EP3386945A1

EP3386945A1 - Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method

Info

Publication number: EP3386945A1
Application number: EP16818971.0A
Authority: EP
Inventors: Ales Halama; Pavel ZVATORA; Michal Voslar; Jan Stach; Michal Zapadlo; Ondrej Dammer; Lukas KREJCIK; Lenka DVORAKOVA; Marketa REZANKOVA; Rostislav VYSLOUZIL
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2015-12-11
Filing date: 2016-12-12
Publication date: 2018-10-17
Also published as: CO2018005941A2; WO2017097275A1; BR112018011788A2; ZA201803749B; MX2018007129A

Abstract

The invention relates to solid forms of the free acid of sacubitril of formula 1, especially a crystalline form, incl. a method of removing chemical impurities from the crude free acid of sacubitril that is characterized in the use of well crystallizing salts of sacubitril with the amines of formula 9, where R1, R2, R3 independently stand for hydrogen or a C1-C7 alkyl, preferably the salt with cyclohexylamine, tert-butylamine or iso-propylamine. The invention further relates to a novel solid, crystalline form of sacubitril (8) - hemisolvate of the potassium salt of sacubitril, incl. a direct and highly efficient and industrially usable preparation methods of a solid form of sacubitril free acid and its pharmaceutically applicable salts, especially the crystalline sodium salt of formula 5, calcium salt of sacubitril of formula 6 and hemisolvate of the potassium salt of sacubitril of formula 8.

Description

Solid forms of (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method

Field of the Invention

The substance sacubitril (also known as AHU-377), with its systematic name (2i-,4S)-5- (biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester of formula (1) is a constituent of a drug for the treatment of hypertension and heart failure. It is especially the supramolecular complex of the sodium salt of sacubitril and the disodium salt of valsartan of formula (2) in the 1:1 ratio of the components, which crystallizes in the pentahemihydrate form, that is of therapeutic use (WO03059345 and WO2007056546, Tetrahedron Lett. 2012, 53, 275-276, WO2015030711). This crystalline combination of sodium salts of sacubitril with valsartan is commonly shortly referred to as LCZ696 or more recently, it is known under the trade name of Entresto (Novartis).

The present invention relates to novel solid forms of the compound referred to as sacubitril, methods of its preparation, including the possibilities of their use for the production of a drug intended for the treatment of hypertension and heart failure. Background Art

The first solution of chemical synthesis of sacubitril of formula 1 was described in the patent application EP555175 and subsequently also in the specialized literature (J. Med. Chem. 1995, 38, 1689-1700). More possibilities of chemical synthesis of sacubitril of formula 1, especially its advanced intermediates are described in the following patent applications: WO2008031567, WO2008083967, WO2009090251, WO2011088797, WO2012025501, WO2012025502 and WO 2014032627.

The final step of chemical synthesis leading to sacubitril is represented by the reaction running in accordance with Diagram 1, wherein the amine of formula 3 is reacted with succinic acid anhydride. The result of this reaction is crude sacubitril in the free carboxylic acid form. A disadvantage of this procedure is the fact that sacubitril in the free carboxylic acid form does not crystallize and therefore the form prepared this way is not suitable for isolation or for chemical purification before the preparation of the sodium salt of sacubitril, which is used in

Diagram 1 Another option of the final steps of the chemical synthesis of sacubitril is represented by the reactions described by Diagram 2, wherein the starting substance is the commercially available acid of formula 4. The amine of formula 3 is isolated as an intermediate product in the hydrochloride form. After releasing of the base, it is subjected to a reaction with succinanhydride in a chlorinated solvent. The result of these reactions is crude sacubitril in the free carboxylic acid form. However, it does not crystallize, and therefore crude sacubitril as a free carboxylic acid is not suitable for isolation in the industrial scale and it does not provide any options of chemical purification before the preparation of a final form, suitable for pharmaceutical use, either.

Diagram 2. Due to unfavorable isolation characteristics of the crude carboxylic acid of (1), complex isolating and purification operations must be used to obtain the sodium salt of sacubitril in an acceptable quality, which are unsuitable in terms of industrial production. A procedure published in the literature may serve as an example of this (J. Med. Chem. 1995, 38, 1689- 1700). This procedure is described by Diagram 3. According to this procedure, the crude acid (1) is first transformed to the respective tert-butylester (4), then the substance is purified by means of chromatography, subsequently the free acid of sacubitril is released again, being freed of some impurities, especially being freed of the diastereoisomeric impurity of formula (S,S-1).

(S.S-1)

However, the acid (1) purified this way was only isolated after evaporation of the solvents in a pasty form and finally it was transformed to the better isolable sodium salt of formula 5 by the action of sodium hydroxide. The direct path from the crude acid to the sodium salt was not used, probably due to the failure to find conditions suitable for isolation of sacubitril free acid in a solid, especially crystalline form.

Besides the pharmaceutically preferred sodium salt of sacubitril three other pharmaceutically usable forms have also been described in patent applications (WO2008031567, WO2008083967, WO2007045663 and WO2003059345), namely: the calcium salt (6), see Diagram 4, salts with triethanol amine (7) and tris(hydroxymethyl)aminomethane (8), see Diagram 5. Data concerning the chemical purity of these salts, their crystalline structure and the yields of their preparation have not been published yet.

Diagram 4. The preparation methods of sacubitril and its pharmaceutically acceptable final forms described so far thus contain a number of operations and solvents that are unsuitable for the industrial scale, e.g. evaporation to a pasty concentrate or the use of chlorinated solvents, are relatively lengthy and their low efficiency considerably limits their use in the commercial scale.

The present invention relates to solid forms of sacubitril, which could be surprisingly prepared successfully and with a number of benefits. The invention further relates to a highly efficient and industrially usable preparation method of a solid form of sacubitril free acid and its pharmaceutically applicable salts, especially the crystalline sodium and calcium salt of sacubitril and a hemisolvate of the potassium salt with acetic acid.

Disclosure of the Invention

The invention consists in finding solid, preferably crystalline forms of sacubitril free acid of formula 1 that can be easily isolated, chemically purified and subsequently transformed to the pharmaceutically preferred solid forms, especially the sodium or calcium salt. The invention further provides a shortened and highly efficient preparation method of sacubitril, without the use of dangerous or environmentally problematic solvents, which is fully usable in the industrial scale and whose product may be a novel crystalline form of sacubitril - hemisolvate of the potassium salt with acetic acid - which at the same time represents a novel pharmaceutically usable salt of sacubitril. Solid forms derived from sacubitril, especially crystalline ones, commonly have great technological and economical significance as they make it possible to obtain a substance usable for pharmaceutical purposes.

Finding forms of any pharmaceutical substance that crystallize well has a principal influence on achieving the required quality, which is a precondition for introduction of a drug in the market. In general, chemical purity of an Active Pharmaceutical Ingredient (abbreviated API) produced in the industrial scale is one of the critical parameters for its commercialization. The U.S. Food and Drug Administration (abbreviated FDA) as well as the European authorities for drug control require, in line with the guidelines of ICH (International Conference on Harmonization) an API to be freed of impurities to the maximum possible extent. The reason is to achieve maximum safety of using the drug in the clinical practice. ICH guidelines identified with the codes Q3A to Q3D deal with impurities, namely Q3A: Impurities in New Drug Substances and Q3C: Guideline for Residual Solvents Based on these guidelines, control authorities usually require that the content of an individual impurity in an API should not exceed the limit of 0.10%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.10% should, in line with the ICH recommendations, be isolated and characterized. It is also recommended to isolate and characterize degradation products that are formed during the shelf life or period until the expiration date.

Solvents in pharmaceutical ingredients are divided into three classes. The first class contains such solvents that should not be used for the production of pharmaceutical substances at all, especially due to toxicity, carcinogenicity or environmental risks. The second class comprises solvents that can be used in a limited manner with regard to their toxicity, especially a specific, maximum acceptable limit (usually expressed in the ppm units ) is defined for every such solvent. In the third class, solvents with a low toxic potential are classified and the maximum acceptable limit for every such solvent is generally defined as 5000 ppm.

Every active ingredient must be analyzed for chemical purity before it is used in a pharmaceutical product. High Performance Liquid Chromatography (HPLC) is usually used for this purpose. Impurities present in the ingredient are then determined by the position of the peak in the HPLC chromatogram while the peak position is usually expressed as the retention time (in minutes) required for the impurity to travel from the place of injection of the sample to the HPLC column filled with a suitable sorbent to the detection place. Retention times (rt) related to the retention time of the standard (it is usually the rt of an active ingredient) are called relative retention times (rrt). Under standard conditions, relative retention times are considered as standard characteristics of the analyzed substance, i.e. they only depend on the chemical structure of the respective constituent. Similarly, active substances are tested for the content of residual solvents by means of gas chromatography, abbreviated as GC.

Equally, a necessary precondition for commercial use of any substance is the possibility to prepare it in the industrial scale, which however differs from the common laboratory synthesis in many aspects and frequently requires a different technological solution of common laboratory operations as evaporation of a solution of the substance into a non-distilling pasty evaporation product, managing the stirring and cooling e.g. during exothermal or heterogeneous processes, elimination of the chromatographic purification of the products and intermediate products of the synthesis and last, but not least also replacement or acceleration of time-consuming processes in the large scale, which make the production inadequately expensive. Similarly, the industrial scale involves considerably stricter requirements for safety or environmental aspects of the process, so there is e.g. the requirement that no chlorinated solvents that are harmful for the environment or the human health as dichloromethane or chloroform be used in the process, etc. Therefore, the transformation of the laboratory synthesis into the industrial scale is often quite a laborious stage of the development of a production method of a new substance, requiring a number of qualitative changes and innovative approaches.

The circumstance that is of principal importance for the present invention is that isolation of the free carboxylic acid in a crystalline form has not been described yet and also no information has been found about any other solid state of the free acid, i.e. about the amorphous state either although this acid as such is well-known for more than twenty years. The synthesis of sacubitril reproduced by us, which consists in a reaction of the amine of formula 3 with the anhydride of succinic acid in accordance with Diagram 1, led to a product that was characterized in having honey-like consistency and a content of impurities exceeding the limit accepted for pharmaceutical products (see Example 1). The surprising finding of conditions that made it possible to obtain the acid of sacubitril of formula 1 in a solid state, especially crystalline state, thus fulfils the aspect of inventive activity as it had not been clear for a long time whether this compound was actually capable of crystallization. The isolated crystalline acid of sacubitril 1 exhibits a number of important technical parameters, especially parameters that confirm the crystalline state and high chemical purity. The crystalline free acid of sacubitril exhibits the following XRPD reflections: 4.4; 13.1; 17.5; 19.5 and 21,4 (° ± 0.2° 2Θ), further a DSC record of an endothermic peak indicating the melting temperature of the crystalline form in the range of 74 ± 3°C and the chemical purity determined by means of HPLC of 99.5% and higher, preferably 99.9% and higher. The crystalline free acid of sacubitril featuring the following parameters can be used for the preparation of pharmaceutically applicable salts, especially the sodium and calcium salt. This fact meets the aspect of industrial applicability of the present invention.

The free acid of sacubitril in the solid state can be obtained by crystallization from a solution of at least one organic solvent, which may be a liquid aromatic hydrocarbon, e.g. toluene, alternatively and preferably a liquid ester of a carboxylic acid in combination with a suitable anti-solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalkanes, e.g. ethyl acetate or isopropyl acetate after an addition of heptane, hexane or cyclohexane. However, if an aromatic substance was used, the isolated crystalline substance was excessively contaminated by the residual solvent, which could not be efficiently removed. This was because the increased content of the solvent caused partial melting of the crystalline free acid of sacubitril prepared this way at temperatures over 35°C already, which did not make it possible to increase the temperature within the drying process. The use of esters of carboxylic acids in combination with a suitable non-polar anti-solvent proved to be technically more advantageous, which finally provided a crystalline substance with the melting point over 70°C and the contents of residual solvents below the limits accepted for pharmaceutical substances. The use of ethyl acetate or isopropyl acetate after an addition of non-polar heptane is quite obvious from the point of view of the limits of the residual solvents as the said solvents are classified in the third class of solvents with the limit of 5000 ppm with respect to the acceptable content. However, for the preparation of the pharmaceutically preferred salts the solid acid of sacubitril isolated from an aromatic hydrocarbon can also be used. The decisive circumstance is the removal of the chemical impurities coming from the preparation process of the crude acid of sacubitril. These impurities are preferably concentrated in the used solvent while the solid acid of sacubitril is isolated by filtration. The residual solvent can then only be removed in the step of preparation of the pharmaceuticall usable salt, e.g. during preparation of the crystalline sodium salt of sacubitril (5).

The crude free carboxylic acid prepared using the procedure in accordance with Diagram 1 is difficult to isolate in a solid form, which is the consequence of its very limited crystallization capability. The ability to create crystalline structures is limited in the case of the free acid to such an extent that none of its solid forms, crystalline or amorphous, has been described so far. This ability is also affected by the presence of impurities that are included in the crude acid due to the performed chemical synthesis. These impurities may be residues of the reacting constituents or the used solvents as well as impurities produced due to insufficient selectivity of the chemical reactions and chemical decomposition of the products or intermediates.

To facilitate crystallization of the free acid of sacubitril, the undesired chemical impurities present in the crude material should preferably be removed. The impurities can be removed using the method when a suitable amine first acts upon a solution of the crude carboxylic acid, producing the respective salt of sacubitril with the amines of formula 9, where Ri, R₂, R₃ independently stand for hydrogen or a C1-C7 alkyl, preferably isolation of the crystalline salt with cyclohexylamine, tert-butylamine or wo-propylamine.

