FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION (See section 10 and rule 13)


"A PROCESS FOR THE PREPARATION OF ZOFENOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai -400 099
The following specification describes the nature of the invention:


FIELD OF THE INVENTION The present invention relates to a process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof. The present invention also provides structurally novel intermediates useful in the synthesis of zofenopril, a pharmaceutical composition and a method of treating hypertension.
BACKGROUND OF THE INVENTION
Zofenopril is a oral angiotensin-1 converting enzyme (ACE) inhibitor which has been approved in EU for the treatment of mild to moderate essential hypertension and Myocardial infarction. Zofenopril calcium is chemically described as (4S)-N-[3-(Benzoylsulfanyl)-2(S)-methylpropionyl]-4-(phenylsulfanyl)-L-proline calcium salt and has the following structure:

U.S. Patent No. 4,316,906 (the '906 patent) describes mercaptoacyl derivatives including zofenopril and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and also discloses a process for the preparation of zofenopril which is illustrated by the scheme below:

One of the impurities of zofenopril or its pharmaceutically acceptable salts is cis-phenyl thioproline acetamide of formula VI.

which is formed in coupling of intermediate compounds during the formation of the compound of formula lla when ethyl acetate or acetic acid or its derivatives is used as solvents.
It is also beneficial to provide zofenopril in solid state and/or additional polymorphic forms, The availability of neutral zofenopril in solid form would be an added advantage in the preparation of pharmaceutically acceptable salts of zofenopril such as zofenopril calcium useful in the preparation of pharmaceutical formulations for the treatment of hypertension.
The present invention provides a process for preparation zofenopril calcium and intermediates which is simple, ecofriendiy, inexpensive, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof.
In one aspect, the present invention provides a process for the preparation of zofenopril of formula la

or a pharmaceutically acceptable salts thereof, comprising:
a) reacting protected cis-4-phenylthio-L-proline alkyl ester compound of formula IV or a salt thereof

where R denotes hydrogen or linear or branched alkyl group or the benzyl group, with S-(-)-3-benzothio- 2-methylpropionic acid compound of formula III or a salt thereof.

III in the presence of coupling agent to form (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline alkyl ester compound of formula II

b) subjecting the resultant compound of formula II to deprotection to form the compound of formula la.
In a second aspect, the present invention provides a process for the preparation of protected cis-4-phenylthio-L-proline alkyl ester compound of formula IV or a salt thereof comprising reacting cis-4-phenylthio-L-proline compound of formula IVb or salt thereof

with an alcohol ROH, where R linear or branched alkyl group or the benzyl group.

In a third aspect, the present invention provides a process for the preparation of zofenopril of formula la or a pharmaceutically acceptable salts thereof, comprising: a) reacting cis-4-phenylthio-L-proline benzyl ester compound of formula IVa or a salt thereof

with S-(-)-3-benzothio-2-methyl propionic acid compound of formula III or ester derivative or a salt thereof

in the presence of coupling agents to form (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline benzyl ester of structural formula lla,

b) subjecting the resultant compound of formula IIa to deprotection to form the compound of formula la.
In a fourth aspect, the present invention provides a process for the preparation of cis-4-phenylthio-L-proline benzyl ester compound of formula IVa or a salt thereof

IVa
comprising reacting cis-4-phenylthio-L-proline compound of formula IVb or salt thereof
with benzyl alcohol.
In a fifth aspect, the present invention provides a compound (4S)-l-[(2S)-3-(benzoyIthio)-2-methylpropionyl]-4-(phenylthio)-L proline benzyl ester of formula IIa or a salt thereof.

In a sixth aspect, the present invention provides a process for the preparation of zofenopril calcium comprising reacting zofenopril with a calcium derivative in the presence of an organic solvent.

in an amount not more than 1,0 area percent by HPLC.
In a seventh aspect, the present invention provides zofenopril calcium comprising the impurity cis-phenyl thioproline acetamide of formula VI

