Phthaloyl amlodipine
Amlodipinebesylate / Amlodipine /Amlodipine maleate Intermediates intermediate WindSonChem (India), a global manufacturer and supplier for Phthaloylamlodipine, 88150-62-3 for R&D, Pilot or Commercials Quantities.
Phthaloylamlodipine, 88150-62-3 available with USFDA, EUGMP, GMP, ISO CERTIFIED and WHO-GMP as per the requirement. Product supply in StandardPackaging & labeling as per FDA along with supportive documentation. We can also offer API of Phthaloyl amlodipine, 88150-62-3.
Abstract
The invention relates to a preparation method of an amlodipine intermediate. The invention aims to provide a technical scheme that has the advantages of high product yield and favorable quality and appearance. The method comprises the following steps: under the catalytic action of acetic acid and piperidine and the condition that generated water is carried out by cyclohexane, reacting 4-[2-(phthaloyl)oxethyl]ethyl acetoacetate and p-chlorobenzaldehyde to obtain 2-(2-chlorobenzene methylene)-4-[2-(phthaloyl)oxethyl]ethyl acetoacetate (intermediate II for short); and in an alcoholic solution under the catalytic action of an organic acid, carrying out cyclization on the intermediate II and 3-aminomethyl crotonate to obtain the amlodipine intermediate 4-(2-chlorphenyl)-3-ethoxylcarboxylic acid-5-methoxylcarboxylic acid-6-methyl-2-(2-phthalamide oxethylmethyl)-1,4-dihydropyridine. The preparation method provided by the invention has the advantages of short reaction time, low energy consumption, stable reaction state, high product yield and favorable product quality and appearance, and is suitable for industrial production.
Description
A kind of amlodipine intermediates preparation
Technical field
The invention belongs to the chemical pharmacy field, particularly a kind of amlodipine intermediates preparation.
Background technology
Amlodipine has a typical dihydropyridine family molecule structure developed by Pfizer Inc. at the earliest. Amlodipine is compared with another calcium antagonist, and except having: the side effect incidence is low, and outside the advantages such as long half time, it also has stronger vasorelaxation action. Therefore, except for being applied to treat hypertension, the stenocardia, be hopeful very much to be used for treatment in heart failure, this is that general calcium antagonist is not available.
Owing to containing a dihydropyridine ring in its molecular structure, the synthetic dihydropyridine ring is requisite in its technology, a critical step. For synthesizing of dihydropyridine ring, patent documentation has reported a lot of methods both at home and abroad, all be to utilize o-chlorobenzaldehyde, METHYL 3 AMINO CROTONATE and beta-dicarbonyl compound to carry out ternary Hantzsch annulation to come to the synthesizing dihydro pyridine ring mostly, long reaction time (about 20 hours) not only, and yield is all on the low side, causes cost higher.
Reported an amlodipine synthetic route as CN101367759, this route is with o-chlorobenzaldehyde, METHYL 3 AMINO CROTONATE and 4-[2-(phthalimide-based) oxyethyl group] methyl aceto acetate (hereinafter to be referred as intermediate compound I) carries out the Hantzsch cyclization, reacted 20 hours.
Though this method is simple to operate, yield is too low, only is 17.4%.
International Patent Application WO 2006003672A1 adopts the technology that CN101367759 reported, yield brings up to 31.7%.
Korean Patent (patent No. 87-909) is that yield is low too with the potential functional group of azido-as amino, only is 19%, and there is potential safety hazard in triazo-compound character instability in addition, is not suitable for industrialization.
What United States Patent (USP) 2002/0068831A1 adopted is the binary ring-closure reaction, though the cyclization yield can be up to 70%, but is ammonification reagent with the ammonium acetate, experiment showed, that the ammonification data are difficult for repeating, and quality product and outward appearance are all relatively poor.