We have found out that some salts of sacubitril with amines crystallize surprisingly easily, so they can be advantageously isolated from the solution in a solid and chemically pure form. The originally contained impurities preferably remain in the used solvent. Thus, conversion of the crude free acid to the crystalline salts with amines leads to removal of impurities coming from the chemical synthesis, especially the lactone of formula 10, with its systematic name (3R, 5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one. This impurity is produced in the last stage of the synthesis by the competing cyclization reaction in accordance with Diagram 6. When dichloromethane was used as the solvent for the execution of the acylation reaction of the amine (3) with succinic acid anhydride, the usual level of the content of the impurity (10) was 1 to 3% (see Example 1), but when other solvents were used, e.g. ethyl acetate, the content of the im urity (10) of more than 3% was observed.

Isolated lactone of formula 10 can be advantageously used as the analytic standard of impurity for setting of analytic methods used for the quality control of sacubitril of formula 1 and its sodium salt of formula 5 or calcium salt of formula 6. On condition of proper setting of the analytic methods the level of this impurity can be controlled and its content can be subsequently reduced below the level of 0.15%, preferably to the level of 0.10% and lower. The lactone of formula 10 can be prepared by an intramolecular cyclization reaction based on the amine of formula 3, or the protonated form of the amine (3) after addition of a suitable base, e.g. lithium hydroxide (see Example 6). The acid of sacubitril can be released from the crystalline salt with the amines by the action of a suitable acid, alternatively by means of a suitable base and subsequently acid. Then, the free carboxylic acid can also be crystallized from a suitable solvent or mixture of solvents using the above mentioned procedures, which will provide the required quality of the substance.

The method of removing the chemical impurities from the free acid of sacubitril may consist of the following steps:

a) converting the crude acid of sacubitril to a well crystallizing salt of sacubitril with the amines of formula 9, where Rl, R2, R3 independently stand for hydrogen or a C1-C7 alkyl, preferably converting it to a salt with cyclohexylamine, tert-butylamine or iso- propylamine and isolation of this crystalline salt,

b) releasing the free acid of sacubitril by the action of a suitable acid upon a solution of the crystalline salt of sacubitril with the amine, preferably by the action of an aqueous solution of an acid, preferably an aqueous solution of hydrochloric acid,

c) isolation of the crystalline free acid of sacubitril from at least one organic solvent, which may be a liquid aromatic hydrocarbon, preferably toluene, alternatively an ester of a carboxylic acid, preferably ethyl acetate or isopropyl acetate after an addition of an anti- solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalcanes, preferably heptane, hexane, or cyclohexane.

As a further object, the invention provides a preparation method of the acid of sacubitril using a procedure that comprises the following steps:

a) preparation of the compound of formula 3 (penultimate) by a reaction of the compound of formula 4 with ethanolic h drogen chloride (see the diagram below);

a reaction of the compound of formula 3 from step a) with succinic acid anhydride in an organic solvent or in a mixture of organic solvents, producing the crude acid of sacubitril (see the diagram below);

wherein the reactions of step a) and b) are conducted without isolation of the intermediates in individual steps.

A preferred embodiment of the procedure is such that ethanolic hydrogen chloride is generated "in-situ", preferably through a reaction of thionyl chloride with ethanol and then the reaction proceeds according to the diagram below.

Another preferred embodiment of the said procedure is that after the reaction in step a) distillation is carried out before step b) with simultaneous addition of an organic solvent, preferably a liquid aromatic hydrocarbon, more preferably toluene. The suitable organic solvent in step a) is added in such a quantity to totally amount to at least 3L/kg of the starting compound of formula 4, preferably at least 4 L/kg, but there is no upper limit. The said preparation method is also characterized in that the at least one organic solvent in step b) is a liquid aromatic hydrocarbon, preferably toluene, a carboxylic acid ester, preferably ethyl acetate or isopropyl acetate and/or a mixture of these solvents. Another preferred embodiment consists in the reaction being initiated by gradual addition of a base selected from the group of tertiary amines, preferably selected from the group: triethylamine, ethyl-diisopropylamine, pyridine or its substituents, preferably 4-dimethylaminopyridine, at a reduced temperature, preferably at a temperature below 10°C, more preferably below 5°C, most preferably at a temperature below 0°C.

The preparation method is further characterized in that after the reaction in step b) an aqueous solution of a mineral acid is added, preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid and the waste salts and not completely reacted compounds are extracted. In another preferred embodiment the solution of sacubitril acid obtained in step b) is concentrated by evaporation. More advantageously, the obtained sacubitril acid solution is further converted to a crystalline salt of s

where R_1? R₂, R3 independently stand for hydrogen or a C1-C7 alkyl, preferably to the salt with cyclohexylamine, tert-butylamine or wo-propylamine.

Another preferred embodiment comprises conversion of the crystalline salt of sacubitril with an amine obtained according to the previous production method to another pharmaceutically acceptable crystalline salt of sacubitril, preferably to the sodium, calcium or potassium salt. In a preferred embodiment, the separated crystalline salt is isolated, more preferably by filtration. As mentioned above, some salts of sacubitril with amines crystallize surprisingly easily, so they can be advantageously isolated from the solution in a solid and chemically pure form. We have experimentally found out that a good crystallization capability of ammonium salts of sacubitril is not a general characteristic of all ammonium salts. The best results, considered from the yield and chemical purity point of view, were achieved by the new isolation process in the case of salts of sacubitril with primary amines that were characterized by a branched alkyl, e.g. cyclohexylamine, wo-propylamine, or tert-butylamine. The contribution of the discovered process of purification of sacubitril in the form of its salts with amines is an exceptionally good ability of these salts to crystallize from solutions of organic solvents, which leads to increased chemical purity at a minimal loss of the isolated substance.

The free acid of sacubitril isolated in the solid state already meets the quality requirements in conformity to the conditions valid for active pharmaceutical ingredients. So it can be advantageously further used for the preparation of pharmaceutically acceptable salts of sacubitril, preferably for the sodium (5) or calcium (6) salt.

Many compounds may exist in various solid forms that may be both crystalline and amorphous. Solid forms may have various internal arrangements with different physicochemical properties depending on the conditions of their preparation. Crystalline forms having different crystal units are referred to as polymorphs while they are usually characterized with different physicochemical properties as chemical stability, hygroscopicity, melting point, solubility, dissolution rate as well as bioavailability. An amorphous product is usually more readily soluble; however, it cannot often be obtained in the required quality and it is also often less stable. Conversely, compared to the amorphous form, a crystalline product is often stable, it is easier to obtain in the pure form and it dissolves more slowly. To distinguish individual solid phases of a compound, a number of analytic methods for solid state investigation can be used, especially spectral methods, e.g. X-ray Powder Diffraction (XRPD), or thermoanalytical methods, e.g. Differential Scanning Calorimetry (DSC). Discovering new solid phases (amorphous forms, crystalline polymorphs, solvates and hydrates) of an active pharmaceutical ingredient offers an opportunity to select a suitable modification with desired physicochemical properties and processability and improve the characteristics of the chemical product. For this reason there is a clear need of new solid forms also in the case of the sodium or calcium salt of sacubitril.

Conversion of the acid of sacubitril of formula 1 to a pharmaceutically acceptable salt is characterized in the action of a suitable agent as the source of a metal cation, which may be the sodium or calcium cation, on a solution of the free acid of sacubitril of formula 1 in a suitable solvent while the solid form of a pharmaceutically preferred salt of sacubitril, preferably a crystalline form, is separated from the solution.

The preparation method of pharmaceutically acceptable salts of sacubitril, preferably the sodium (5) and calcium (6) salt is characterized in the action of an inorganic or organic salt, oxide, alcoholate, hydride or metal hydroxide, which may be sodium or calcium, upon a solution of the free acid of sacubitril 1 in a suitable solvent. As the source compounds of sodium reagents selected from the group: sodium hydroxide, sodium methanolate, sodium ethanolate, sodium zso-propoxide, sodium tert-butylate or sodium acetate can be advantageously used. As the source compounds of sodium reagents selected from the group: calcium chloride, calcium acetate or calcium hydroxide can be advantageously used.

The preparation of the sodium or calcium salt is further characterized in the use of at least one solvent selected from the group: esters of C1-C5 organic acids with C1-C6 alcohols, C1-C6 alcohols, C3-C6 ketones, C4-C6 ethers, water, liquid aromatic hydrocarbons, C1-C7 alkanes, C3-C7 cycloalkanes, preferably then the following solvents or their mixtures: ethyl acetate, isopropyl acetate, methanol, ethanol, isopropyl alcohol, water or mixtures of these solvents in any ratios. Liquid esters of carboxylic acids, preferably ethyl acetate or isopropyl acetate, can be advantageously used as a suitable solvent for the preparation of the crystalline sodium salt of sacubitril. Water or its mixtures with alcohols can be advantageously used as a suitable solvent for the preparation of the calcium salt of sacubitril. The use of esters of carboxylic acids, especially ethyl acetate, isopropyl acetate or alcohols from the group of ethanol, propyl alcohols or butanol is quite obvious from the point of view of the limits of the residual solvents as the said solvents are classified in the third class of solvents with the limit of 5000 ppm with respect to the acceptable content.

In particular, the sodium salt of sacubitril can be prepared using the procedure consisting of the following steps with a number of benefits:

a) dissolving the free acid of sacubitril 1 in a mixture of toluene and ethyl acetate, alternatively in a mixture of toluene and isopropyl acetate,

b) adding a solution of a suitable agent, which is the source of 0.95 to 1.05 equivalents of the sodium ion, preferentially a solution of sodium hydroxide in ethanol or a solution of sodium ethanolate in ethanol.

c) vacuum evaporation of the solvents, incl. removal of water or ethanol together with the evaporated toluene,

d) adding at least one solvent selected from the group of toluene, ethyl acetate and isopropyl acetate as a suitable solvent to obtain a crystalline form of the sodium salt of sacubitril.

The benefits of the discovered approach can be specifically for the sodium salt of sacubitril documented by the following points:

a) the use of ethanol and ethyl acetate eliminates the risk of reesterification reactions, i.e. occurrence of impurities differing with the alkyl group in the ester functional group in the skeleton of sacubitril,

b) water or ethanol is preferably removed together with distillation of the used toluene, c) ethyl acetate used as the final solvent for crystallization of the sodium salt of sacubitril is classified in the third class of solvents with the limit of 5000 ppm from the point of view of its acceptable content,

d) the discovered process exhibits a high yield, usually over 90%, e) the obtained product is crystalline and is characterized with a high chemical purity of 99.5% and higher, preferably 99.9% and higher,

f) the obtained product exhibits low hygroscopicity.

Two crystal modifications of the sodium salt of sacubitnl, polymorph I and polymorph II (see Examples 4a and 4b) were successfully prepared using the above mentioned procedures. Both the isolated polymorphs of the crystalline sodium salt of sacubitril of formula 5 exhibit a number of important technical parameters, especially parameters that confirm the crystalline state and high chemical purity. The crystalline polymorph I of the sodium salt of sacubitril of formula 5 exhibits the following reflections in XRPD: 3.0; 6.1; 11.9; 16.4, 18,2 and 19.8 (° ± 0.2° 2Θ), further a DSC record of an endothermic peak indicating the melting temperature of the crystalline form in the range of 167 ± 3°C and the chemical purity determined by means of HPLC of 99.5% and higher, preferably 99,9% and higher. The crystalline polymorph II of the sodium salt of sacubitril of formula 5 exhibits the following reflections in XRPD: 4.0; 8.1; 10.5; 18.5, 22,5 and 24.4 (° ± 0.2° 20), further a DSC record of an endothermic peak indicating the melting temperature of the crystalline form in the range of 166 ± 3°C and the chemical purity determined by means of HPLC of 99.5% and higher, preferably 99,9% and higher. Other advantages of polymorph I for the purposes of preparation of pharmaceutical products is that this crystalline sodium salt shows very low hygroscopicity up to 50% ambient relative humidity, i.e. at 50% relative humidity water sorption of max. 0.3% was observed. The crystalline sodium salts of sacubitril featuring these physicochemical parameters meet the quality requirements accepted for active pharmaceutical product and so they can be advantageously used for the preparation of a drug for the treatment of hypertension and heart failure.

The preparation procedure of the sodium salt of sacubitril was already described in the patent application EP555175 and subsequently also in the specialized literature (J. Med. Chem. 1995, 38, 1689-1700), but the solid state and the yield of the prepared salt was not specified in any detail, just the melting point of 159-160°C was mentioned. The above mentioned procedure was reproduced, see Example 4e while the amorphous form of the sodium salt was obtained with the yield of 61% and the melting point of 159-161°C. In addition, the original procedure was characterized in the use of solvents that are classified in the second class of solvents from the point of view of the acceptable content, namely dichloromethane with the limit of 600 ppm and hexane with the limit of 290 ppm. The established circumstances document suitability of the newly found crystalline forms of the sodium salt of sacubitril and the method of their preparation.

