Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds

Definitions

• 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.
• EP 89167 and corresponding US 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)-l,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. 4,879,303, is the active ingredient in the prescription pharmaceutical composition NORVASC sold by Pfizer Pharmaceuticals for management of hypertension and angina pectoris.
• 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).
• phthalimidoamlodipine 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 azido- amlodipine 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 (Bl) and amino protected aminoethoxy- methylacetoacetate (CT).
• A substituted benzaldehyde
• Bl methyl 3-aminocrotonate
• CT amino protected aminoethoxy- methylacetoacetate
• the compound (Cl') is prepared by a condensation of ethyl 2- chloroacetoacetate (shown hereinafter as compound (F)) with an appropriately substituted sodium alkoxide.
• compound (F) ethyl 2- chloroacetoacetate
• an appropriately substituted sodium alkoxide ethyl 2- chloroacetoacetate
• -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 (Dl) (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 (El) (prepared in situ from the above amino-protected aminoethoxymethylacetoacetate (CT) and ammonium acetate).
• Dl benzylidene derivative
• A o-chlorobenzaldehyde
• 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.
• a first aspect of the invention relates to a compound having the formula (3):
• R 2 represents a C ⁇ -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:
• R 2 each independently represent a C ⁇ -C 4 alkyl group.
• the compounds of formula (2) can be deprotected to form compounds of formula (1):
• Rj 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.
• 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.
• the present invention deals with new compounds, alkyl 2-(o- chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetates of formula (3)
• R 2 represents a C ⁇ -C 4 alkyl group and it preferably represents an ethyl group (compound 3 a), a methyl group (compound 3 b) or an isopropyl group (compound 3 c).
• 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.
• 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).
• 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.
• the product (3) separates out in an oily state.
• 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.
• the process provides the compound (3a) as outlined below.
• the usual ratio of cis- and trans isomers of the compound (3) formed in the process of our invention is from about 7:3 to about 5:5, respectively.
• compounds (3a) and (3c) are usually formed in a cis:trans ratio of about 6:4 while the compound (3b) is usually formed at about a 1:1 ratio of cis:trans.
• Another possibility for preparing the compounds of formula (3) could be by reacting o-chlorobenzaldehyde with an alkyl 2-chloroacetylacetoacetate (F), such as ethyl 2-chloroacetylacetoacetate (Fl), under general conditions described in EP 212340, to form a benzylidene-2-chloroacetylacetoacetate intermediate of formula (4).
• F alkyl 2-chloroacetylacetoacetate
• Fl ethyl 2-chloroacetylacetoacetate
• G N-(2-hydroxyethyl)phthalimide
• Ri and R 2 each independently represent a Cj-C alkyl group.
• the reaction between (3) and (B) may preferably be performed in a suitable solvent, e.g. in isopropanol, at elevated temperatures, advantageously at 70-90°C, as the reaction is thermally driven.
• the speed of reaction may be enhanced by the addition of a catalytic amount of a strong acid and/or by addition of a dehydrating agent, e.g., a molecular sieve, for trapping the formed water.
• the product (2) may be isolated in a solid state after cooling the reaction mixture and/or after concentration of the reaction mixture.
• the product (2) can be purified by recrystallization from a solvent such as methanol, ethanol, 2-propanol, ethyl acetate, etc. or a mixture of two more of such solvents. After a single recrystallization, e.g. from ethyl acetate, the product typically exhibits a purity higher than 98%.
• the use of the compound (3) of our invention in the synthesis of phthalimidoamlodipine (2a) and other related phthalimido-protected precursors avoids the disadvantages of both disclosed synthetic variants of the prior art.
• it allows for a reduction in side products by producing a stable intermediate that is easily separable from the rest of the reactive starting materials, thereby reducing the chance of side effects in subsequent reaction steps.
• it does not require an extra step of conversion of a keto group to an amino group which decreases the overall yield of the process and further it does not require an isolation of the intermediate in a crystalline state.