In an eighth aspect, the present invention provides zofenopril calcium comprising cis-phenyl thioproline acetamide impurity of formula VI in an amount not more than 0.5% area percent, as measured by HPLC.
In a ninth aspect, the present invention provides zofenopril calcium comprising cis-phenyl thioproline acetamide impurity of formula VI in an amount not more than 0.1% area percent, as measured by HPLC.
In a tenth aspect, the present invention provides zofenopril in isolated solid form. In another aspect, the present invention provides zofenopril in substantially crystalline form. In yet another aspect, the present invention provides zofenopril in substantially amorphous form.
In yet further aspect, the present invention provides a process for preparing zofenopril comprising the steps of:
a) providing a solution of zofenopril salt in a mixture of water and organic solvent.
b) subjecting the-solution to hydrolysis;
c) recovering the desired solid form of zofenopril.
In a still yet another aspect, the present invention provides X-ray powder diffraction pattern Zofenopril free acid obtained by the process of present invention characterized by with peak at about 9.45 ± 0.2 degrees 2-theta, which is substantially as shown in Fig. 2.
In another aspect, the present invention provides tertiary butyl amine salt of zofenopril which is preferably in crystalline form.
Zofenopril tertiary butyl amine salt of present invention is characterized by X-ray powder diffraction pattern with characteristic peaks at about 3.0, 6.1, 8.4, 10.3. 11.2, 12.2, 12,3, 15.2, 16.5, 17.2, 18.2, 18.7, 18.9, 19.7, 20.6, 21.4, 23.5, 25.8 and 27.2 ± 0.2 degrees 2-theta,which is substantially as shown in Fig. 3.
In a still yet another aspect, the present invention provides X-ray powder diffraction pattern of Zofenopril dicyclohexyl amine salt obtained by the process of present invention characterized by peak at about 6.9, 10.7, 11.8, 15.4, 17.0, 17.7, 18.2, 18.7, 19.1, 19.5, 21.3, 22.6 and 27.6 + 0.2 degrees 2-theta, which is substantially as shown in Fig. 4.

In a yet further aspect, the present invention provides a pharmaceutical composition comprising zofenopril or its pharmaceutically acceptable salts and at least a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: is a schematic representation of an embodiment of the process of present invention.
Fig. 2: is an X-ray powder diffraction pattern of zofenopril free acid prepared by Example 4.
Fig. 3: is an X-ray powder diffraction pattern of zofenopril tertiary butyl amine salt prepared by
Example 1. Fig. 4: is an X-ray powder diffraction pattern of zofenopril dicyclohexylamine salt prepared by Example 3.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof.
The present invention provides a process for the preparation of zofenopril of formula la

[la]
or a pharmaceutically acceptable salts thereof, comprising:
a) reacting protected cis-4-phenyIthio-L-proline alkyl ester compound of formula IV or a salt thereof

where R denotes a hydrogen or linear or branched alkyl group or the benzyl group, with S-(-)-3-benzothio-2-methyl propionic acid compound of formula III or a salt thereof


in the presence of coupling agent to form (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline alkyl ester compound of formula II

in which R has the same meaning as defined for formula IV
b) subjecting the resultant compound of formula II to deprotection to form the compound of formula la.
The reaction of step (a) is carried out by a condensation reaction known in peptide synthesis, using suitable coupling agents such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) and the like.
Impurities in an API known in the art may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starling materials, synthetic by-products, and degradation products. Impurities in zofenopril or any active pharmaceutical ingredient (API) are undesirable and. in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
As noted above, one of the impurities which arises during the formation of zofenopril is cis-phenyl thioproline acetamide of formula VI.
The International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including

purification steps, such as crystallization, distillation, and liquid-liquid extract ion. in the manufacturing process.
The reaction of step (a) is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and preferably it can dissolve the reagents to some extent. The solvents that can be used include but are not limited to halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like or mixtures thereof; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof.
The reaction can take place over a wide range of temperatures; In general, it would be convenient to perform the reaction at a temperature of from about-10°C to about 120° C or reflux temperatures of the solvents used. Preferably from about 30°C to about 110 °C, this may vary depending on the nature of the reactants and on the solvents employed.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, time required can be from about 1 hour to about 20 hours. Preferably from 1 hour to 10 hours.
The deprotection reaction of step (b) is carried out by catalytic hydrogenation in the presence of hydrogen or by acid treatment. The hydrogenation catalysts that can be used for example platinum, palladium on charcoal carbon, platinum oxide, palladium dioxide, Raney nickel and the like; acids that can be used is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, and the like.
The deprotection reaction is carried out in the presence of a solvent. The solvents that can be used include but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixtures thereof; esters such as ethylacetate, isopropylacetate, tertiary butyl acetate and the like or mixtures thereof; ethers such as tetrahydrofuran, 1,4-dioxane, and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like or mixtures thereof; aprotic polar solvents such as N,N-

dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof; or their aqueous mixtures.
The reaction can take place over a wide range of temperatures. In general, the reaction is carried at temperatures of about 30°C to about 100° C. Preferably from about 30°C to about 75°C, this may vary depending on the nature of the reactants and the solvents employed.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time required for completion of the reaction can be from about 1 hour to about 20 hours. Preferably from l hour to 10 hours.