The entire process (see Diagram 7) that can be applied to obtain a preferred salt of sacubitril, preferably crystalline sodium or calcium salt of sacubitril and that uses the features of the present invention may consist of the following steps:

a) preparation of the crude free acid of sacubitril 1 by a reaction of the amine of formula 3 with succinic acid anhydride,

b) converting the crude acid of sacubitril to a well crystallizing salt of sacubitril with the amines of formula 9, wherein R_ls R₂, R₃ independently stand for hydrogen or a C1-C7 alkyl, preferably converting it to a salt with cyclohexylamine, tert-butylamine or iso- propylamine and isolation of this salt,

c) releasing the free acid of sacubitril by the action of a suitable acid upon a solution of the salt of sacubitril with the amine, preferably by the action of an aqueous solution of an acid, preferably an aqueous solution of hydrochloric acid,

d) isolation of the crystalline free acid of sacubitril from at least one organic solvent, which may be a liquid aromatic hydrocarbon, preferably toluene, alternatively an ester of a carboxylic acid, preferably ethyl acetate or isopropyl acetate after an addition of an anti- solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalcanes, preferably heptane, hexane, or cyclohexane,

e) action of a suitable reagent as a source of the sodium or calcium ion upon the solution of the free acid of sacubitril 1 obtained using the procedure in accordance with point (d), preferably by the action of a reagent selected from the group: sodium hydroxide, sodium methanolate, sodium ethanolate, sodium /so-propoxide, sodium tert-butylate, sodium acetate, calcium chloride, calcium acetate or calcium hydroxide upon a solution of the acid of sacubitril 1 in ethyl acetate, isopropyl acetate or water,

f) isolating the crystalline sodium salt of formula 5 or calcium salt of formula 6 prepared using the procedure in accordance with point (e).

Points (b) and (c) can be eliminated from the entire preparation process of the pharmaceutically preferred salts of sacubitril, depending of the level of impurities contained in the crude free acid of sacubitril prepared in accordance with point (a).

In one aspect, the invention relates to solid forms of sacubitril of formula 1, especially a crystalline form of the free acid and its crystalline sodium salt of formula 5 or calcium salt of formula 6, incl. a method of removing chemical impurities from the crude free acid of sacubitril that is characterized in the use of well crystallizing salts of sacubitril with amines, preferably the salt with cyclohexylamine, tert-butylamine or wo-propylamine. The invention further relates to highly efficient and industrially usable preparation methods of a solid form of sacubitril free acid and its pharmaceutically applicable salts, especially the crystalline sodium salt of formula 5 and calcium salt of sacubitril of formula 6.

Ri> ^R2. ^R3 independently stand for a C1-C6 alkyl or hydrogen the crystalline form of sacubitril free acid

®® ®

Ca Na

Diagram 7.

Another object of this invention is a solid form of the potassium salt of sacubitril of formula 8, preferably in a crystalline form.

(8)

Still another object of this invention is a crystalline form of the potassium salt of sacubitril that contains these characteristic reflections in the X-ray powder pattern measured with the use of CuKa radiation: 6.2; 7.2; 11.7; 16.3 and 20.0 ± 0.2° 2-theta.

Another object of this invention is a preparation method of the solid form of the potassium salt of sacubitril that contains the following steps:

a) dissolution of the free acid or salt of sacubitril, preferably a salt of sacubitril with amines, and extraction in a mixture of an aqueous solution of a mineral acid, preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid, and with an organic solvent immiscible with water or a mixture of organic solvents, preferably ethyl acetate and toluene, or isopropyl acetate and toluene and concentration by evaporation;

b) addition of a solution of a reagent that is the source of 0.95 to 1.05 equivalents of the potassium ion, preferably a solution of potassium acetate in an alcohol, more preferably in ethanol, which is obtained either directly by the use of acetic acid, or is generated "in- situ'''' by mixing of potassium hydroxide or the potassium salt of a weak acid and acetic acid, preferably KOH and CH₃COOH or K₂S0₃ and CH₃COOH, possibly KHC0₃ and CH₃COOH;

c) concentration by evaporation of a part of the solvents;

d) after the addition of at least one solvent selected from the group: toluene, ethyl acetate or isopropyl acetate, a solid form of the potassium salt of sacubitril was obtained by crystallization.

Last, but not least, an object of this invention is also the use of the solid form of the potassium salt of sacubitril for the preparation of other pharmaceutically acceptable salts of sacubitril, preferably any crystalline salt, more preferably the sodium or calcium crystalline salt and the use of the solid form of the potassium salt of sacubitril for the preparation of a drug for the treatment of hypertension and heart failure.

During optimization of the synthesis of sacubitril, the conditions of the reaction sequence according to Diagram 2 could be adjusted in such a way that after the first reaction the reaction mixture can be concentrated at just a slightly reduced pressure by ~03 bar to approx. 1/3 of the original volume of the solution (reaction mixture) and then the distillation continues at simultaneous addition of the respective quantity of higher-boiling toluene in the total quantity of approx. 4 L/kg of the starting compound (4). This way, the mixture is freed of residues of all the volatile constituents from the reaction, as the original solvent (EtOH), hydrogen chloride, sulfur and carbon dioxide, ethyl-tert-butyl ether, isobutylene, or possibly water residues, without isolation of the compound (3) or evaporation of the mixture to a non- distilling evaporation product, and the final solution then essentially represents the intermediate (3) dissolved in toluene, which can be, with regard to a high purity of -99% - according to high-performance liquid chromatography - directly used in the next reaction stage. This increases the efficiency of the process as yield losses during the isolation of the compound (3) are avoided and at the same time the solvent for crystallization of the intermediate product (3), the time for crystallization, isolation and drying and last, but not least, the waste in the form of mother liquor after the crystallization are saved. A particular description of the embodiment is included in Example 1.

Another task within the development of the process was to replace the commonly used dichloromethane, which is however undesired for the industrial scale, for the 2^nd reaction stage of Diagram 2. We have managed to experimentally prove that the reaction of the amine (3) with succinanhydride can be conducted well in a mixture of toluene and ethyl acetate at suitable conditions as succinanhydride is easy to dissolve in ethyl acetate (unlike the commonly used dichloromethane). An important aspect of the execution of the 2^nd reaction stage is the selected reaction temperature in combination with an altered sequence of the addition of constituents. This is because normally, before the addition of succinanhydride as the entire reaction base, the addition of the base releases the electron pair of the amino group of the compound (3) for the reaction, which is occupied by the hydrogen proton in the hydrochloride form. However, we have managed to experimentally prove that the free base of the compound of formula 3 is unstable, especially in a basic environment and changes, due to the intramolecular attack of the amino group on the carboxyl of the structure of formula 3b, to the lactam of formula 5 according to Diagram 8:

Diagram 8.

This undesired side reaction then runs to such an extent that it later made preparation of the impurity standard (5) possible! For these reasons, the sequence of adding the reactant and base to the reaction mixture should be reversed, and the base, e.g. a base from the group of tertiary amines as triethylamine or N,N-diisopropyl-ethylamine (DIPEA) should be preferably added slowly, at a reduced temperature to the stirred mixture of the compound of formula 3 and succinanhydride in a mixture of toluene and ethyl acetate. This way, a high conversion rate and selectivity of the second reaction in Diagram 2 can be achieved, so that the purity of the reaction mixture then achieves up to 97% according to HPLC and the content of the undesired impurity of formula 5 will not exceed 2%! This considerably reduces the requirements for the subsequent purification of the final product and consequently the total yield of the process.

The processing of the reaction mixture is then easy, when first an aqueous solution of a mineral acid is added (e.g. a solution of hydrochloric, hydrobromic, sulfuric or orthophosphoric acid), which is, after good mixing, separated again as the immiscible bottom phase, extracting ballast salts of triethylamine and residues of the possible unreacted compound of formula 3 from the mixture while the protonated sacubitril acid remains in the extract. The mixture is then freed of the residues of the acid by subsequent extraction with water. The extract obtained this way (top organic layer) represents a solution of sacubitril of formula 1 in the mixture of ethyl acetate and toluene with the purity of up to 98% according to HPLC. The extract is then concentrated again and dried by removing of approx. 2/3 of the obtained solvent by distillation. A particular preparation method of the crude sacubitril acid in the solution is described by Example 2. If the entire process is conducted in a suitable matter, the solution of the product obtained this way can be directly used for the preparation of the final product (API).

However, since the purity of the final mixture depends on the parameters and execution of the entire production process, but naturally also on the purity of the used starting acid of formula 4, the product may be re-purified if necessary either by repeated crystallization of one of the possible salts of sacubitril, or possibly by crystallization and isolation of a suitably selected sequence, e.g. of two salts of sacubitril, depending on the spectrum of impurities contained in the starting material of formula 4.

However, solid forms of a number of compounds may have various internal arrangements, frequently with different physicochemical properties depending on the conditions of their preparation. Crystalline forms having different crystal units are referred to as polymorphs. They usually exhibit different physicochemical properties as chemical stability, hygroscopicity, melting point, solubility, dissolution rate as well as bioavailability. An amorphous product is usually more readily soluble; however, it cannot often be obtained in the required quality and it is also often less stable. Conversely, compared to the amorphous form, a crystalline product often exhibits higher stability and it is easier to obtain in the pure form and on the other hand, it dissolves more slowly.

To distinguish individual solid forms of a compound, a number of analytic methods for solid state investigation can be used, especially spectral methods, e.g. X-ray Powder Diffraction (XRPD), or thermoanalytical methods, e.g. Differential Scanning Calorimetry (DSC). Discovering new solid phases (amorphous forms, crystalline polymorphs, solvates and hydrates) of an active pharmaceutical ingredient offers an opportunity to select a suitable modification with desired physicochemical properties and processability and improve the characteristics of the chemical product.

A surprisingly good crystalline form of sacubitril from the point of view of isolation and final purification is represented by, as determined experimentally, some ammonium salts. We have managed to show that some salts of sacubitril with some amines crystallize surprisingly easily, so they can be advantageously isolated from the solution in a solid and chemically pure form. The originally contained impurities preferably remain in the used solvent. Thus, conversion of the crude free acid to the crystalline salts with amines leads to removal of impurities coming from the chemical synthesis, or the used starting material of formula 4. The execution is also surprisingly easy and it consists in mixing of a solution of the crude sacubitril carboxylic acid with a suitable amine in a suitable solvent, best in ethyl acetate or isopropyl acetate, when the respective salt with the used amine of formula 6, where R_ls R₂, R₃ independently stand for hydrogen or a C1-C7 alkyl, subsequently crystallizes. In this respect, the crystalline salts with cyclohexylamine, tert-butylamine or zso-propylamine are advantageous. If the ammonium salt is suitably selected, the obtained product, e.g. the cyclohexylammonium salt of sacubitril may directly represent the pharmaceutically acceptable final form in a quality required for an API and in a high yield of the synthesis (~ 94%). A particular preparation procedure of the ammonium salt is documented by Example 3.

Another suitable crystalline form of sacubitril is represented by the sodium salt, which can be prepared from a solution of the crude free acid by slow neutralization with a solution of caustic soda, or suitably selected sodium salt of a weak acid in a suitable solvent, preferably NaOH (1 molar equivalent) in ethanol at the room temperature. Suitable sodium salts, usable for neutralization of the crude acid of sacubitril and the preparation of the sodium salt of sacubitril are represented e.g. by sodium alcoholate, NaHC0₃, Na₂C0₃, Na₂S0₃, NaHS0₃, Na₂S₂0₅, usually added in the form of a solution or suspension with methanol, ethanol or isopropanol, ethyl acetate etc. The neutralization of sacubitril acid is followed by concentration of the mixture at a reduced pressure to about 1/3 of the original volume. Dilution with toluene or isopropyl acetate and repeated concentration by removing of the same quantity of the solvent, which leads to swapping of the original solvent and removal of the residues of water or sulfur or carbon dioxide etc., depending on the type of the base used for the neutralization. After the swapping of the solvents, the mixture is diluted with ethyl acetate and left to crystallize at the laboratory temperature for a few hours. The crystalline product of formula 7 is obtained, which is suitable for isolation in a high yield (~93%) and quality (> 99.5%) and at the same time represents a form that is suitable for pharmaceutical use. A particular example of the preparation method of the sodium salt is presented in Example 4.

Another suitable candidate both for the isolation and purification and at the same time for direct pharmaceutical use could be the potassium salt of sacubitril. However, it has not been described yet in an isolable crystalline form. We have not repeatedly managed to obtain it either. The description of such a failed attempt at preparation of the potassium salt of sacubitril is presented in Example 5. However, quite an unexpected breakthrough in the attempts to prepare the potassium salt of sacubitril was brought by an experiment when potassium acetate, well soluble in ethanol, was used for the neutralization of sacubitril acid instead of potassium hydroxide. It was after mixing of the crude acid of sacubitril and an ethanolic solution of CH₃COOK, subsequent concentration of the mixture at a reduced pressure to about 1/3 of the original volume and swapping of the residual solvents with toluene that after dilution of the final mixture with ethyl acetate, crystallization of the solid product was observed in the form of white suspension. After isolation of the product and drying at 50°C at a reduced pressure a solid product was obtained with the melting temperature of 104 - 110°C that exhibits high chemical purity (> 99.5%) according to HPLC and a crystalline state with the following characteristic reflections in XRPD: 6.2; 7.2; 11.7; 16.3 and 20.0° ( ± 0.2° 2ff). The particular preparation method is presented in Examples 6 and 7. The cause of this unexpected success and at the same time the actual composition of the obtained crystalline product could only be elucidated by a performed analysis of the product with the use of nuclear magnetic resonance (1H-NMR and ¹³C-NMR) and the result was confirmed by an acid-basic determination of the content of the substance with hydrochloric acid with a known titre and an approximate determination of the content of acetic acid in the product (6% m/m) with the use of Gas Chromatography (GC). All the available results equally show that the potassium salt of sacubitril probably only crystallizes in the stoichiometric ratio of 2:1 with acetic acid, which means that the obtained product is not the pure potassium salt of sacubitril, but it is the hemisolvate of the potassium salt of sacubitril with acetic acid the structure of which can be expressed with formula 8.