• the fact that the chlorobenzaldehyde is reacted in a separate step so that the unreacted portion may be absent from the final cyclization reaction is advantageous in both the yield and purity of the compounds of formula (2).
• the compounds of formula (2) can be subjected to a deprotecting step to form a compound of formula (1).
• Ri and R 2 each independently represent a C ⁇ -C 4 alkyl group.
• Phthalimidoamlodipine and other compounds of formula (2) may be converted to amlodipine and corresponding analogues as represented by formula (1) by any of the conventional methods of deprotection of the phthalimido group such as those disclosed in EP 89167.
• deprotecting agents include ethanolic methylamine, hydrazine hydrate or alkali metal hydroxide /acid treatment. Particularly preferred however is a variant of the first method that employs commercially available aqueous solution of methylamine.
• the reaction with aqueous methylamine may be performed at a temperature from the ambient to approx. 60°C, preferably at 25-40°C.
• amlodipine free base is subsequently separated out from the concurrently produced methylphthalimide by an extraction of the aqueous reaction mixture with a water immiscible organic solvent, e.g. by toluene, and, optionally, is isolated from the solution in that solvent.
• a water immiscible organic solvent e.g. by toluene
• Amlodipine as well as all the compounds of formula (1) may be isolated as a free base and/or it may be converted into an acid addition salt by a reaction of the base with the corresponding acid.
• acid addition salts of amlodipine and of other compounds of formula (1) may be prepared without isolating the corresponding free base.
• a solution of amlodipine free base obtained from the step of deprotection of phtalimidoamlodipine may be used as well.
• the solution of crude base, without need of isolation of such free base is contacted with corresponding acid, and the formed salt is separated from the solution.
• Suitable acid addition salts include pharmaceutically acceptable acid addition salts of amlodipine such as amlodipine besylate, hydrochloride, fumarate, maleate and mesylate, including solvates and hydrates thereof. Particularly suitable are amlodipine maleate and amlodipine mesylate monohydrate.
• the compounds of formula (1) can be formulated into a pharmaceutical composition comprising an effective amount of amlodipine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition is in the form of a unit dose having from 1 to 25 mg of the compound of formula (1), measured as the free base. This usually provides a dose sufficient to treat or prevent angina or hypertension.
• Suitable dosage forms include oral solid dosage forms such as tablets and capsules or liquid forms such as for oral or parenteral administration.
• the compositions can be made by known techniques such as wet or dry granulation techniques including direct compression tabletting.
• the compounds of formula (1) can also be used as reference standards or markers for checking the purity of amlodipine. Particularly useful are the analogues of amlodipine of the formulae (lb), (lc), (Id), (le) and (If).
• the compounds (lb) - (If) are important side products/impurities which may appear in the industrial production of amlodipine, especially when an alcohol solvent is employed. That is, the compounds of formula (2) and formula (1) can undergo transesterification such that Ri or R 2 or both are changed from one alkyl group to another. Thus, the following compounds (2b)-(2f) may also arise during the production of amlodipine from the phthalimidoamlodipine precursor and are also useful as markers or reference standards for monitoring purity.
• the compounds (2b)-(2f) When present as an unintended transesterification impurity/side-product, the compounds (2b)-(2f) will also convert into their corresponding compound (lb)-(lf) during the deprotection step.
• the compounds of formula (1) can also undergo transesterification thereby changing the alkyl group in one or both of the Ri and R 2 positions. Transesterification can occur unintentionally during the production of amlodipine, either by the present process or the prior methods, where an alcohol solvent such as ethanol, isopropanol, etc. is used. Transesterification reactions may appear in whatever production step in the production of phthalimidoamlodipine, so that a producer should appreciate to have a method by which the amounts of such undesired products could be monitored.
• the process of the present invention allows for the formation of the compounds (lb) - (If) and (2b) - (2f) in a sufficiently pure state so as to be suitable for use as a reference standard or marker in detecting the presence of these potential impurities in the amlodipine, its salts, its precursors, and its compositions including pharmaceutical compositions, and in the phthalimidoamlodipine, its salts, and its compositions, respectively.
