula:
Figure imgf000007_0001
[0014] A di-aryl substituted analog can be prepared in a similar fashion using an aryl- substituted secondary amine instead of a secondary di-alkylamine. An exemplary di-aryl analog of amodiquine can be prepared using a di-aryl amine, such as diphenyl amine instead of diethylamine, and such diphenyl analog is represented by the formula:
Figure imgf000007_0002
It will be appreciated that different alkyl-substituted or aryl-substituted analogs of amodiaquine can be prepared by selecting a suitable secondary amine.
[0015] Another illustrative synthesis involves using a 3-aminophenol. For example, such a synthesis can be illustrated as follows:
Figure imgf000008_0001
1. Acetic acid, reflux, 3 h
2. CH20, iPr2NH, acetic acid, 14 h
Figure imgf000008_0002
[0016] In a similar fashion, an analog having a di-aryl phenyl group is obtainable as follows:
Figure imgf000009_0001
Figure imgf000009_0002
[0017] In one of its aspects, an illustrative one-pot synthesis is described in Example 3.
[0018] In one of its aspects a method described herein advantageously utilizes a one- pot process for preparing a compound, or its pharmaceutical salts, and preferably the compound is represented by the formula:
Figure imgf000010_0001

[0074] To a mixture of 4-aminophenol (11.4 grams, 0.104 mol) and 4,7- dichloroquinoline (19.8 grams, 0.10 mol), acetic acid was added (60 ml, 3.0 volumes w/v relative to 4,7-dichloroquinoline) with stirring at room temperature and the resulting mixture was heated with stirring at 110°C for about one hour. The mixture was cooled to 20°C and formaldehyde (14.06 grams of a 32% aqueous solution, 0.150 mol, 1.5 mol eq) and diethylamine (10.95 grams, 0.150 mol, 1.5 mol eq were sequentially added to the same reaction vessel). The reaction mixture was then heated and reaction occurred at 50°C for four hours. The mixture was cooled in an ice water bath and 22 mL of 37% aqueous hydrochloric acid solution (containing 0.264 mol of HC1) was added at a rate so that the internal temperature did not exceed 40°C. Stirring was continued for an additional 2 hours to complete the precipitation of the desired product as yellow crystals The precipitated crystals were collected by filtration and dried at room temperature to a constant weight to obtain 42.7 grams of amodiaquine dihydrochloride dihydrate (92% yield) in a purity of greater than 99% as determined by HPLC analysis. [0075]

WO2011073322A1 *Dec 16, 2010Jun 23, 2011Institut National De La Sante Et De La Recherche Medicale (Inserm)7-chloro-quinolin-4-amine compounds and uses thereof for the prevention or treatment of diseases involving formation of amyloid plaques and/or where a dysfunction of the app metabolism occurs
US3855286 *Sep 27, 1972Dec 17, 1974Ciba Geigy CorpN-carboxymethyl-n-(2-hydroxybenzyl) aspartic acid and derivatives thereof

1*DELARUE-COCHIN ET AL.: 'Synthesis and antimalarial activity of new analogues of amodiaquine' EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, [Online] vol. 43, 2008, pages 252 - 260 Retrieved from the Internet: <> [retrieved on 2013-05-07]
GUO ET AL.: 'Chiral Bronsted Acid-Catalyzed Direct Asymmetric Mannich Reaction' J. AM. CHEM. SOC., [Online] vol. 129, 2007, pages 3790 - 3791 Retrieved from the Internet: <URL:> [retrieved on 2013-05-07]



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