comprising reacting cis-4-phenylthio-L-proline compound of formula IVb or salt thereof
In another embodiment of the present invention, there is provided a process for the preparation of protected Cis-4-phenylthio-L-proline alkyl ester compound of formula IV or a salt thereof

with an alcohol ROH, where R linear or branched alkyl group or the benzyl group.
The alkyl or aryl esters of compound of formula IV can be prepared by reaction of compound of formula IVb with an alcohol of general formula ROH where R is alkyl or aryl in the presence of organic solvent; preferably benzyl.
The alcohols that can be used include but are not limited to methanol, ethanol. isopropanol, tertiary butyl alcohol, benzyl alcohol and the like, preferably benzyl alcohol.
The organic solvents that can be used include but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixtures thereof; esters such

as ethylacetate, isopropylacetate, tertiary butyl acetate and the like or mixtures thereof; ethers such as tetrahydro furan, 1,4-dioxane, and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-hetane, cyclohexane, toluene, xylene and the like or mixtures thereof; aprotic polar solvents such as N,N-dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof; or their aqueous mixtures, preferably toluene.
The reaction can take place over a wide range of temperatures. In general, the reaction is carried at temperatures of about 30°C to about 100° C. Preferably the reaction temperature can be from about 30°C to about 75 °C, and this may vary depending on the nature of the reactants and the solvents employed.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time required for completion of the reaction can be from about 1 hour to about 10 hours, preferably from about 1 hour to about 5 hours.
The esters of compounds of formula IVb, optionally, are converted into acid addition or carboxylic acid salts by reacting with hydrochloric acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, benzene sulfonic acid, paratoluene sulfonic acid and the like, preferably paratoluenesulfonic acid.
The present invention provides a process for the preparation of zofenopril of formula la

or a pharmaceutically acceptable salts thereof, comprising: a) reacting cis-4-phenylthio-L-proline benzyl ester compound of formula IVa or a salt thereof


with S-(-)-3-benzothio-2-methyI propionic acid compound of formula III or ester derivative or a salt thereof

in the presence of coupling agents to form (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L-proline benzyl ester of formula Ha,

b) subjecting the resultant compound of formula IIa to deprotection to form the compound of formula la.
The reaction of step (a) is carried out by a condensation reaction known in peptide synthesis, using suitable coupling agents such as dicyclohexylcarbodiimide and 1 -hydroxybenzotriazole and the like.
The reaction of step (a) is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and preferably it can dissolve the reagents to some extent. The solvents that can be used include but are not limited to halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene

and the like or mixtures thereof; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof.
The reaction can take place over a wide range of temperatures. In general, it would be convenient to perform the reaction at a temperature of from about -10°C to about 120° C or reflux temperatures of the solvents used. Preferably the reaction temperature can be from about 30°C to about 110 °C, and this may vary depending on the nature of the reactants and on the solvents employed.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, time required can be from about 1 hour to about 20 hours, preferably from about 1 hour to about 10 hours.
Typically, the molar amount of compound of formula III may be about 1 to about 2 times the molar amount of the compound of formula IVa. preferably about 1 to about 1 : the molar amount of coupling agents may be about 1 to about 4 times the molar amount of the compound of formula IVa. preferably about 1 to about 1.
The deprotection reaction of step (b) is carried out by catalytic hydrogenation in the presence of hydrogen. The hydrogenation catalysts that can be used for example platinum, palladium on charcoal carbon, platinum oxide, palladium dioxide, Raney nickel and the like, preferably palladium-carbon.
The deprotection reaction is carried out in the presence of a solvent. The solvents that can be used include but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixtures thereof; esters such as ethylacetate, isopropylacetate, tertiary butyl acetate and the like or mixtures thereof; ethers such as tetrahydrofuran, 1,4-dioxane, and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like or mixtures thereof ; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof; or their aqueous mixtures.

The reaction can take place over a wide range of temperatures. In general, the reaction is carried at temperatures of about 30°C to about 100° C, preferably from about 30°C to about 75 °C, which may vary depending on the nature of the reactants and the solvents employed.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time required for completion of the reaction can be from about 1 hour to about 20 hours, preferably from 1 hour to about 10 hours.

comprising reacting Cis-4-phenylthio-L-proline compound of formula IVb or salt thereof
The present invention provides a process for the preparation of cis-4-phenylthio-L-proline benzyl ester compound of formula IVa or a salt thereof

with benzyl alcohol.
The organic solvents that can be used include but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixtures thereof; esters such as ethylacetate, isopropylacetate, tertiary butyl acetate and the like or mixtures thereof; ethers such as tetrahydrofuran, 3,4-dioxane, and the like or mixtures thereof; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like or mixtures thereof; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like or mixtures thereof; or their aqueous mixtures, preferably toluene.
The reaction can take place over a wide range of temperatures. In general, the reaction is carried at temperatures of about 30°C to about 100° C. Preferably the reaction temperature can be

from about 30°C to about 75 °C which may vary depending on the nature of the reactants and the solvents employed.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time required for completion of the reaction can be from about 1 hour to about 10 hours, preferably from 1 hour to about 5 hours.
The esters of compounds of formula IVb can optionally be converted into acid addition or carboxylic acid salts by reacting with hydrochloric acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, benzene sulfonic acid, paratoluene sulfonic acid and the like, preferably paratoluene sulfonic acid.
The present invention provides (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline benzyl ester compound of formula I la