• compounds (2b) - (2f) are preparable in an essentially pure state by following the process of the invention as described above.
• the compounds of formula (2) may be subjected to a (deliberate) transesterification reaction to provide other compounds of the same general formula (2), however bearing other groups Ri, R 2 .
• An example of this process is set forth hereinafter for the synthesis of (2e).
• the compound (3a) of our invention reacts with ethyl 3 -aminocrotonate (compound (B2)).
• the compound (3b) reacts with methyl 3-amino crotonate (Bl) to yield the desired product (2c).
• the compound (3b) can be prepared, inter alia, by condensation of o- chlorobenzaldehyde with methyl 4-(2-(phthalimido)ethoxy)acetoacetate (compound C2).
• Compound C2 can be prepared by a prior art procedure as described above for compound Cl'.
• compound (3b) reacts with ethyl 3- aminocrotonate (B2) in analogy with the above.
• Compound C3 can be prepared by a prior art procedure as described above for compound Cl'.
• the prepared compound (3c) reacts with methyl 3-amino crotonate (Bl) to yield the desired product (2f) under basically same conditions as outlined above.
• phthalimidoamlodipine (2a) is transesterified by heating in isopropanol under catalysis of a strong acid, e.g. sulfuric acid.
• Amlodipine analogues (lb) - (If) may be obtained from corresponding phthalimidoamlodipine analogues (2b) - (2f) under reaction conditions as known and/or as described above for the synthesis of amlodipine. Accordingly, compounds (lb) - (If) may be purified to a desired degree of purity by conventional purification methods and/or may be converted into conventional acid addition salts and optionally purified. Alternatively, the compounds (lb) - (If) can be prepared by subjecting amlodipine to a (deliberate) transesterification reaction.
• amlodipine products or phthalimidoamlodipine
• a process of testing of purity of products comprising amlodipine advantageously comprises, in essence, any technique that can resolve or otherwise detect the presence of the target compound.
• this type of assay include thin layer chromatography (TLC) and high performance liquid chromatography (HPLC).
• amlodipine product to be assayed for the presence of any one or more of potential amlodipine impurities (lb)-(lf) is any product that comprises amlodipine free base or any acid addition salt of amlodipine.
• the amlodipine product include the reaction mixture obtained after deprotection of phthalimidoamlodipine, crude amlodipine free base recovered during synthesis, purified amlodipine free base, reaction mixture obtained in the production of acid addition salts of amlodipine, crude acid addition salt of amlodipine or purified acid addition salt of amlodipine of any suitable form including crystalline forms or amorphous forms, and pharmaceutical unit dosage forms containing the same.
• Acid addition salt of amlodipine means any acid addition salt, however salts with pharmaceutically acceptable acids are preferred; examples of such salts are amlodipine besylate, amlodipine maleate, amlodipine fumarate, amlodipine hydrochloride, amlodipine mesylate etc.
• amlodipine products are made in batches or lots for production purposes. A production lot should be checked to insure that the level of any of amlodipine analogue (lb)-(lf) is within specification; i.e., a quality control test to insure that the amlodipine impurities (lb)-(lf) are below a predetermined limit.
• a sample from the production lot is taken and assayed for the presence of amlodipine analogue and preferably also for the content of amlodipine.
• the production lot must contain less than 1.0 wt %, preferably less than 0.5 %, more preferably less than 0.2% and most preferably less than 0.1% of any of the compounds (lb)-(lf) based on the amount of amlodipine or amlodipine salt.
• the entire production lot, minus any retained sample(s) will be released by the manufacturer unless an unacceptable level of amlodipine impurity is found. In that case, the production lot will not be sold or released; i.e. neither placed in commerce nor used in production of final forms.
• amlodipine analogue (lb)-(lf) is assayed under a set of conditions to produce a reference standard analytical result.
• a "reference standard analytical result” may be a quantitative or qualitative result and can be in any form including numerical, graphical, pictorial, etc. In some cases the result can be stored electronically for later comparisons.
• Assaying of the amlodipine product results in an analytical result for the sample.