(8) The structure of formula 8 with the relative molecular weight MW = 449.58 + 1/2. 60.05 = 479.61 was mainly determined based on the results of the NMR measurements. A Bruker Avance 500 spectrometer with the measuring frequency of 500.131 MHz was used to measure the 1H-NMR and ¹³C-NMR spectra of solutions of the sample with the concentration of 25 mg/ml in deuterated dimethyl sulfoxide (DMSO-d6). The chemical shifts were related to the internal standard tetramethylsilane (TMS; δ = 0 ppm). The characteristic obtained 1H-NMR spectrum of the hemisolvate of the potassium salt of sacubitril with acetic acid is shown in figure 2. The molar ratio of the potassium salt of sacubitril and the acetic acid in the dissolved sample of the product can be determined from the measured 1H-NMR spectrum as the ratio of the integral intensities of the signals related to the number of the respective hydrogen atoms. Here, the measured solution of the sample of the substance represents a mixture of the potassium salt of sacubitril and acetic acid in the used solvent (DMSO-dV) in the molar ratio in which both the constituents were represented in the original crystalline sample. The ratio of the areas under individual peaks in the spectrum divided by the number of hydrogen atoms whose signal is concerned provides the molar ratio of individual constituents. The resulting areas of the signals of hydrogen atoms of the equivalent groups however correspond to the sum of the contributions of 1H atoms of each individual group or atom - overlap - in the spectrum.

To determine the stoichiometry of the potassium salt of sacubitril and acetic acid in the sample, the signal of 1H NMR spectrum with the chemical shift of δ = 1.74 ppm was used, which represents the overlapped signals of the CH₃ group of acetic acid and one hydrogen from the CH₂ groups in sacubitril at the total relative intensity of 2.5. Out of this, the unit signal corresponds to the response of 1 hydrogen of the C¾ group of sacubitril and the remaining 1.5 fall on the methyl of acetic acid. This means that the stoichiometric ratio of the potassium salt of sacubitril to acetic acid in the sample = 1/1 : 1.5/3 = 1 : 0.5. List of individual signals for the 1H-NMR spectrum in Fig. 2:

1H NMR (DMSO-d₆): 8.35 (d, 1H, J = 8.3 Hz, NH), 7.64 (d, 2H, J = 7.9 Hz, ArH), 7.57 (d, 2H, J = 8.2 Hz, ArH), 7.44 (t, 2H, J = 7.8 Hz, ArH), 7.33 (t, 1H, J = 7.9 Hz, ArH), 7.26 (d, 2H, J = 8.1 Hz, ArH), 3.98 (q, 2H, J = 7.1 Hz, CH₃-CH₂-0), 3.89 (m, 1H, NH-CH), 2.70 (dd, 1H, J = 6.6; 13.4 Hz, CH₂-Ar), 2.63 (dd, 1H, J = 6.7; 13.4 Hz), 2.48 (m, 1H, CH₃-CH), 2.17 (m, 2H+2H, CH₂-COOK + CH₂-CONH), 1.74 (s, 3/2 H, CH₃COOH), 1.73 (ddd, 1H, J = 4.2; 10.4; 13.7 Hz, CH-CH₂-CH), 1.37 (ddd, 1H, J= 4.0; 10.1; 13.6 Hz, CH-CH₂-CH), 1.11 (t, 3H, J= 7.1 Hz, CH₃-CH2-O), 1.04 (d, 3H, J= 6.9 Hz, CH₃-CH)

The results of the measurement of the C-NMR spectrum of the solution of the sample in DMSO-d6 is then shown in figure 3 - where the positive signals corresponds to carbon atoms with none or with two hydrogen atoms while the signals directed below the zero line indicate carbon atoms with an odd number of linked hydrogen atoms, i.e. 1 or 3. List of individual signals for the C-NMR spectrum in Figure 3 : ¹³C NMR (DMSO-de): 175.42 (C=0 sacubitril); 174.90 (C=0 sacubitril); 173.04 (C=0 acetate); 172.18 (C=0 sacubitril); 140,02 (quart. Ar-C); 138.13 (quart. Ar-C); 137.72 (quart. Ar-C); 129.78 (ArCH); 128.85 (ArCH); 127.11 (ArCH); 123.42 (ArCH); 126.26 (ArCH); 59.60 (CH₃-CH₂-0); 47.99 (NH-CH); 40.59 (CH₂-Ar); 37.65 (CH-CH₂-CH); 35.91 (CH₃- CH); 33.11 (CH₂-COOK or CH₂-CONH); 32.82 (CH₂-COOK or CH₂-CONH); 23.49 (CH₃ acetate); 17.91 (CH₃-CH); 13.97 (CH₃-CH₂-0)

Also, the results of acid-basic titration of a solution of 0.25 g of a sample of the measured substance in 20 ml of methanol and 10 ml of purified H₂0 with an aqueous solution of 0.1 M HC1 with an exactly known (titre) concentration correspond well to the structure of formula 8 with the relative molecular weight MW = 449.58 + 1/2. 60.05 = 479.61. The titration corresponds to gradual protonation of the anion of sacubitril (weak acid) in its potassium salt by a strong acid (HO) used as the titration agent. The point of equivalence corresponded to pH s 4 as indicated in figure 4 showing the actual titration curve. The charge of the measured substance, its assumed structure of formula 8, concentration of the titration agent and its consumption on achievement of the point of equivalence can be used to easily calculate the content of potassium ions in the titrated sample. The contents of potassium obtained experimentally this way, which varied in the range of 8.0 to 8.3%, conformed well to the theoretical content of potassium of 8.15%, which results from the relative molecular weights of potassium (MWK = 39.098) and the relative molecular weight of the hemisolvate of the potassium salt of sacubitril with acetic acid of formula 8, MW = 479.61.

The results of a series of more experiments focused on investigating the crystallization capability of the potassium salt and its yield depending on the quantity of acetic acid, which was added to the mixture before the entire crystallization, also correspond to crystallization of the potassium salt of sacubitril exclusively in the form of a solvate with acetic acid. The results of the experiments carried out with the use of the procedure of Examples 5, 6 and 8 are summarized in Table 1, showing the yields of the product depending on the different quantity of acetic acid in the mixture. Pearson's Correlation Coefficient between the molar ratio of acetic acid and sacubitril in the mixture and the obtained product yield (4. against the last column of the table) achieves the value R = 0.99!

Table 1: The results of preparation of the potassium salt of sacubitril at different quantities of acetic acid in the mixture

An advantage of this new crystalline form of sacubitril is especially the fact that it can be prepared in a high total yield of -90%, it is a crystalline, well isolable substance with a good purification capacity, so the purity of the product is usually also high > 99.7%, so it meets the quality requirements acknowledged for active pharmaceutical products and since it is at the same time a pharmaceutically acceptable form, it can be advantageously used for the preparation of a drug for the treatment of hypertension and heart failure without further treatment.

The above mentioned salts of sacubitril, both ammonium, as e.g. the cyclohexylammonium salt, and the sodium salt or potassium salt of sacubitril in the form of hemisolvate with acetic acid are generally compounds that are soluble in water, and therefore they can be advantageously used for the preparation of the calcium salt - of formula 9, which is insoluble in water, if necessary. You just need to add by dripping an aqueous solution of a calcium salt soluble in water, best calcium chloride or acetate to an aqueous solution of one of the above mentioned salts of sacubitril. A white suspension of the calcium salt of sacubitril is obtained virtually immediately, which can be isolated by filtration and after washing with water. A white powder is obtained in the yield of 94 - 96% with regard to the used input salt of sacubitril. A particular embodiment is described in Examples 9 and 10.

Sacubitril can also be easily and with a high yield (> 90%) converted from one form soluble in water to another one, which may be advantageous especially if it is necessary to add a purification step due to a poorer quality of the input raw material of formula 4. E.g. the crude ammonium salt of sacubitril can be used to prepare the sodium salt or potassium salt in the form of a hemisolvate with acetic acid. The input ammonium salt is dissolved in an emulsion of toluene, ethyl acetate and diluted aqueous solution of a mineral acid (e.g. a solution of hydrochloric, hydrobromic, sulfuric or orthophosphoric acid). After thorough stirring up, the bottom acidic ballast layer is separated and the organic layer is extracted with water. Then, the organic layer is concentrated by evaporation of about 2/3 of the solvents and the concentrate is diluted with ethyl acetate. By addition of ammonium acetate and swapping of the solvents, the re-purified product is prepared in the form of hemisolvate of the potassium salt of sacubitril with acetic acid, or analogously, neutralization with the basic sodium salt and subsequently crystallization from ethyl acetate provides the sodium salt of sacubitril. A particular embodiment of this is described by Examples 6 and 11. The hemisolvate of the potassium salt of sacubitril with acetic acid can be quite analogously converted to the sodium salt, as described in the particular case in Example 12.

Alternatively, e.g. the ammonium salt can be purified by recrystallization from a suitable solvent, best ethyl acetate, as described in Example 13. Brief description of the Drawings

Fig. 1 XRPD pattern of the crystalline free acid of sacubitril of formula 1, prepared in accordance with Example 2b. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle.

Fig. 2 XRPD pattern of the crystalline sodium salt of sacubitril of formula 5, polymorph I, prepared in accordance with Example 4a. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle.

Fig. 3 XRPD pattern of the crystalline sodium salt of sacubitril of formula 5, polymorph II, prepared in accordance with Example 4b. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle. Fig. 4 XRPD pattern of the amorphous sodium salt of sacubitril of formula 5, prepared in accordance with Example 4d. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle.

Fig. 5 XRPD pattern of the crystalline calcium salt of sacubitril of formula 6, prepared in accordance with Example 5c. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle.

Fig. 6 DSC record for the crystalline acid of sacubitril of formula 1 prepared in accordance with Example 2b.

Fig. 7 DSC record for the crystalline sodium salt of sacubitril of formula 5 prepared in accordance with Example 4a. (polymorph I)

Fig. 8 DSC record for the crystalline sodium salt of sacubitril of formula 5 prepared in accordance with Example 4b. (polymorph II) Fig. 9 HPLC chromatogram of the crude acid of sacubitril of formula 1 with an increased content of the impurity lactone (10), which a peak with the retention time of 5.86 min corresponds to. Fig. 10 HPLC chromatogram of the crystalline acid of sacubitril of formula 1 prepared using the procedure of Example 2b.

Fig. 11 XRPD pattern of the crystalline hemisolvate of the potassium salt of sacubitril with acetic acid (8), prepared according to Example 6. The pattern illustrates dependence of diffused radiation intensity on the 2-theta diffraction angle.

Fig. 12 1H NMR spectrum of the hemisolvate of the potassium salt of sacubitril and acetic acid in DMSO-d6 showing the dependence of relative intensities of the signals of hydrogen atoms on their chemical shift.

Fig. 13 C NMR spectrum of the hemisolvate of the potassium salt of sacubitril and acetic acid in DMSO-d₆ showing the dependence of relative intensities of the signals of carbon atoms in the molecule on their chemical shift. Fig. 14 Titration curve indicating the dependence of pH of a titrated solution of 0.244 g of the hemisolvate of the potassium salt of sacubitril with acetic acid (8) in a mixture of 20 ml of methanol and 10 ml of water during titration with hydrochloric acid at the concentration of 0.112 moldm^"3. Examples

The object of the invention will be clarified in a more detailed way with examples, which, however, do not have any influence on the invention scope defined in the claims. EXAMPLE 1 (synthesis of the crude salt of sacubitril)

The amount of 100 ml of dichloromethane and 12 ml of triethylamine was added to 10 g of the amine hydrochloride (3). The mixture was agitated at the laboratory temperature for approx. 10 minutes. This was followed by addition of 4.3 g of succinanhydride and agitation of the mixture at the laboratory temperature for 4 hours. 100 ml of 1M HC1 was added to the mixture, the layers were separated, the organic layer was washed with water and dried over sodium sulphate. After filtration of the desiccant the solvent was evaporated in vacuum (75°C, 10 mbar) and the product was obtained in the form of transparent honey. According to HPLC analyses the product usually contained 97.5 to 98.5% of the desired substance. The rest up to 100% is represented by impurities, especially the lactone (10), see Example 6.

1H NMR (DMSO-D6): 1.06 (d, 3H), 1.12 (t, 3H), 1.39 (t, 1H), 1.77 (t, 1H), 2.30 (m, 2H), 2.40 (m, 2H), 2.49 (m, 1H), 2.70 (m, 2H), 3.92 (m, 1H), 3.99 (q, 2H), 7.26 (d, 2H), 7.35 (t, 1H), 7.46 (t, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.77 (d, 1H), 12.11 (bs, 1H).

EXAMPLE 2 (procedures of preparation and isolation of the crystalline acid of sacubitril)

honey-like form crystalline form

EXAMPLE 2a (crystallization of the free acid of sacubitril from an aromatic solvent)

Sacubitril free acid (16.5 g), characterized in having honey-like consistency was dissolved at 70°C in 70 ml of toluene and the solution was stirred overnight at a temperature of 20-25°C. The obtained suspension was cooled down to a temperature of 5-10°C, subjected to filtration and the filtration cake was blown with a stream of nitrogen until a powder-like product was obtained, which was subsequently vacuum-dried at a temperature of about 20°C. The amount of 14.0 g of the product was obtained in the form of fine crystalline powder, which contains, according to 1H NMR, residual toluene on the level of 18 mol% and which starts to melt at a temperature over 35°C. The crystalline form was characterized by means of XRPD, which conforms to the crystalline form obtained using the procedure in accordance with Example 2b. The 1H NMR spectrum measured for the solution in DMSO-i/6 corresponds to the spectrum of sacubitril free acid.