11a or a salt thereof.
The present invention provides a process for the preparation of zofenopril calcium comprising reacting zofenopril with a calcium derivative in the presence of an organic solvent.

in an amount not more than 1.0 area percent, as measured by HPLC.
The present invention provides zofenopril calcium comprising the impurity cis-phenyl thioproline acetamide of formula VII

The present invention provides zofenopril calcium comprising cis-phenyl thioproline acetamide impurity of structural formula VII in an amount not more than 0.5% area percent, as measured by HPLC.
The present invention provides zofenopril calcium comprising cis-phenyl thioproline acetamide impurity of structural formula VII in an amount not more than 0.1% area percent, as measured by HPLC.
Optionally the compounds of formulae II and IV can be obtained by the so-called one pot reaction.
The compound of formula (III) or a saft thereof used as one of the starting materials, can be prepared according to the method described in US 4,559,178, which is incorporated herein by reference.
The compound of formula (IVb) or a salt thereof used as one of the starting materials can be prepared according to the method described in US 4,462,943, which is incorporated herein by reference.
After completion of the reaction, isolation of the desired compound from the reaction mixture can be carried out by common operation, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. may be combined.
Optionally the process of present invention is carried out by one pot synthesis.
The compound of formula la or I are optionally purified by recrystallisation using a solvent or mixture of solvents; or by converting into their corresponding pharmaceuticaily acceptable salts and then processed back to the compounds of formula la or I.
There is no particular restriction on the nature of the pharmaceutical salts described above, provided that, where they are intended for therapeutic use, they are pharmaceuticaily acceptable. Examples include acid addition salts such as salts with mineral acids, especially hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; and salts with organic carboxylic acids, such as acetic acid, propionic acid, butyric acid, fumaric acid, tartaric acid, oxalic acid, malonic acid, maleic acid, matic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid,

lactic acid, gluconic acid or citric acid. These pharmaceutical salts are used as intermediates in the preparation and purification of compounds of formula la or I.
These intermediate salts of compound of formula la are converted into desired metal salts by reaction of same with a derivative of metal alkali or alkaline earth metal such sodium, potassium, magnesium and calcium acid in the presence of a solvent, preferably a calcium salt.
Further processing option include the isolation of the free acid and/or the addition of seed crystals of said salt to obtain the desired crystals of said salt, i.e., calcium salt.
The solvent for salt dissolution that can be used is any liquid which has no adverse effect on the reaction and it can dissolve the reactants and the reagents to some extent. The solvents include ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like and mixtures thereof or their aqueous mixtures; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; nitriles such as acetonitrile, propionitrile, or mixtures thereof; preferably acetone, ethyl acetate, or acetonitrile.
The temperatures that can be used can range from about -20°C to about 100 °C, preferably from about 0° C to about 70° C. The time period for carrying out the reaction can be from about 5 minutes to about 10 hours, preferably 10 minutes to 5 hours. The precipitated salt of compound of formula la can be isolated from the reaction mixture by conventional methods known in the art, such as filtration or by evaporation of the solvent(s).
Like any synthetic compound, zofenopril or a pharmaceutically acceptable salt thereof can contain extraneous compounds or impurities that can come from many sources. These extaneous materials can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in zofenopril or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially

absent. For example, the International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the API, zofenopril calcium, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
In one embodiment, zofenopril or a pharmaceutically acceptable salt thereof obtained by the above process comprises the following impurities


namely L-proline impurity compound of formula (A), 4-hydroxy proline impurity compound of formula (B), N-(2-carbonyl pyrrolidine) -L-proline impurity compound of formula (C). N,N'-dicyclohexylurea impurity compound of formula (E) each one in an amount of less than about 0.15%. The total purity of the zofenopril or a pharmaceutical!}' acceptable salt thereof obtained b\ the above processes is of at least about 98%. more preferably, at least about 99% and most preferably at least about 99.5%. Preferably, the purity is measured as described above.
The present invention further provides zofenopril in pure form, preferably isolated solid zofenopril. The zofenopril may be in substantially crystalline form or in substantially amorphous form. The '906 patent discloses the preparation of zofenopril as foamy solid using metal and alky! amine salts of zofenopril as starting materials.
As the calcium salt of zofenopril is insoluble in organic solvents the purification of the final compound is difficult, so the isolation of zofenopril in isolated substantially solid form is essential either by conventional crystallization techniques by direct reaction or by conversion into other pharmaceutically acceptable salts and purification of them by recrystallisations in solvents or mixture of solvents or acid base treatment and then converting directly into the desired calcium salt of zofenopril.
The difference in the physical properties of different solid state forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other solid state forms of the same compound or complex.
The discovery of zofenopril in substantially solid state provides a new opportunity to improve the performance of the active pharmaceutical ingredient ("API"), zofenopril calcium or other salts, by producing solid forms of pure zofenopril having improved characteristics, such as stability, flowability, and solubility. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
The present invention provides a process for preparing zofenopril in isolated solid form comprising the steps of;