• the sample analytical result is compared in some fashion to the reference standard analytical result for corresponding amlodipine analogue.
• the comparison can be done manually such as by visual observation and/or by an automated procedure.
• the reference standard analytical results can be obtained essentially concurrently with the sample analytical results such as immediately before, during or immediately after the assaying of the amlodipine product sample, or they can be obtained earlier, even months or years earlier.
• the reference standard analytical results are electronically stored and used by a computer algorithm to determine the presence of the amlodipine analogue and its amount.
• This latter embodiment includes calibrating the equipment based on the reference standard analytical results or results derived therefrom and/or providing a so-called internal normalization. All such comparisons, whether direct, indirect, manual or automated, are included within the meaning of "comparing.”
• the assay used in determining the reference standard analytical results is generally also the same assay with the same set of conditions used to test the amlodipine product, although such is not necessarily required.
• TLC samples of the tested amlodipine product, and reference standards of amlodipine analogues are chromatographed on a suitable chromatographic plate by a suitable developing liquid (mobile phase) under set conditions. These conditions include the solvent, the concentration of the sample in the solvent and the amount of solution applied to the plate. Selecting appropriate solvents and concentrations is well known within the art.
• the analytical results produced under these conditions may include the R f value, namely the ratio of distance traveled by the corresponding material to the distance traveled by the solvent, and/or the size of the spot produced on the chromatogram.
• the reference standard is applied at the same time and to the same chromatographic plate as the tested sample thereby allowing for side-by-side comparisons.
• the reference standard is already defined and is simply compared with the developed sample chromatogram.
• Amlodipine analogues may also be premixed in defined ratios to form a mixed reference standard.
• one process for testing the purity of a sample comprising amlodipine comprises the steps of: a) dissolving a sample comprising amlodipine in a solvent to produce a sample solution b) dissolving a sample of any or more of amlodipine analogues lb) - If) in a solvent to produce a reference solution c) subjecting the sample solution and the reference solution to thin layer chromatography to obtain a TLC chromatogram for each and d) estimating the intensity of any secondary spot obtained from the sample solution which corresponds in Rf value to the reference marker, against the intensity of the spot due to the corresponding amlodipine analogue in the chromatogram of the reference solution.
• a process for testing the of a sample comprising amlodipine comprises the steps of: a) dissolving a sample comprising amlodipine in a solvent to produce one or more sample solutions b) dissolving a sample of any or more of amlodipine analogues (lb)— (If) in a solvent to produce a reference solution c) injecting the sample and reference solutions to an HPLC column and d) estimating the peak areas of each solution and calculating from these the content of the or any of the amlodipine analogue (s) (lb)-(lf) in each sample solution.
• the method includes the additional step of b') dissolving amlodipine and a suitable external standard(s) to produce a system suitability solution, and injecting the system suitability solution onto the HPLC column to determine resolution factor(s).
• a parameter known as the Response factor (R) may be used.
• the response factor is a previously determined ratio of a numerical result (e.g. peak area at HPLC) obtained by testing a sample of the aspartate or the maleamide, by a given analytical technique, to the corresponding numerical result obtained by testing the same amount of pure amlodipine maleate at an equivalent concentration.
• the known response factor for amlodipine aspartate or amlodipine maleamide can be used to calculate the amount of that particular marker in the test sample. In this way, the relative amount of the impurity to the amlodipine maleate in the sample can be determined as is well known in the art.
• phthalimidoamlodipine products for the presence and amount of phthalimidoamlodipine impurities (2b)-(2f) is important as, knowing the corresponding result, a producer may properly decide whether and how the phthalimidoamlodipine product may be purified or otherwise reprocessed before its conversion to amlodipine and, accordingly, whether or how the conditions in production of phthalimidoamlodipine should be adjusted to obtain a product with improved quality.
• Phthalimidoamlodipine having the content of any of analogues (2b)-(2f) below a predetermined limit may yield amlodipine essentially free of the corresponding amlodipine impurities (lb)-(lf) so that the amlodipine is not required to be further purified; thus saving time and energy and improving the overall economy of the amlodipine production.