EXAMPLE 2b (crystallization of sacubitril free acid from a mixture of a liquid carboxylic acid ester and a non-polar anti-solvent)

The salt of sacubitril with cyclohexylamine (7.03 g) was suspended in 70 ml of isopropyl acetate at the laboratory temperature. 15 ml of 2M HC1 was added to the stirred suspension. The organic phase was separated and washed with water. The organic phase was concentrated in vacuum (20 mbar) at 25°C to approx. 10 ml of a gel-like residue, which is a mixture of the acid of sacubitril and isopropyl acetate. The amount of 100 ml of heptane was added to this mixture and the mixture was stirred at the laboratory temperature until a suspension was obtained. The solid fraction was separated by filtration. The filter cake was washed with 10 ml of heptane and dried at 40°C and the pressure of 200 bar in a vacuum drier for at least 8 hours. Yield 98.7%, chemical purity according to HPLC 99.9%, the melting point determined by DSC is 74°C (Fig. 6) according to GC the product does not contain any residual solvents. The crystalline form was characterized by means of XRPD (Fig. 1, Table 1.). The 1H NMR spectrum measured for the solution in DMSO- 6 corresponds to the spectrum of sacubitril free acid. EXAMPLE 3 (procedures of preparation and isolation of salts of sacubitril with amines, incl. releasing of sacubitril free acid from an ammonium salt)

EXAMPLE 3a (general procedure of preparation and isolation of salts of sacubitril with amines)

Ri> ^R2. R3 independently stand for a C1-C6 a Iky I or hydrogen

Crude sacubitril acid of formula 1 was dissolved in an organic solvent. An amine was added to the solution in the quantity corresponding to 1.1 equivalents of sacubitril. The mixture was agitated. The separated crystalline salt was isolated by filtration, washed with mother liquor and the used solvent and dried in vacuum.

The yield of the salt with tert-butylamine was 81.5%, the chemical purity according to HPLC was 99.4%. 1H NMR (DMSO-D6): 1.06 (d, 3H), 1.13 (t, 3H), 1.17 (s, 9H), 1.38 (m, 1H), 1.76 (m, 1H), 2.22 (s, 3H), 2.24 (m, 1H), 2.68 (m, 2H), 3.91 (m, 1H), 4.00 (q, 2H), 7.27 (d, 2H), 7.35 (t, 1H), 7.46 (t, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.08 (d, 2H).

The yield of the salt with zso-propylamine was 79.6%, the chemical purity according to HPLC was 99.5%. 1H NMR (DMSO-D6): 1.06 (d, 3H), 1.10 (d, 6H), 1.13 (t, 3H), 1.38 (m, IH), 1.76 (m, IH), 2.22 (s, 3H), 2.24 (m, IH), 2.68 (m, 2H), 3.14 (m, IH), 3.91 (m, IH), 4.00 (q, 2H), 7.27 (d, 2H), 7.35 (t, IH), 7.46 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 8.03 (d, 2H).

EXAMPLE 3b (method of preparation and isolation of the crystalline salt of sacubitril with cyclohexylamine)

20.0 g of crude sacubitril acid of formula 1 was dissolved in 200 ml of ethyl acetate. Cyclohexylamine was added to the solution in the quantity corresponding to 1.1 equivalents of sacubitril. The mixture was agitated, the separated crystalline salt was isolated by filtration, washed with mother liquor, ethyl acetate and dried in vacuum. The yield of the salt with cyclohexylamine was 93%, the chemical purity according to HPLC was 99.89%. 1H NMR (DMSO-D6): 1.06 (d, 3H), 1.09-1.25 (m, 3H), 1.13 (t, 3H), 1.38 (m, IH), 1.55 (m, IH), 1.68 (m, 2H), 1.76 (m, IH), 1.82 (m, 2H), 2.22 (s, 3H), 2.23 (m, IH), 2.63-2.74 (m, 3H), 3.91 (m, IH), 4.00 (q, 2H), 7.27 (d, 2H), 7.35 (t, IH), 7.46 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 8.04 (d, 2H).

EXAMPLE 3c (releasing the free acid of sacubitril from the ammonium salt)

Ri_> Rz' ^R3 independently stand for a C1-C6 alkyl or hydrogen The salt of sacubitril with cyclohexylamine (20.0 g) was dissolved in 200 ml of dichloromethane, 20 ml of 2M HC1 was added to the solution and the layers were divided. The organic phase was washed with 2 x 20 ml of water, 1 x 10 ml of salt brine and dried over sodium sulphate. The drying agent was removed by filtration and the solved evaporated in vacuum. The amount of 16.5 g of the product was obtained in the form of transparent honey. The 1H NMR spectrum measured for the solution in DMSO-dd corresponds to the spectrum of sacubitril free acid.

EXAMPLE 4 (procedures of preparation and isolation of the sodium salt of sacubitril)

EXAMPLE 4a (crystalline sodium salt of sacubitril obtained with the use of sodium hydroxide as the source of the sodium ion, polymorph I)

Sacubitril free acid (20.16 g, 0.049 mol) is dissolved in a mixture of 55 ml of toluene and 35 ml of ethyl acetate. The solution of 1.93 g of sodium hydroxide (0.048 mol) in 43 ml of ethanol is added to the stirred solution of the acid during 30 min and at the temperature of 20°C. The mixture is concentrated in vacuum by evaporation of approx. 100 ml of the solvents. The amount of 50 ml of toluene is added and the mixture is concentrated again by evaporation of approx. 50 ml of the solvents. The concentrated residue is slowly diluted by addition of 230 ml of ethyl acetate. The mixture is stirred for at least 2.5 hours. During this time period the crystalline product is separated. The obtained suspension is gradually cooled down to 15 - 18°C and after approximately 30 minutes of stirring the product is filtered off and washed with about 25 ml of ethyl acetate. The isolated product is dried in vacuum at 50°C until a constant weight is achieved. The amount of 19.9 g of the crystalline product (yield 94%) was obtained, chemical purity according to HPLC 99.9%, the melting point determined by DSC is 167°C (Fig. 7). 1H NMR (DMSO-D6): 1.05 (d, 3H), 1.12 (t, 3H), 1.36 (t, 1H), 1.74 (t, 1H), 2.06 (m, 2H), 2.16 (m, 2H), 2.63-2.72 (m, 3H), 3.89 (m, 1H), 3.99 (q, 2H), 7.27 (d, 2H), 7.36 (t, 1H), 7.45 (t, 2H), 7.57 (d, 2H), 7.65 (d, 2H), 8.65 (d, 1H). The crystalline form was characterized by means of XRPD (Fig. 2, Table 2.). EXAMPLE 4b (crystalline sodium salt of sacubitril obtained with the use of sodium ethanolate as the source of the sodium ion, polymorph Π)

Sacubitril free acid (20.16 g, 0.049 mol) is dissolved in a mixture of 55 ml of toluene and 35 ml of ethyl acetate. A solution of sodium ethanolate (0.048 mol, the solution was obtained by dilution of a commercially available solution supplied by the company Sigma- Aldrich, 17.9 ml of a 21% wt. solution of sodium ethanolate in ethanol, further diluted by addition of 25 ml of ethanol) is added to a stirred solution of the acid by dripping during 30 min and at the temperature of 20°C. The mixture is concentrated in vacuum by evaporation of approx. 100 ml of the solvents. The amount of 50 ml of toluene is added and the mixture is concentrated again by evaporation of approx. 50 ml of the solvents. The concentrated residue is slowly diluted by addition of 100 ml of toluene and 250 ml of ethyl acetate. The mixture is stirred for at least 2.5 hours. During this time period the crystalline product is separated. The obtained suspension is gradually cooled down to 15 - 16°C and after approximately one hour of stirring the product is filtered off and washed with about 20 ml of ethyl acetate. The isolated product is dried in vacuum at 50°C until a constant weight is achieved. The amount of 19.5 g of the crystalline product (yield 92%) was obtained, chemical purity according to HPLC 99.9%, the melting point determined by DSC is 166 ± 3°C (Fig. 8). The 1H NMR spectrum measured for the solution in DMSO-c/6 corresponds to the spectrum of the sodium salt of sacubitril. The crystalline form was characterized by means of XRPD (Fig. 3, Table 3.).

EXAMPLE 4c (sodium salt of sacubitril obtained with the use of sodium acetate as the source of the sodium ion)

Sacubitril free acid (20.16 g, 0.049 mol) is dissolved in a mixture of 55 ml of toluene and 35 ml of ethyl acetate. A solution of sodium acetate in ethanol (0.048 mol, 3.94 g of anhydrous sodium acetate dissolved in 45 ml of ethanol) is added by dripping to a stirred solution of the acid during 30 min and at the temperature of 20°C). The mixture is washed with water and concentrated in vacuum by evaporation of approx. 100 ml of the solvents. The amount of 50 ml of toluene is added and the mixture is concentrated again by evaporation of approx. 50 ml of the solvents. The concentrated residue is slowly diluted by addition of 230 ml of ethyl acetate. The mixture is stirred for at least 2.5 hours. During this time period the crystalline product is separated. The obtained suspension is gradually cooled down to 15 - 18°C and after approximately 30 minutes of stirring the product is filtered off and washed with about 25 ml of ethyl acetate. The isolated product is dried in vacuum at 50°C until a constant weight is achieved. Obtained amount 19.1 g of the product (yield 90%), chemical purity in accordance with HPLC 99.8%. The ^lH NMR spectrum measured for the solution in DMSO-c/6 corresponds to the spectrum of the sodium salt of sacubitril. EXAMPLE 4d (amorphous sodium salt of sacubitril)

THF was added to the crystalline acid of sacubitril. 1 equivalent of sodium tert-butoxide was added to the stirred solution. The mixture was stirred at the laboratory temperature until a slightly turbid solution was obtained. Then, it was filtered and heptane was added to the clear filtrate until a turbid solution was produced. This was followed by vacuum concentration and addition of a mixture of heptane and dichloromethane in the constituent ratio of 3:1. The turbid solution was concentrated in vacuum and the obtained suspension was agitated at the laboratory temperature. Filtering and vacuum drying followed after that. The isolated significantly amorphous sodium salt was characterized by means of XRPD (Fig. 4). The 1H NMR spectrum measured for the solution in DMSO- 6 corresponds to the spectrum of the sodium salt of sacubitril.

EXAMPLE 4e (sodium salt of sacubitril - reference example obtained from the literature: J Med. Chem. 1995, 38, 1689-1700)

The free acid of sacubitril (0.83 g, 2.0 mmol) was stirred in a mixture of 1M sodium hydroxide (2 ml) and tetrahydrofuran (10 ml) at the laboratory temperature for 5 minutes. The solvents were then dried in vacuum and the rest was stirred in a mixture of dichloromethane and hexaiie until the solid phase was obtained. The product was isolated by filtration and dried freely. The amount of 0.54 g of the sodium salt was obtained (yield 61%), melt, point 159- 161°C, the X-ray powder pattern is identical to the form in accordance with Example 4d, the 1H NMR spectrum measured for the solution in OMSO-d6 corresponds to the spectrum of the sodium salt of sacubitril.

EXAMPLE 5 (procedures of preparation and isolation of the calcium salt of sacubitril)

EXAMPLE 5a (preparation procedure of the calcium salt of sacubitril with the use of calcium chloride)

The free acid of sacubitril (0.42 g) was stirred up in 5 ml of water and calcium chloride dihydrate dissolved in water (1 g in 5 ml of water) was added. The mixture was agitated at 50°C for 3 hours, then it was cooled down to 25°C. The separated crystalline product was filtered off and dried (yield 92%, chemical purity 99.7% in accordance with HPLC).

EXAMPLE 5b (preparation procedure of the calcium salt of sacubitril with the use of calcium acetate)

The free acid of sacubitril (0.42 g) was stirred up in 5 ml of water and calcium acetate dissolved in water (0.85 g in 5 ml of water) was added. The mixture was agitated at 50°C for 3 hours, then it was cooled down to 25°C. The separated product was filtered off and dried (yield 90%, chemical purity 99.7% in accordance with HPLC). EXAMPLE 5c (preparation procedure of the calcium salt of sacubitril with the use of calcium hydroxide)

The free acid of sacubitril (0.85 g) was stirred up in 20 ml of water and 20 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the acid was separated and the mixture was evaporated on a vacuum evaporator. The evaporation product was dissolved in 20 ml of acetone and 2.43 ml of a suspension of calcium hydroxide was added that had been prepared by suspending (0.74 g) in water (10 ml). The mixture was homogenized in an ultrasonic bath and then it was left to evaporate in a vacuum drier at the room temperature. The amount of 11.3 g of the crystalline salt (96%, 99% HPLC) was obtained. The crystalline calcium salt was characterized by means of XRPD (Fig. 5, Table 4.).