a) providing a solution of zofenopril salt in a mixture of water and organic solvent.
b) subjecting the solution to hydrolysis;
c) recovering the desired solid form of zofenopril.
In a) above, providing a solution of Zofenopril salt in a mixture of water and organic solvent.
The solution of zofenopril salt can be obtained by dissolving zofenopril salt in a mixture of water and suitable organic solvent(s). The solvent(s) that can be used in combination with water include but are not limited to alcoholic solvents, ketones, nitriles, aprotic polar solvents or mixtures thereof; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and mixtures thereof; alcohol solvents include but are not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; ketonic solvents include but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone and the like; nitrile solvents include but are not limited to acetonitrile, propionitrile and the like; aprotic polar solvents may include N,N-dimethylformide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) and the like; or mixtures thereof in various proportions without limitation.
The salt dissolution in (a) above might be further defined as described below, as preferably carried out by dissolving a water soluble salt of zofenopril in a mixture of water and an organic solvent.
The salt of zofenopril used can be selected from salt forming ion compounds derived from such bases like metal ions, e.g., aluminum, aikaii metal ions, such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, aralkylamines like, dibenzylamine, N,N-dibenzylethylenediamine, lower alkylamines like methyiamine, tertiarybutylamine, procaine, hydroxy substituted lower alkylamines like tris (hydroxymethyl)aminoethane. lower alkyl-piperidines like N-ethylpiperidine, cycloalkylamines like cyclohexylamine or dicyclohexylamine, l-adamantanamine, benzathine, or salts derived from basic amino acids like arginine, lysine or the like. Preferably tertiarybutylamine. These and other salts which are not necessarily physiologically acceptable are useful in isolating or purifying a product acceptable for the purposes described. The salts are produced by reacting the acid form of the compound with an equivalent of the base

supplying the desired basic ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing. The free acid form can be obtained from the salt by conventional neutralization techniques, e.g., with potassium bisulfate, hydrochloric acid, etc.
The temperature for getting clear and homogenous solution can range from about 25°C to about 75°C or boiling point of the solvents used, preferably from about 25°C to about 40°C.
The solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.
In (b) above, subjecting the solution to hydrolysis
The acids that can be used for hydrolysis include mineral acids such as hydrochloric acid, hydrobromic acid, preferably aqueous hydrochloric acid.
The pH of the final solution may be, for example, from about I to about 5. In c) above, recovering the desired solid form of zofenopril.
Recovery of zofenopril can be achieved by any conventional methods known in the art, for example filtration.
The process may optionally include further drying of the product obtained from the solution by any method known in the art.
Crystallization may be induced by decreasing the solubility of zofenopril, e.g. by cooling the mixture, by evaporation of some of the solvents or by mixing with, e.g. by adding, some precipitating solvent or anti-solvent. The crystallization may start spontaneously, but it is preferable to add seeds of the desired form of neutral zofenopril.
Crystallization is induced by mixing with, e.g., by addition of, a solution of an acid such that the pH of the final solution is still high enough to prevent significant degradation of the product. The organic solvent(s) is preferably a water miscible solvent(s) such as for instance, acetone, acetonitrile or a lower alkyl alcohol. The starting material of present invention is preferably a water soluble salt of zofenopril, for example a basic salt, particularly a tertiary butyl amine salt.
The starting material used in the salt dissolution process, described herein may be a zofenopril salt, which may be of any polymorphic form known in the art.
The resulting precipitate of zofenopril is generally in a solid form, which is either substantially in crystalline form or substantially in amorphous form. When the neutral zofenopril is

crystallized, the crystals may be separated from the solution, e.g. by filtration or centrifugal ion, followed by washing with a washing liquid, preferably a solvent or a mixture in which the particular form of neutral zofenopril has a very low solubility, for example, an anti-solvent.
The substantially solid zofenopril can be dried under conditions which avoid degradation of the product, which can be from about 25°C to about 35° C, and at reduced pressure of about e.g. about 5 mbar to about 20 mbar, for e.g. from about 1 hour to about 48 hours, preferably below about 25°C and at reduced pressure of about 5 mbar. for about 30 minutes to about 2 hours.
Zofenopril free acid obtained by the process of present invention is characterized by X-ray powder diffraction pattern with peaks at about 9.45 ± 0.2 degrees 2-theta, which is substantially as shown in Fig. 2.
In yet another embodiment, the present invention provides tertiary butyl amine salt of zofenopril which is preferably in crystalline form.
Zofenopril tertiary butyl amine salt of present invention is characterized by X-ray powder diffraction pattern with characteristic peaks at about 3.0, 6.1, 8.4, 10.3. 11.2, 12.2, 12.3, 15.2, 16.5, 17.2, 18.2, 18.7, 18.9, 19.7, 20.6, 21.4, 23.5, 25.8 and 27.2 ± 0.2 degrees 2-theta, which is substantially as shown in Fig. 3.
In a still yet another aspect, the present invention provides X-ray powder diffraction pattern of Zofenopril dicyclohexyl amine salt obtained by the process of present invention with characteristic peaks at about 6.9, 10.7, 11.8, 15.4, 17.0, 17.7, 18.2, 18.7, 19.1, 19.5, 21.3, 22.6 and 27.6 ± 0.2 degrees 2-theta, which is substantially as shown in Fig. 4.
X-ray powder diffraction measurements were performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (CuKal = 1.54060A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded at start angle from 2° to 50° 20, a step size 0.0167° with a time per step of 1000 seconds.
In another embodiment, the present invention provides a pharmaceutical composition comprising zofenopril or its pharmaceutically acceptable salts obtained by the processes described herein and at least a pharmaceuticaily acceptable carrier.
Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for

administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The zofenopril or its pharmaceutically acceptable salts obtained by the process disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the zofenopril or its pharmaceutically acceptable salts is oral. The dosage forms may contain the zofenopril or its pharmaceutically acceptable salts as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients.
Capsule dosages will contain the zofenopril or its pharmaceutically acceptable salts which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate.
carboxymethylethylcel lulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like

magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
The process for the preparation of zofenopril or its pharmaceutically acceptable salt of the present invention is simple, eco-friendly and easily scaleable.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES
EXAMPLE 1: PREPARATION OF ZOFENOPRIL TERTIARY BUTYL AMINE
250 ml of Toluene, 25.0 g (0.096 moles) of 4-phenylthio L-proline hydrochloride and 18.66 g. of triethylamine were charged into a clean and dry 4 neck RBF followed by stirring for about 1 hour at 25-30°C. 22.66 g. (0.l0lmoles) of S-(-) benzoylthio-2-methyl-propionic acid, 13.64 g. (0.101 moles) of 1-Hydroxy benzotriazole (HOBT) and 22.79 g. (0.111 moles) dicyclohexyl carbodiimide (DCC) was added at regular intervals of time every 5-10 mins. The resultant reaction mass was stirred at 30-35°C for about 2-3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was cooled to about 5-10°C followed by stirring for about 2 hrs. The solid (dicyclohexyl urea) was filtered on celite and the celite bed was washed with 50 ml of cold toluene. The clear filtrate was taken in a clean and dry 500ml 4 neck RBF and 100ml water was charged. The pH of the reaction solution was adjusted to about 9-9.5 with 10% sodium carbonate solution followed by stirring for about 30 min. The aqueous layer was separated and the toluene layer was extracted with 2x100ml water. Both aqueous layers were combined and 250 ml of methylene dichloride was charged to it. The pH of the above reaction mass was adjusted to below 2 with Hydrochloric acid. The reaction mass was filtered and the filtrate was collected into a clean and dry RBF. The organic and aqueous layers were separated and the aqueous layer was extracted with 2 x 100ml of methylene dichloride. Both the organic layers were combined and dried over anhydrous sodium sulphate. The organic layer was distilled completely at about 35°C under vacuum. The oily mass was degassed for I hr under high vacuum. Weight of degassed oily mass - 47g; MASS (M-H) - 428 (Zofenopril free acid).
225 ml Acetonitrile was added to the oily mass and the reaction mass was stirred to obtain clear solution at about 25-30°C. 7.96g (0.109mol) of tert-butylamine was charged at 25-30°C.

The resultant reaction mass was stirred for about 1hr at about 25-30°C. The reaction mass was heated to reflux at about 80-85°C for about 90 min The reaction mass was slowly cooled to about 25-30°C.
Reaction mass was cooled to about 0-5°C and stirred for about ihr. The solid separated was filtered and the solid was washed with 150ml Acetonitrile and running wash with 50ml Acetonitrile. The solid obtained was dried at about 40-45°C under vacuum to afford 42.5g of the title compound as white crystalline powder. EXAMPLE 2: PREPARATION OF ZOFENOPRIL FREEACID IN SOLID FORM FROM ZOFENOPRIL TERTIARY BUTYL AMINE SALT 10gZofenopril tert-butylamine salt, I50mf methylene chloride and 100ml of water were charged into a clean and dry 4 neck round RBF. pH was adjusted to about 4.0-5.0 with hydrochloric acid . Reaction mass was stirred for about 30 min. Organic and aqueous layers were separated and aqueous layer was extracted with 2x100ml of methylene chloride. Total methylene chloride layer was combined and treated with sodium sulphate. The methylene chloride was distilled completely and degassed. Foamy solid mass was obtained in flask. 40ml of petroleum ether was added to the foamy solid mass. The mass was stirred at about 5-10 C for about 30-45 min.under nitrogen atmosphere. The solid separated was filtered under nitrogen. Suck dried under nitrogen until the last droplet of mother liquor. The material was unloaded immediately under nitrogen, packed under nitrogen and kept at 2-8°C. yield : 8 grams. EXAMPLE 3 : PREPARATION OF ZOFENOPRIL DICYLCOHEXYL AMINE SALT
630 ml of Acetonitrile was added to the 105g (0.244moles) of zofenoprii oily mass and the reaction mass was stirred to obtain clear solution at about 25-30°C. 44.3g (0.244mole) of dicyclohexylamine was added slowly over about 2-3 hours at about 25-30°C, The resultant reaction mass was stirred for about 1hr at about 25-30°C. The reaction mass was slowly cooled to about 0-5°C and was stirred for about 5-6 hours. The solid separated was filtered and the solid was washed with 150ml acetonitrile and washed with 2x150ml of diethylether. The solid obtained was dried at about 40-45°C under vacuum to afford 130g of the title compound as white crystalline powder. EXAMPLE 4: PREPARATION OF ZOFENOPRIL FREEACID IN SOLID FORM FROM ZOFENOPRIL DICYLCOHEXYL AMINE SALT