• the impurity level should be less than 1 wt %, preferably less than 0.5 wt %, more preferably less than 0.2 wt % and even less than 0.1 wt %.
• a batch of phthalimidoamlodipine is tested for purity by removing a sample therefrom and assaying for one or more of the potential phthalimidoamlodipine impurities (2b)-(2f). The presence and amount of impurity are determined by comparison to a known reference standard analytical result for the impurity such as by HPLC or TLC as described above. If the sample is determined to contain the impurity below a predetermined level, then the phthalimidoamlodipine batch is subjected to a deprotection step to form a batch of amlodipine.
• the phthalimidoamlodipine batch can be re-processed or purified such as by crystallization in order to reduce the impurity level below the predetermined limit, or it may be discarded.
• amlodipine product is not produced when the product will inevitably have too much amlodipine impurity. Not only can such a process improve efficiency and cut waste but also, in some circumstances, it may be easier to separate the phthalimidoamlodipine impurities from phthalimidoamlodipine than it is to separate the amlodipine impurities from amlodipine; thereby improving the overall yield.
• the batch of phthalimidoamlodipine from which a sample is taken can be either the crude or isolated phthalimidoamlodipine product or it can be a purified product.
• a purified product can be obtained by (re)crystallizing the isolated product one or more times as described above. Other purification techniques can also be used, if desired.
• the level of phthalimidoamlodipine impurity is set to 1.0 wt % or less, more typically 0.5 wt % or less, and even less than 0.1 wt %.
• the phthalimidoamlodipine batch is determined to contain the less than the predetermined amount of impurity, the batch is subjected to deprotection and converted to a batch of amlodipine.
• the amlodipine is generally converted to a pharmaceutically acceptable salt thereof and then combined with at least one pharmaceutically acceptable excipient to form a pharmaceutical unit dosage form such as a tablet or a capsule.
• These unit dosage forms contain an effective amount of amlodipine.
• the amlodipine batch, or the amlodipine salt, or the amlodipine unit dosage form, or a combination thereof are subjected to an assay for the level of at least one amlodipine impurity of (lb)-(lf). If the level of amlodipine impurity is above a predetermined level, then the amlodipine product may be reprocessed or otherwise not released or sold.
• a portion of the raw product was purified by a chromatography on silica gel 60 using a 1 : 1 (v/v) mixture of ethyl acetate and n- heptane as the eluent. After collection of the fraction containing the product, the solvent was evaporated leaving an oil.
• NMR shows a mixture of Z and E- isomers, whereby the Z/E ratio is approximately 6:4.
• the 1H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated chloroform at 400 MHz.
• Toluene layer was extracted with 310 ml of water. Toluene was distilled off at max.
• the compound was synthesized according to the same procedure as in Example 8 , but starting from crystalline compound 2b ) (purity - 98.4%).
• the 1H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethylsulfoxide at 400 MHz.
• 13 C-NMR spectrum The 13 C - NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethylsulfoxide at 100.6 MHz.
• the 1H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethylsulfoxide at 400 MHz.
• the ' H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated chloroform at 400 MHz.
• Step 2 Condensation with methyl 3 -aminocrotonate 20 g of the oil prepared according to Step 1 was dissolved in 30 ml of isopropanol and 5.1 g of methyl 3 -aminocrotonate was added under nitrogen. The mixture was heated to reflux for 18 hours under stirring. The mixture was cooled to room temperature and evaporated to dryness. 15 ml of glacial acetic acid was added. A solid was formed which was filtered off and washed with 5 ml of glacial acetic acid. The crude product was recrystallized from 25 ml of ethyl acetate. After drying at 50°C under vacuum, 10.2 g of a slightly yellow solid was obtained. The solid was recrystallized from ethyl acetate leaving 9.8 g of a solid. 1H-NMR spectrum:
• the 1H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated chloroform at 400 MHz.
• the C - NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated chloroform at 100.6 MHz.

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