EXAMPLE 6 (synthesis of a process impurity - lactone (10))

32 ml of ethanol and 0.28 of lithium hydroxide were added to 4.0 g of the amine (3) hydrochloride. The obtained solution was stirred overnight until a turbid solution was obtained. The mixture was subsequently stirred for 3 hours and heated up at the reflux temperature of the solvent. This was followed by evaporation of the solvent, dissolution of the residue in 50 ml of dichloromethane, filtering of the turbid solution, washing with 15 ml of water and drying of the organic phase over sodium sulphate. After the removal of the drying agent by filtration, heptane (100 ml) was added to the solution, dichloromethane was evaporated in vacuum, the separated product was filtered off and dried. The amount of 2,21 g (yield 80%) of the lactone (10) was obtained. The HPLC peak of the lactone (10) exhibits the same retention time (5.86 min) as the main impurity present in the crude acid of sacubitril, see Example 1, further Fig. 9 and 10. 1H NMR (DMSO- d6): 0.97 (d, 3H), 1.62 (m, 1H), 1.98 (m, 1H), 2.17 (m, 1H), 2.69 (dd, 1H), 2.81 (dd, 1H), 3.73 (m, 1H), 7.32 (d, 2H), 7.34 (t, 1H), 7.45 (t, 2H), 7.59 (d, 2H), 7.65 (d, 2H), 7.75 (bs, 1H). EXAMPLE 7 (preparation procedure of the penultimate of formula 3 without its isolation)

The amount of 140 g of the starting substance of formula 4 is stirred up in 640 ml of anhydrous ethanol in a 2L reactor. Then, 40 ml of thionyl chloride (SOCl₂ 1.5 eq) is added to the stirred mixture at a temperature of approx. 5 - 10°C during -20 minutes. After approx. 30 minutes of stirring, the mixture is heated up to the temperature of 50°C and it is stirred for 1 hour at this temperature. After that, the reaction mixture is concentrated by removing of approx. 420 ml of the volatile constituents by distillation at a reduced pressure (-0.25 bar). Then, distillation continues at a pressure of -0.2 to 0.1 bar under simultaneous adding of 580 ml of toluene (at the same time, about 580 ml of the solvents are removed by distillation). The concentrate of the mixture is diluted with 450 ml of toluene. The resulting light yellow solution of the compound of formula 3 has the purity of 98.9% according to HPLC and is further used for the preparation of the crude acid of sacubitril.

The amount of 36.7 g of succinanhydride, dissolved in 580 ml of ethyl acetate, is added to a solution of the hydrochloride of the amine of formula 3 in toluene, prepared according to Example 1, at RT. Being stirred, the mixture is cooled down to 0°C. Then, at the temperature of ~2°C, a solution of 115 ml of triethylamine in 115 ml of ethyl acetate is slowly added to the stirred mixture during approx. 80 minutes and the obtained mixture is stirred for another 3 hours at a temperature of 0 - 5°C. Then, a solution of 41 ml of 36% hydrochloric acid in 280 ml of water is added at ~20°C and the emulsion is stirred for about 15 minutes at RT. After the separation of the phases, the top organic layer is further extracted with 200 ml of purified water. The obtained solution of sacubitril in the organic solvent is then concentrated at a slightly reduced pressure (-0.2 bar) by evaporation of about 1100 ml of the solvents. The distillation then continues at simultaneous adding of 280 ml of toluene (approximately the same quantity of the solvents is removed by distillation at the same time). The final solution of sacubitril in toluene achieved the purity of 98.0% according the HPLC while the main contained impurity is the lactam of formula 5, which amounted to 1.85%. The solution of the crude acid of sacubitril is further used for the preparation of the selected salt. EXAMPLE 9 (method of preparation and isolation of the crystalline salt of sacubitril with cyclohexylamine)

A solution of the crude product in toluene, prepared according to Example 2, was diluted with 1200 ml of ethyl acetate. 41 ml of cyclohexylamine was then added to the stirred solution at 50°C during about 15 minutes. The mixture was stirred for approx. 2.5 hours, being slowly cooled down. The separated crystalline salt was isolated by filtration at the temperature of 10°C, washed with cooled ethyl acetate and dried at 45°C. The yield of the salt with cyclohexylamine amounted to 175 g, which corresponds to 93.9% with respect to the charged quantity of 140 g of the starting compound of formula 4. The chemical purity of the product achieved 99.9% according to HPLC. 1H NMR (DMSO-D6): 1.06 (d, 3H), 1.09-1.25 (m, 3H), 1.13 (t, 3H), 1.38 (m, 1H), 1.55 (m, 1H), 1.68 (m, 2H), 1.76 (m, 1H), 1.82 (m, 2H), 2.22 (s, 3H), 2.23 (m, 1H), 2.63-2.74 (m, 3H), 3.91 (m, 1H), 4.00 (q, 2H), 7.27 (d, 2H), 7.35 (t, 1H), 7.46 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 8.04 (d, 211). EXAMPLE 10 (procedure of preparation and isolation of the sodium salt of sacubitril)

A solution of the crude product in toluene, prepared using the procedure of Examples 1 and 2, was neutralized by adding of a solution of 14.2 g of sodium hydroxide (0.355 mol) in 400 ml of absolute ethanol by dripping during 20 minutes and at the temperature of 22°C. The mixture was then concentrated in vacuum by evaporation of approx. 450 ml of the solvents. The concentrate was diluted with 360 ml of toluene and the mixture was concentrated again by evaporation of approx. 360 ml of the solvents. The concentrated solution of the product was diluted by addition of 1800 ml of ethyl acetate at the laboratory temperature and the mixture was stirred at the room temperature for approx. 7 hours. The crystalline product was obtained during this period. The obtained suspension was gradually cooled down to 16°C and after approx. 30 minutes the product was isolated by filtration and washed with approx. 140 ml of ethyl acetate. After drying of the product in vacuum at 50°C, the amount of 147 g of a white crystalline powder was obtained (yield with regard to the charged compound of formula 4 ~ 92.9%) at the chemical purity of 99.7% according to HPLC with the melting point according to DSC of ~166°C. 1H NMR (DMSO-D6): 1.05 (d, 3H), 1.12 (t, 3H), 1.36 (t, 1H), 1.74 (t, 1H), 2.06 (m, 2H), 2.16 (m, 2H), 2.63-2.72 (m, 3H), 3.89 (m, 1H), 3.99 (q, 2H), 7.27 (d, 2H), 7.36 (t, 1H), 7.45 (t, 2H), 7.57 (d, 2H), 7.65 (d, 2H), 8.65 (d, 1H).

EXAMPLE 11 (failed preparation procedure of the potassium salt of sacubitril)

10.0 g of the cyclohexylammonium salt of sacubitril was charged into a flask with a magnetic stirrer and 30 ml of toluene and 30 ml of ethyl acetate were poured over it. Then, a solution of 1.70 ml of concentrated hydrochloric acid in 20 ml of water was added under intensive stirring. Approx. after 10 minutes of stirring at RT, the bottom ballast phase was separated. The top organic layer was then further extracted with about 15 ml of purified water (approx. 10 minutes' stirring). The top organic phase containing the product was then concentrated at a reduced pressure (-0.2 - 0.1 bar) on a rotary evaporator by removing of all the solvents by distillation (about 57 ml removed by distillation).

A prepared solution of 1.09 g of potassium hydroxide in 25 ml of absolute ethanol was slowly added by dripping to the obtained solution of sacubitril acid under intensive stirring at ~24°C. Then, the mixture was concentrated at a reduced pressure (-0.2 bar) on a rotary evaporator by removing of approx. -24 ml of the solvents by distillation. After dilution of the concentrate with 30 ml of toluene the mixture was concentrated again by evaporation of about 20 ml of the solvents. The stirred concentrate was diluted by adding of 100 ml of ethyl acetate and the solution was left to be stirred by a magnetic stirred until the morning of the next day. However, the product did not appear in the mixture, and therefore the mixture was left for about another 7 days at -18°C. However, no product was obtained either (experiment no. 1 in Table 1).

EXAMPLE 12 (preparation method of the potassium salt of sacubitril from the salt with cyclohexylamine)

10.0 g of the cyclohexylammonium salt of sacubitril was charged into a flask with a magnetic stirrer and 30 ml of toluene and 30 ml of ethyl acetate were poured over it. Then, a solution of 1.70 ml of concentrated hydrochloric acid in 20 ml of water was added under intensive stirring. Approx. after 10 minutes of stirring at RT, the bottom ballast phase was separated. The organic layer was then further extracted with about 15 ml of purified water (approx. 10 minutes' stirring). The top organic phase containing the product was then concentrated at a reduced pressure (-0.2 - 0.1 bar) on a rotary evaporator by removing of all the solvents by distillation (about 58 ml removed by distillation).

A prepared solution of 1.90 g of potassium acetate in 25 ml of absolute ethanol was slowly added by dripping to the obtained solution of sacubitril acid under intensive stirring at ~24°C. Then, the mixture was concentrated at a reduced pressure (-0.2 bar) on a rotary evaporator by removing of approx. -23 ml of the solvents by distillation. After dilution of the concentrate with 30 ml of toluene the mixture was concentrated again by evaporation of about 20 ml of the solvents. The stirred concentrate was diluted by adding of 100 ml of ethyl acetate and the solution was left to be stirred by a magnetic stirred until the morning of the next day. The obtained suspension was cooled down to 16°C and after about 30 min of stirring the product was filtered off and washed with approx. 10 ml of icy ethyl acetate. After drying in vacuum, first at 45°C and then at 60°C until a constant weight was achieved and crushing, the amount of 8.73 g of a white powder was obtained (corresponding to the yield of 93% of the hemisolvate of the potassium salt of sacubitril with acetic acid) with the melting point of 108°C and purity of 99.9% (experiment no. 2 in Table 1). 1H NMR (DMSO-d₆): 8.35 (d, 1H, J = 8.3 Hz, NH), 7.64 (d, 2H, J= 7.9 Hz, ArH), 7.57 (d, 2H, J = 8.2 Hz, ArH), 7.44 (t, 2H, J = 7.8 Hz, ArH), 7.33 (t, 1H, J = 7.9 Hz, ArH), 7.26 (d, 2H, J= 8.1 Hz, ArH), 3.98 (q, 2H, J= 7.1 Hz, CH₃-CH₂-0), 3.89 (m, 1H, NH-CH), 2.70 (dd, 1H, J= 6.6; 13.4 Hz, CH₂-Ar), 2.63 (dd, 1H, J = 6.7; 13.4 Hz), 2.48 (m, 1H, CH₃-CH), 2.17 (m, 2H+2H, CH₂-COOK + CH₂-CONH), 1.74 (s, 3/2 H, CH₃COOH), 1.73 (ddd, 1H, J = 4.2; 10.4; 13.7 Hz, CH-C¾-CH), 1.37 (ddd, 1H, J= 4.0; 10.1; 13.6 Hz, CH-CH₂-CH), 1.11 (t, 3H, J= 7.1 Hz, CH₃-CH₂-0), 1.04 (d, 3H, J= 6.9 Hz, CH₃-CH)

EXAMPLE 13 (direct preparation of the potassium salt of sacubitril with the potassium acetate)

A solution of 34.7 g of potassium acetate (0.353 mol) in 420 ml of absolute ethanol was added by dripping to a solution of the crude product in toluene, prepared using the procedure of Examples 1 and 2 during 15 min and at the temperature of 22°C. Then, the mixture was concentrated at a reduced pressure (-0.2 bar) by evaporation of approx. 460 ml of the solvents. The concentrate was diluted with 360 ml of toluene and the mixture was concentrated again by evaporation of approx. 355 ml of the solvents. The concentrated solution of the product was diluted by addition of 1900 ml of ethyl acetate at the temperature of 45 °C and the mixture was cooled down to 15°C under stirring during approx. 6 hours. The product was then isolated from the obtained suspension by filtration and it was washed with about 160 ml of ethyl acetate. After drying in vacuum at 55°C, the amount of 161 g of a white crystalline product was obtained (the yield with regard to the charged compound of formula 4 was 92%) at the chemical purity of 99.8% according to HPLC with the melting point according to DSC of ~107°C. EXAMPLE 14 (preparation of the potassium salt of sacubitril from the salt with cyclohexylamine - Table 1)

30.0 g of the cyclohexylammonium salt of sacubitril was charged into a 0.5L flask with a magnetic stirrer and 90 ml of toluene and 90 ml of ethyl acetate were poured over it. Then, a solution of 5.0 ml of concentrated hydrochloric acid in 60 ml of water was added under intensive stirring. Approx. after 10 minutes of stirring at RT, the bottom ballast phase was separated. The top organic layer was then further extracted with about 45 ml of purified water (approx. 10 minutes' stirring). The top organic phase containing the product was then concentrated at a reduced pressure (-0.2) on a rotary evaporator by removing of about 60 - 70 ml of the solvents by distillation.

A prepared solution of 3.30 g of potassium hydroxide and the amount of glacial acetic acid defined in Table 1 in 80 ml of absolute ethanol were slowly added by dripping to the obtained solution of sacubitril acid under intensive stirring at ~24°C. Then, the mixture was concentrated at a reduced pressure (-0.2 bar) on a rotary evaporator by removing of approx. ~110 ml - 120 ml of the solvents by distillation. After dilution of the concentrate with 60 ml of toluene the mixture was concentrated again by evaporation of about 60 ml of the solvents. The stirred concentrate was slowly diluted at the temperature of ~45°C by addition of 320 ml of ethyl acetate and at 40 - 44°C it was seeded with the product and left to crystallize for at least 4 hours. The mixture was gradually further cooled to 15 - 17°C during approx. 2 hours and after about 30 minutes of stirring the product, if obtained, was filtered off and washed with about 25 ml of cold ethyl acetate. The obtained products were dried in vacuum at 55°C until a constant weight was achieved. The theoretical yield of the hemisolvate of the potassium salt of sacubitril with acetic acid with regard to the input charge of 30 g of the cyclohexylamine salt corresponds to 28.17 g - the practical yields are summarized for individual experiments in Table 1. In the case no. 5, when no product was obtained, the mixture was left for about another 3 days at -18°C. However, the product did not appear in the mixture and the experiment is recorded in Table 1 as the experiment no. 5 with zero yield. EXAMPLE 15 (preparation procedures of the calcium salt of sacubitril from the hemisolvate of the potassium salt)

(8) (9)

40 g of the hemisolvate of the potassium salt of sacubitril with acetic acid was dissolved at 30°C in 500 ml of purified water. Then, during about 30 minutes, under stirring a solution of 9.80 g of calcium chloride dihydrate (CaCl₂.2H₂0; 0.066 mol) in 40 ml of purified water was added by dripping. After 2 hours of stirring the white suspension was cooled down to 18°C and the product was filtered off. After washing with water (about 50 ml) the wet product was dried in vacuum at 55°C until a constant weight was achieved. The amount of 34.1 g of a white powder (yield 95%) was obtained at the purity of 99.9% according to HPLC.