10g of Zofenopril DCHA salt, 150ml Methylene chloride and 100ml of water were charged into a clean and dry RBF. pH was adjusted to about 4.0-5.0 with hydrochloric acid . Reaction mass was stirred for about 30 min. Organic and aqueous layers were separated and Aqueous layer was extracted with 2x100ml of methylene chloride. Total methylene chloride layer was combined and treated with sodium sulphate. The methylene chloride was distilled completely and degassed. Foamy solid mass was obtained in flask.' 40ml of petroleum ether was added to the foamy solid mass. The solid mass was stirred at about 5-10°C for about 30-45 min.under nitrogen atmosphere. The product was filtered under nitrogen. Suck dry under nitrogen until the last droplet of mother liquor. The material was unloading immediately under nitrogen, packed under nitrogen and kept at 2-8°C. Yield: 6.5grams. EXAMPLE 5: PREPARATION OF ZOFENOPRIL CALCIUM FROM ZOFENOPRIL
TERTIARY BUTYL AMINE SALT USING CALCIUM ACETATE 9.0g of Zofenopril tert-butylamine and 90ml of water were charged into a clean and dry 500ml 4 neck RBF. Adjusted the pH to about 8.0-8.5 with 20% caustic solution, 20ml water was distilled out under vacuum for removing the tert-butylamine at 55-60°C. Again 20ml DM water was added and distilled out the 20ml of water from the reaction mass at 55-60°C. Again 20ml DM water was added in the reaction mass. Reaction mass was heated to about 55-60 C. The aqueous solution of calcium acetate in equimolar ratio was charged to the reaction mass at about 55-60 C. The mass was stirred at 55-60°C for about 10-12 hrs. The reaction mass was cooled to about 40-42°C and the solid separated was filtered and washed with 45ml warm water The product was suck dried and dried at about 50-55°C under vacuum to afford 7.5g of the title compound. EXAMPLE 6: PREPARATION OF ZOFENOPRIL CALCIUM FROM ZOFENOPRIL
TERTIARY BUTYL AMINE SALT 9.0g of Zofenopril tertiary butylamine and 90ml water were charged into a clean and dry 500ml 4 neck RBF, The pH was adjusted to about 8.0-8.5 with 20% caustic solution, 20ml water was distilled out under vacuum for removing the tertiary butylamine at 55-60°C and 20ml DM water was charged and again distilled out the 20ml of water from the reaction mass at 55-60°C Again 20ml DM water was charged in the reaction mass. Reaction mass was heated to about 55-60°C. The aqueous solution of calcium chloride dihydrate in equimolar ratio was charged to the reaction mass at about 55-60°C. The resultant reaction mass was stirred at about 55-60°C for about 10-12 hrs. The reaction mass was cooled to about 40-42°C. The solid separated was filtered and

