Process for making amlodipine

Details Process for making amlodipine Process for making amlodipine

2001-08-27

2003-11-25

Fan, Jane (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06653481

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel intermediates useful in the synthesis of amlodipine and related compounds as well as to processes of making and using the same.
2. Description of the Related Arts
EP 89167 and corresponding U.S. Pat. No. 4,572,909 describe a class of dihydropyridine derivatives that exhibit antianginal and antihypertensive properties. One of the compounds disclosed therein has become a commercially important compound that is now known as amlodipine: or 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester, having the following formula:
This compound, in the form of its besylate salt as described in EP 244 944 and in corresponding U.S. Pat. No. 4,879,303, is the active ingredient in the prescription pharmaceutical composition NORVASC sold by Pfizer Pharmaceuticals for management of hypertension and angina pectoris.
Generally, the synthetic route disclosed in EP 89167 for making amlodipine and the other related dihydropyridine compounds comprises forming the corresponding amino-group protected precursor followed by deprotection. Suitable protecting groups for the amino side chain group include benzylamino, dibenzylamino, azido and phthalimido groups. One of the precursors for amlodipine uses a phthalimido protecting group and is represented by the following formula (2a).
This compound, which is hereinafter referred to as “phthalimidoamlodipine,” has certain advantages among other amino-protected precursors for amlodipine as it may be easily separated from the reaction mixture without danger (e.g. the azidoamlodipine is explosive) and is converted to amlodipine by simple, common deprotection procedures, e.g. by reaction with methylamine, hydrazine etc. It is thus considered to be a particularly useful key intermediate for industrial production of amlodipine.
J. Med. Chem. 1986, 29, 1696-1702 discloses two routes for making the phthalimidoamlodipine and other related amino-protected precursors. The first route comprises reacting a substituted benzaldehyde (A), such as 2-chlorobenzaldehyde, with methyl 3-aminocrotonate (B 1) and amino protected aminoethoxy-methylacetoacetate (C1′).
The compound (C1′) is prepared by a condensation of ethyl 2-chloroacetoacetate (shown hereinafter as compound (F)) with an appropriately substituted sodium alkoxide. Where —N(prot) represents a phthalimido-group, the alkoxide can be N-(2-hydroxyethyl)phthalimide (shown hereinafter as compound G).
The second route disclosed in this article, comprises reacting a benzylidene derivative (D1) (prepared in an extra step by an addition of a compound of formula (A), such as o-chlorobenzaldehyde, to methyl acetoacetate) with a substituted aminocrotonate (E1) (prepared in situ from the above amino-protected aminoethoxymethylacetoacetate (C1′) and ammonium acetate).
This variant was also applied to the synthesis of phthalimidoamlodipine (2a) in WO 00-24714. Therein, the intermediating phthalimido-substituted aminocrotonate (E1) was not prepared in situ but was prepared and isolated in a solid state in an extra step prior to the reaction with the benzylidene compound.
The above methods suffer from yield and/or purity inefficiencies due to the reactivity of starting materials leading to formation of side products. For example, phthalimidoamlodipine is reported in the above-mentioned J. Med. Chem. Article as being prepared in 25% yield by following the first scheme (see compound 41 in Table I on page 1698). It would be desirable to provide a process for making phthalimidoamlodipine and related compounds in good yield and with good purity.
SUMMARY OF THE INVENTION
It has now been discovered that phthalimidoamlodipine (2a) as well as related phthalimido-protected precursors can be prepared by a convenient method, with a good yield and purity, by employing a new starting material. Accordingly, a first aspect of the invention relates to a compound having the formula (3):
Wherein R
2
represents a C
1
-C
4
alkyl group, preferably an ethyl group. The compounds of formula (3) can be reacted with an alkyl 3-aminocrotonate of formula (B) to form a phthalimido-protected precursor of formula (2) as shown below:
wherein R
1
and R
2
each independently represent a C
1
-C
4
alkyl group. The compounds of formula (2) can be deprotected to form compounds of formula (1):
Preferably R
1
is methyl and R
2
is ethyl whereby the process forms amlodipine via the phthalimidoamlodipine (2a). The other compounds of formula (1) are also useful as calcium channel blockers for treating angina or hypertension. Additionally, these compounds and the corresponding phthalimido-protected precursors of formula (2) are useful as reference standards or markers for checking the respective purity of amlodipine or phthalimidoamlodipine, a salt thereof, or a composition containing the same; i.e. assaying for these formula (1) compounds which can be formed as side-products in commercial manufacture of amlodipine via transesterification for example.
DETAILED DESCRIPTION OF THE INVENTION
The present invention deals with new compounds, alkyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetates of formula (3)
wherein R
2
represents a C
1
-C
4
alkyl group and it preferably represents an ethyl group (compound 3a), a methyl group (compound 3b) or an isopropyl group (compound 3c).
The compound (3) may be prepared in a sufficiently pure state and simply isolated from a crude reaction mixture by any conventional techniques. Such an isolated form of the compound (3) can be further purified if needed or used directly in the next synthetic step. Due to the presence of a carbon—carbon double bond in the molecule, the compound (3) may be prepared as a mixture of cis- and trans- isomers or as a single cis- or trans isomer. The formation of a trans-isomer is driven thermodynamically (trans-isomer is preferably formed at elevated temperatures), while the formation of cis-isomer is driven kinetically. From the use aspects, the compound (3) in a form of a mixture of cis-and trans isomers is preferred; however, single isomers are also within the scope of the invention.
Among the compounds of general formula (3), the compound (3a) is particularly important as it represents an industrially applicable intermediate in the synthesis of amlodipine.
The present invention also provides a process for providing the compound of formula (3), comprising reacting o-chlorobenzaldehyde with alkyl 4-(2-(phthalimido)ethoxy)acetoacetate of formula (C).
Typically the reaction is carried out in a reaction solvent, preferably an organic solvent such as an alcohol, especially isopropanol or in a hydrocarbon such as benzene, advantageously in a presence of an organic base such as piperidine or piperidine acetate. The solvent should be one in which the compound (3) product is only sparingly soluble, so that it may be separated from the rest of the unreacted starting materials and also from any potential side products. The reaction may be performed at temperatures from close to ambient up to the boiling point of the solvent, usually about 20 to 55° C., preferably at 20-40° C. Water formed by the reaction may be separated out e.g. by azeotropic distillation though this is not required.
If the reaction is performed in isopropanol, the product (3) separates out in an oily state. Preferably the compound (3) oil is recovered and used directly without further purification to form phthalimidoamlodipine as such oil contains only minor amounts of impurities and the remaining starting materials can be easily removed. Recovery can be by any known technique and is typically accomplished by a liquid—liquid phase separation optionally with washing of the oil product. It should be understood that such washing is not intended to be considered a “purification step”, but rather merely part of the recovery. Thus, it is an advantage of this process that although the disadvantages of an “in-situ” production of (3) are avoided, the isolat

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