EXAMPLE 16 (preparation method of the calcium salt of sacubitril from the cyclohexylammonium salt)

42 g of the cyclohexylammonium salt of sacubitril was dissolved in 420 ml of purified water at about 30°C. Then, during about 20 minutes, under stirring a solution of 12.30 g of calcium acetate monohydrate (Ca(CH₃COO)₂.H₂0; 0.07 mol) in 120 ml of purified water was added by dripping. After 2.5 hours of stirring the white suspension was cooled down to 17°C and the product was filtered off. After washing with about 55 ml of water, the wet product was dried in vacuum at 55°C until a constant weight was achieved. The amount of 33.25 g of a white powder (yield ~94%) was obtained at the purity of 99.85% according to HPLC.

EXAMPLE 17 (preparation of the sodium salt of sacubitril from the cyclohexylammonium salt)

80.0 g of the cyclohexylammonium salt of sacubitril, having the purity of 99.7% (HPLC), was charged into a 1L glass reactor and 240 ml of toluene and 240 ml of ethyl acetate were poured over it. Then, a solution of 13.5 ml of concentrated hydrochloric acid in 160 ml of water was added under intensive stirring. After 15 minutes of stirring at the laboratory temperature, the bottom ballast phase was separated. The organic layer was then further extracted with 120 ml of purified water (approx. 10 minutes' stirring). The top organic phase containing the product was then concentrated at a reduced pressure (-0.2) by removing of about 200 ml of the solvents by distillation.

A prepared solution of 6.20 g of sodium hydroxide in 150 ml of absolute ethanol was slowly added by dripping to the obtained solution of sacubitril acid (1) under intensive stirring at ~23°C. The mixture was then concentrated by removing of about 305 ml of the solvents by distillation at a reduced pressure (-0.2 bar). The concentrate was diluted with 160 ml of toluene and then it was concentrated again at a reduced pressure (-0.15 bar) by evaporation of the same quantity of the solvents. The mechanically stirred concentrate was then diluted by addition of 800 ml of ethyl acetate and at 25°C it was seeded with the product and left to crystallize for 8 hours. The stirred mixture was then further cooled down to 15 - 17°C and after about 30 min of stirring the product was filtered off and washed with approx. 65 ml of cold ethyl acetate. After drying in vacuum at 55°C, the amount of 63.8 g of white, crystalline sodium salt of sacubitril (yield 94%) was obtained at the purity of 99.9% and melting point of 167°C.

1H NMR (DMSO-D6): 1.05 (d, 3H), 1.12 (t, 3H), 1.36 (t, 1H), 1.74 (t, 1H), 2.06 (m, 2H), 2.16 (m, 2H), 2.63-2.72 (m, 3H), 3.89 (m, 1H), 3.99 (q, 2H), 7.27 (d, 2H), 7.36 (t, 1H), 7.45 (t, 2H), 7.57 (d, 2H), 7.65 (d, 2H), 8.65 (d, 1H).

EXAMPLE 18 (preparation of the sodium salt of sacubitril from the hemisolvate of the potassium salt)

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56.5 g hemisolvate of the potassium salt of sacubitril with acetic acid, having the purity of 99.6% (HPLC), was charged into a 1L glass reactor and 180 ml of toluene and 180 ml of ethyl acetate were poured over it. Then, a solution of 10.1 ml of concentrated hydrochloric acid in 120 ml of water was added under intensive stirring. After 15 minutes of stirring at the laboratory temperature, the bottom aqueous phase was separated. The top organic layer was extracted twice with 90 ml of purified water. The organic phase containing the product was then concentrated at a reduced pressure (-0.2) by removing of about 157 ml of the solvents by distillation.

A prepared solution of 4.70 g of sodium hydroxide in 120 ml of absolute ethanol was slowly added by dripping to the obtained solution of sacubitril acid under intensive stirring at ~23°C. The mixture was then concentrated by removing of about 230 ml of the solvents by distillation at a reduced pressure (-0.2 bar). The concentrate was diluted with 120 ml of toluene and then it was concentrated again at a reduced pressure (-0.15 bar) by evaporation of the same quantity of the distillate. The mechanically stirred concentrate was then diluted by addition of 600 ml of ethyl acetate and at 26°C it was seeded with the product and left to crystallize for 6.5 hours. The mixture was then, being stirred, further cooled down to 15 - 17°C and after about 30 min of stirring the product was filtered off and washed with approx. 50 ml of cold ethyl acetate. After drying in vacuum at 55°C, the amount of 47.5 g of white, crystalline sodium salt of sacubitril (yield 93%) was obtained at the purity of 99.85% and melting point of 167°C.

EXAMPLE 19 (purification of the crude cyclohexylammonium salt by crystallization) 62 g of the cyclohexylammonium salt of sacubitril, having the purity of 99.6% (HPLC), was dissolved in 450 ml of ethyl acetate at about 70°C. The obtained solution was gradually cooled down to 10°C during about 3 hours. The obtained white crystalline substance was aspirated on a filter, washed with 50 ml of cold ethyl acetate and then dried in vacuum at 45°C. The amount of 59.6 g of the re-purified product (yield ~96%) was obtained, having the purity of 100.0% (HPLC).

EXAMPLE 20 (alternative preparation procedure of the penultimate (3) without its isolation)

70 g of the starting compound of formula 4 is stirred up in 320 ml of anhydrous ethanol. Then, gaseous hydrogen chloride (approx. 20 g of HC1, i.e. 3 eq.) is supplied to the stirred mixture at a temperature of approx. 0 - 7°C during ~45 minutes from a pressurized bottle. After 45 minutes of stirring, the mixture is heated up to the temperature of 50°C and it is stirred for 1.5 hours at this temperature. After that, the reaction mixture is concentrated by removing of approx. 220 ml of the volatile constituents by distillation at a reduced pressure (-0.25 bar). Then, the mixture is diluted with 130 ml of toluene and the distillation continues at the pressure of -0.2 to 0.1 bar until approx. 130 ml of the solvents are evaporated. The concentrate is diluted again with 130 ml of toluene and it is concentrated again by evaporation of approximately the same quantity of the solvents. The concentrate is diluted with 220 ml of toluene. The resulting light yellow solution of the compound of formula 3 has the purity of 98.8% according to HPLC and is further used for the preparation of the crude acid of sacubitril. EXAMPLE 21 (alternative preparation method of crude sacubitril acid without isolation)

The amount of 18.3 g of succinanhydride, dissolved in 300 ml of ethyl acetate, is added to a solution of the hydrochloride of the amine of formula 3 in toluene, prepared according to Example 15, at RT. Being stirred, the mixture is cooled down to 10°C. Then, at the temperature of 8 - 10°C, a solution of 67 ml of N,N-diisopropyl-ethylamine in 60 ml of ethyl acetate is slowly added to the stirred mixture during approx. 90 minutes and the obtained mixture is stirred for another 3 hours at a temperature of 8— 11°C. After that, at ~20°C, the amount of 150 ml of a 9% aqueous solution of sulfuric acid is added and the emulsion is stirred for approx. 15 minutes at RT. After the separation of the phases, the top organic layer is further extracted with 100 ml of purified water. The obtained solution of sacubitril in the organic solvent is then concentrated at a slightly reduced pressure (-0.2 bar) by evaporation of about 550 ml of the solvents. The distillation then continues at simultaneous adding of 150 ml of toluene (approximately the same quantity of the solvents is removed by distillation at the same time). The final solution of sacubitril in toluene achieved the purity of 98.2% according the HPLC, the main contained impurity being the lactam of formula 5, which amounted to 1.8%. The solution of the crude acid of sacubitril is further used for the preparation of the selected salt.

EXAMPLE 22 (method of preparation and isolation of the crystalline salt of sacubitril with cyclohexylamine)

A solution of the crude product in toluene, prepared according to Example 15, was diluted with a mixture of 300 ml of ethyl acetate and 300 ml of isopropyl acetate. 20 ml of cyclohexylamine was then added to the stirred solution at 55°C during about 10 minutes. The mixture was stirred for approx. 2 hours, being slowly cooled down. The separated crystalline salt was isolated by filtration at the temperature of 13°C, washed with cooled ethyl acetate and dried at 50°C. The yield of the salt with cyclohexylamine amounted to 88 g, which corresponds to 94.4% with respect to the charged quantity of the starting compound of formula 4. The chemical purity of the product achieved 99.8% according to HPLC. EXAMPLE 23 (preparation of the sodium salt of sacubitril from the cyclohexylammonium salt)

80.0 g of the cyclohexylammonium salt of sacubitril, having the purity of 99.8% (HPLC), was charged into a glass reactor and 450 ml of isopropyl acetate was poured over it. Then, under intensive stirring, a solution of 13 ml of 48% hydrobromic acid and 2.0 ml of 85% H₃P0₄ in 160 ml of water was added. After 15 minutes of stirring at the laboratory temperature, the bottom ballast phase was separated. The organic layer was then further extracted with 120 ml of purified water. The top organic phase containing the product was then concentrated at a reduced pressure (-0.2) by removing of about 180 ml of the solvents by distillation.

A solution of 51.0 g of 21% sodium ethanolate in ethanol, diluted with 120 ml of absolute ethanol, was slowly added by dripping to the obtained solution of sacubitril acid of formula 1 under intensive stirring at ~22°C. The yellowish solution of the product was then concentrated at a reduced pressure (-0.2) by removing of about 300 ml of the solvents by distillation. The concentrate was diluted with 200 ml of toluene and then it was concentrated again at a reduced pressure (-0.15 bar) by evaporation of the same quantity of the solvents. The mechanically stirred concentrate was then diluted by addition of 800 ml of ethyl acetate and at 25°C it was seeded with the product and left to crystallize for 16 hours. The stirred mixture was then further cooled down to 16 - 18°C and after about 45 min of stirring the product was filtered off and washed with approx. 65 ml of cold ethyl acetate. After drying in vacuum at 55°C, the amount of 64 g of white, crystalline sodium salt of sacubitril (yield 94%) was obtained at the purity of 100.0% and melting point of 166°C.

ANALYTICAL METHODS AND DATA (A, B, C, D, E and F):

A High-performance liquid chromatography (HPLC)

The HPLC chromatograms were measured using a UHPLC system Agilent 1290 Infinity LC. For the analyses, an ACQUIT Y CSH Phenyl-Hexyl column was used; 100 mm x 3.0 mm I. D.; 1,7 μιη. As the mobile phase, a mixture of acetonitrile (30%) and HC10₄ was used (70%, lml of HC10₄ per 1L of water). The measurements were carried out in a gradient mode with the mobile phase flow of 0.6 ml/min at 60°C in the column. B X-ray powder diffraction (XRPD)

The Xray powder patterns of the crystalline acid of sacubitril of formula 1, two polymorphs of the crystalline sodium salt (5), amorphous form of the sodium salt of formula 5, crystalline calcium salt of formula 6 and the crystalline hemisolvate of the potassium salt of sacubitril with acetic acid (8) were measured using an X'PERT PRO MPD PANalytical diffractometer under the following experimental conditions:

Radiation: CuKa (λ = 1.54178 A)

Excitation voltage: 45 kV

Anode current: 40 mA

Measured range: 2 - 40° 20

Increment: 0.02 20

The values of the measured characteristic diffraction angles 20, interplanar spacings d and relative signal intensities are presented in tables 1-5.

Table 1. Values of characteristic diffraction angles 20, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline free acid of sacubitril of formula 1.

Pos. [°2Th.] d [A] Rel. Int. [%]

4.16 21.204 59.8

4.41 20.023 79.1

5.18 17.051 11.9

5.52 16.003 34.2

6.49 13.606 18.4

8.24 10.722 11.8

8.68 10.184 16.2

9.96 8.876 25.4

11.00 8.039 3.1

12.43 7.113 19.7 13.09 6.757 42.0

13.93 6.353 25.1

14.35 6.168 16.9

16.54 5.354 46.1

17.52 5.059 100.0

18.01 4.920 59.9

19.54 4.539 57.4

21.43 4.143 59.7

22.65 3.922 8.2

24.70 3.602 15.4

26.08 3.414 7.8

27.32 3.262 5.6

28.02 3.182 4.8

29.35 3.041 4.8

30.39 2.939 5.1

Table 2. Values of characteristic diffraction angles 2Θ, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline sodium salt of sacubitril of formula 5, polymorph I.

21.46 4.138 19.0

22.23 3.996 17.1

22.59 3.933 6.9

23.64 3.761 20.8

24.04 3.699 7.0

24.31 3.659 8.6

24.82 3.584 11.4

26.13 3.407 14.6

26.77 3.328 12.9

27.53 3.238 5.1

27.93 3.192 4.9

28.40 3.140 9.8

31.64 2.825 5.1

32.05 2.791 5.7

35.79 2.507 3.6

36.92 2.433 2.6

37.63 2.388 2.1

Table 3. Values of characteristic diffraction angles 20, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline sodium salt of sacubitril of formula 5, polymorph II.