washed with warm water till the chloride ion content is negligible. The solid obtained was dried at
about 50-55°C under vacuum to afford 7.5 grams of the title compound.
EXAMPLE 7 : PREPARATION OF ZOFENOPRIL CALCIUM FROM ZOFENOPRIL SOLID
5g of Zofenopril and 40 ml water were charged into a clean and dry 4neck RBF and the pH was adjusted to about 8.0-8.5 with 20% caustic solution The resultant reaction mass was heated to about 40-45°C. Aqueous solution of calcium chloride dihydrate was prepared (dissolved 1.2g of calcium chloride dihydrate in 4V water) 20% volume of the above solution of calcium chloride dihydrate was slowly added or till haziness to the reaction mass at about 40-45°C. The mass was stirred at about 40-45°C for about 25-30 mins. The resultant reaction mass was heated to about 55-58°C and stirred for about 4-6 hrs. The reaction mass was cooled to about 35-40°C. The solid separated was filtered and solid was washed with 20ml of water. The solid obtained was dried at about 50-55°C under vacuum to afford 4 grams of the title compound.
EXAMPLE 8: PREPARATION OF ZOFENOPRIL CALCIUM FROM ZOFENOPRIL SOLID 5g of Zofenopril and 40 ml water were charged into a clean and dry 4neck RBF and
adjusted the pH to about 8.0-8.5 with 20% caustic solution. The reaction mass was heated to about
40-45°C. Aqueous solution of calcium acetate was prepared (dissolved 1.3g of Calcium Acetate in
4V water) 20% volume of the above solution of calcium acetate was slowly added or till haziness
into the reaction mass at 40-45°C. The mass was stirred for 25-30 mins at 40-45°C.The reaction
mass was heated to at 55-58°C. The resultant reaction mass was stirred at about 55-58°C for about
4-6 hrs. The reaction mass was cooled to about 35-40°C for about 1 hour. The solid separated was
filtered and the solid was washed with 20ml of water. The solid obtained was dried at about 50-
55°C under vacuum to afford 4 grams of the title compound.

The present invention particularly provides:
A) 1. A process for the preparation of zofenopril of formula la

or a pharmaceutically acceptable salts thereof, comprising: a) reacting protected cis-4-phenyIthio-L-proline alkyl ester compound of formula IV or a salt thereof

where R denotes a hydrogen, linear or branched alkyl group or the benzyl group, with S-(-)-3- benzothio-2-methyl propionic acid compound of formula III or a salt thereof

in the presence of coupling agent to form (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline alkyl ester compound of Formula II

in which R has the same meaning as defined for formula IV

b) subjecting the resultant compound of formula II to deprotection to form the compound of
formula la. B) The process as described in A, wherein the protected Cis-4-phenylthio-L-proIine alkyl ester
compound of formula IV or a salt thereof

is prepared by the process comprising:
reacting cis-4-phenylthio-L-proline compound of formula IVb or salt thereof

with an alcohol ROH, where R linear or branched alkyl group or the benzyl group. C) A process for the preparation of zofenopril of formula la

or a pharmaceutically acceptable salts thereof, comprising: a) reacting cis-4-phenylthio-L-proline benzyl ester compound of formula IVa or a salt thereof


with S-(-)-3-benzothio-2-methyl propionic acid compound of formula III or ester derivative or a salt thereof

in the presence of coupling agent to form (4S)-]-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline benzyl ester of structural Formula Ha,

b) subjecting the resultant compound of formula IIa to deprotection to form the compound of formula la.
D) The process as described in A or C above, wherein the coupling agent is 1 -hydroxy
benzotriazole and dicyclohexylcarbodiimide.
E) The process as described in C, wherein the deprotection is carried out by hydrogenation
using hydrogenation catalyst palladium-carbon.

reacting cis-4-phenylthio-L-proline compound of formula IVb or salt thereof
F) The process as described in C, wherein the Cis-4-phenylthio-L-proline benzyl ester
compound of formula IVa or a salt thereof is prepared by the process comprising:


IVb with benzyl alcohol. G) A compound (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline benzyl ester of structural Formula IIa

IIa or a salt thereof.
H) The process for the preparation of zofenopril calcium wherein the zofenopril prepared by the process described in A or C above is reacted with a calcium derivative in the presence of an organic solvent
I) The zofenopril calcium comprising the impurity Cis-phenyl thioproline acetamide of structural formula VII

in an amount not more than 1.0 area percent by HPLC.
J) The zofenopril calcium comprising Cis-phenyl thioproline acetamide impurity of structural
formula VII in an amount not more than 0.5% area percent by HPLC. K) The zofenopril calcium comprising Cis-phenyl thioproline acetamide impurity of structural formula VII in an amount not. more than 0.1% area percent by HPLC.

L) Zofenopril in substantially solid form.
M) Zofenopril as defined in 'L' above, wherein it is in substantially crystalline form. N) Zofenopril as defined in 'L' above, wherein it is in substantially amorphous form. O) A process for preparing zofenopril as defined in 'L' above comprising providing a solution of zofenopril salt in a mixture of water and organic solvents, adding an acid to the solution; recovering the desired solid form of zofenopril. P) The process as defined in 'O' above, wherein the organic solvent is selected
alcoholic solvents, ketones, nitriles, esters, aprotic polar solvents and mixtures thereof. Q) The process as defined in P above, wherein the solvent is selected
methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, N,N-dimethylformam dimethylsulfoxide or mixtures thereof. R) A process as defined in 'O' above, wherein the pH of the solution after the addition
of the acid is between 1 and 4. S) A process as defined in 'O', wherein the salt of zofenopril is selected from base salts like ammonium salts, alkali metal salts like
sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases like dicyclohexylamine salts, tertiary butyl amine.