24.44 3.639 7.5

26.34 3.381 2.4

26.92 3.310 2.6

Table 4. Values of characteristic diffraction angles 2Θ, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline calcium salt of sacubitril of formula 6.

Table 5.

Values of characteristic diffraction angles 2Θ, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline hemisolvate of the potassium salt of sacubitril with acetic acid (8)

00130

55

7.15 12.362 59.5

7.74 11.414 9.1

9.05 9.760 5.0

11.71 7.549 29.7

11.88 7.442 19.3

12.60 7.022 13.7

13.79 6.419 17.6

15.18 5.833 5.1

15.58 5.683 7.2

16.29 5.438 39.8

17.29 5.126 8.2

17.41 5.090 6.7

18.04 4.913 13.1

18.67 4.749 36.5

19.25 4.608 15.9

19.72 4.498 21.3

20.03 4.429 100.0

20.65 4.297 16.2

20.83 4.262 16.2

21.15 4.197 18.9

21.37 4.155 12.9

21.61 4.109 24.9

21.94 4.048 14.3

22.97 3.868 9.8

23.60 3.766 11.2

23.90 3.720 11.1

24.22 3.671 12.9

24.61 3.614 8.1

24.91 3.572 16.2

25.50 3.490 9.2

26.00 3.425 9.1

26.38 3.376 17.3

27.12 3.286 8.3

27.60 3.229 11.5

28.38 3.142 5.5

29.53 3.022 8.1

29.89 2.987 4.8

30.92 2.890 6.7

32.05 2.790 4.0

32.96 2.715 4.4 C 1H NMR

The 1H NMR spectra were measured using a Bruker Avance 500 spectrometer with the measuring frequency of 500.131 MHz. The spectra were measured for solutions in DMSO-D6, the chemical shifts were related to the internal standard of TMS δ = 0 ppm.

D Differential Scanning Calorimetry (DSC)

The records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer. The sample charge in a standard Al pot (40 μϋ,) was between 3-4 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min stabilization at the temperature of 0°C and then of heating up to 250°C at the heating rate of 10°C/min. As the carrier gas 4.0 N₂ was used at the flow of 20 ml/min.

E Melting point

The melting points of the crystalline substances were measured on a Kofler block at the sample heating rate of 4- 10°C per minute.

F Measurement of hygroscopicity

The dynamic vapor sorption (DVS) patterns were measured with a DVS Advantage 1 device made by the company Surface Measurement Systems. The sample charge in a quartz pot was 22-23 mg and the temperature in the device is 25.1-25.2°C. Used measurement program: the sample was loaded with two cycles with the course from the relative humidity of 0% to 90% (sorption) and then from 90% to 0% RH (desorption). This procedure was repeated in the second cycle. As the carrier gas 4.0 N₂ was used at the flow of 200 seem

Claims

1. A solid form of the free acid of sacubitril, with the systematic name of (2 -,4S)-5- (biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid methyl ester of formula 1, preferably a crystalline form of the free acid of sacubitril.

2. The solid form according to claim 1 in a crystalline form that exhibits the following characteristic reflections in the X-ray powder pattern measured with the use of CuKa radiation: 4.4; 13.1; 17.5; 19.5 and 21.4 ± 0.2° 2-theta.

3. The solid form according to claim 2, characterized with the DSC record of an endothermic peak showing the melting point of the crystalline form of 74 ± 3°C.

4. The solid form according to any one of claims 1 to 3, characterized in having a chemical purity determined by means of HPLC of at least 99.5%, preferably at least 99.9%.

5. A purification method of the crude free acid of sacubitril to obtain the solid form defined in claims 1 to 4, characterized in that chemical impurities are removed from the crude free acid of sacubitril using a procedure comprising the following steps:

a) converting the crude free acid of sacubitril to a crystalline salt of sacubitril with the amines of formula 9,

wherein Rl, R2, R3 independently stand for hydrogen or a C1-C7 alkyl, preferably the salt with cyclohexylamine, tert-butylamine or so-propylamine and isolation of this crystalline salt,

b) releasing the free acid of sacubitril by treating a solution of said amine salt of sacubitril with an acid, preferably with an aqueous solution of a mineral acid, more preferably an aqueous solution of hydrochloric acid,

c) isolation of the crystalline free acid of sacubitril from at least one organic solvent, wherein the organic solvent is a liquid aromatic hydrocarbon, preferably toluene, or an ester of a carboxylic acid, preferably ethyl acetate or isopropyl acetate, together with an anti-solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalcanes, preferably heptane, hexane, or cyclohexane.

6. A method for preparing sacubitril acid, characterized in that it comprises the following steps:

a) preparation of the compound of formula 3 by a reaction of the compound of f rmula 4 with ethanolic hydrogen chloride;

a reaction of the compound of formula 3 from step a) with succinic acid anhydride in an organic solvent or in a mixture of organic solvents, producing the crude acid f sacubitril;

7. The method of preparing according to claim 6, characterized in that the ethanolic hydrogen chloride is generated "in-situ", preferably through a reaction of thionyl

8. The method of preparing according to any one of claims 6 and 7, characterized in that after the reaction in step a) distillation is carried out before step b) with simultaneous addition of an organic solvent, preferably a liquid aromatic hydrocarbon, more preferably toluene.

9. The method of preparing according to claim 8, characterized in that the organic solvent in step a) is added in an adequate quantity, which amounts in total to at least 3 L/kg of the starting compound of formula 4, preferably at least 4 L/kg.

10. The method of preparing according to any one of claims 6 to 9, characterized in that the at least one organic solvent in step b) is a liquid aromatic hydrocarbon, preferably toluene, a carboxylic acid ester, preferably ethyl acetate or isopropyl acetate, and/or a mixture of these solvents.

11. The method of preparing according to any one of claims 6 to 10, characterized in that the reaction is initiated by gradual addition of a base selected from the group of tertiary amines, preferably selected from the group: triethylamine, emyl-diisopropylamine, pyridine or its substituents, preferably 4-dimethylaminopyridine, at a reduced temperature, preferably at a temperature below 10°C, more preferably below 5°C, most preferably at a temperature below 0°C.

12. The method of preparing according to any one of claims 6 to 11, characterized in that after the reaction in step b) an aqueous solution of a mineral acid is further added, preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid and the waste salts and not completely reacted compounds are extracted.

13. The method of preparing according to any one of claims 6 to 12, characterized in that the solution of sacubitril acid obtained in step b) is subsequently concentrated by evaporation.

14. The method of preparing according to any one of claims 6 to 13, characterized in that the obtained solution of sacubitril acid is further converted to a crystalline salt of sacubitril with the

wherein R_l5 R₂, R₃ independently stand for hydrogen or a C1-C7 alkyl, preferably to the salt with cyclohexylamine, tert-butylamine or so-propylamine.

15. The method of preparing according to claim 14, characterized in that the obtained crystalline amine salt of sacubitril is further converted to another pharmaceutically acceptable crystalline salt of sacubitril, preferably to the sodium, calcium or potassium salt.

16. The method of preparing according to claim 14 or 15, characterized in that the separated crystalline salt is isolated, preferably by filtration.

17. A method for preparing pharmaceutically acceptable salts of sacubitril, preferably the sodium salt of formula 5 and calcium salt of formula 6, characterized in that an inorganic or organic salt, oxide, alcoholate, hydride of hydroxide of a metal is treated with a solution of the free acid of sacubitril of formula 1 in a solvent, wherein the metal is preferably sodium or calcium.

18. The method according to claim 17, characterized in that the at least one solvent is selected from the group: esters of C1-C5 organic acids with C1-C6 alcohols, C1-C6 alcohols, C3-C6 ketones, C4-C6 ethers, water, liquid aromatic hydrocarbons, C1-C7 alkanes, C3-C7 cycloalkanes, preferably the following solvents or their mixtures: ethyl acetate, isopropyl acetate, methanol, ethanol, isopropyl alcohol, water or mixtures of these solvents in any ratios.

19. The method according to claims 17 or 18, characterized in that sodium hydroxide, sodium methanolate, sodium ethanolate, sodium zso-propoxide, sodium tert-butylate or sodium acetate is used as the source compound of sodium.

20. The method according to claims 17 or 18, characterized in that calcium chloride, calcium acetate or calcium hydroxide is used as the source compound of calcium.

21. The method according to any one of claims 17 to 19, characterized in that ethyl acetate or isopropyl acetate is used as the solvent for the preparation of the crystalline sodium salt of sacubitril of formula 5.

22. The method according to any one claims 17, 18 and 20, characterized in that water or its mixtures with alcohols, preferably with C1-C6 alcohols is used as the solvent for the preparation of the calcium salt of sacubitril of formula 6.

23. The method according to claim 17, characterized in that the solution of the free acid of sacubitril is prepared using the procedure comprising the following steps:

a) preparation of the crude free acid of sacubitril of formula 1 by a reaction of the amine of formula 3 with succinic acid anhydride,

b) isolation of the crystalline free acid of sacubitril from at least one organic solvent, wherein the organic solvent is a liquid aromatic hydrocarbon, preferably toluene, or an ester of a carboxylic acid, preferably ethyl acetate or isopropyl acetate, together with an anti-solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalcanes, preferably heptane, hexane, or cyclohexane,

c) optionally, converting the isolated crystalline free acid of sacubitril to a solution.

24. The method according to claim 17, characterized in that the solution of the free acid of sacubitril is prepared using the procedure comprising the following steps:

b) converting the crude acid of sacubitril to a crystalline salt of sacubitril with the amines of formula 9, wherein Rl, R2, R3 independently stand for hydrogen or a CI - C7 alkyl, preferably converting it to a salt with cyclohexylamine, iert-butylamine or zso-propylamine and isolation of this salt,

c) releasing the free acid of sacubitril by the treatment of a solution of said amine salt of sacubitril with an acid, preferably with an aqueous solution of a mineral acid, more preferably an aqueous solution of hydrochloric acid,

d) isolation of the crystalline free acid of sacubitril from at least one organic solvent, where the organic solvent is a liquid aromatic hydrocarbon, preferably toluene, or an ester of a carboxylic acid, preferably ethyl acetate or isopropyl acetate, together with an anti-solvent selected from the group of C1-C7 alkanes or C3-C7 cycloalkanes, preferably heptane, hexane, or cyclohexane,

e) optionally, converting the isolated crystalline free acid of sacubitril to a solution.

25. A solid form of the sodium salt of sacubitril of formula 5, preferably in a crystalline form.

26. The solid form according to claim 25 in a crystalline form (polymorph I) that exhibits the following characteristic reflections in the X-ray powder pattern measured with the use of CuKa radiation: 3.0; 6.1; 11.9; 16.4; 18.2 and 19.8 ± 0.2° 2-theta.

27. The solid form according to claim 26, characterized with the DSC record of an endothermic peak showing the melting point of the crystalline form of 167 ± 3°C.

28. The solid form according to claim 25 in a crystalline form (polymorph II) that exhibits the following characteristic reflections in the X-ray powder pattern measured with the use of CuKa radiation: 4.0; 8.1; 10.5; 18.5; 22.5 and 24.4 ± 0.2° 2-theta.

29. The solid form according to claim 28, characterized with the DSC record of an endothermic peak showing the melting point of the crystalline form of 166 ± 3°C.

30. A preparation method of the crystalline sodium salt of sacubitril according to any one of claims 25 to 29, comprising the following steps:

e) dissolving the free acid of sacubitril of formula 1 in a mixture of toluene and ethyl acetate, alternatively in a mixture of toluene and isopropyl acetate,

f) adding a solution of an agent that is a source of 0.95 to 1.05 equivalents of the sodium ion, preferably a solution of sodium hydroxide in ethanol or a solution of sodium ethanolate in ethanol.

g) evaporation of the solvents,

h) adding at least one solvent selected from the group: toluene, ethyl acetate or isopropyl acetate to obtain a crystalline form of the sodium salt of sacubitril.

31. A solid form of the potassium salt of sacubitril of formula 8, preferably in crystalline form.

(8)

32. The solid form according to claim 31 that exhibits the following characteristic reflections in the X-ray powder pattern measured with the use of CuKa radiation: 6.2; 7.2; 11.7; 16.3 and 20.0 ± 0.2° 2-theta.

33. A method for preparing the solid form of the potassium salt of sacubitril according to any one of claims 31 and 32, characterized in that it comprises the following steps: a) dissolution of the free acid or salt of sacubitril, preferably a salt of sacubitril with amines, and extraction in a mixture of an aqueous solution of a mineral acid, preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid, and with a water- immiscible organic solvent immiscible with water or a mixture of organic solvents, preferably ethyl acetate and toluene, or isopropyl acetate and toluene and concentration by evaporation;

b) addition of a solution of a reagent that is the source of 0.95 to 1.05 equivalents of the potassium ion, preferably a solution of potassium acetate in an alcohol, more preferably in ethanol, which is obtained either directly by the use of acetic acid, or is

generated "m-57^'tw" by mixing of potassium hydroxide or the potassium salt of a weal- acid and acetic acid, preferably KOH and CH₃COOH or K₂S0₃ and CH3COOH, possibly KHCO3 and CH3COOH; c) concentration by evaporation of a part of the solvents; d) after the addition of at least one solvent selected from the group: toluene, ethyl acetate or isopropyl acetate, a solid form of the potassium salt of sacubitril was obtained by crystallization.

34. The lactone of formula 10, with the systematic name of (3R, 55)-5-biphenyl-4ylmethyl- 3-methylpyrrolidin-2-one for use as an impurity standard for the setting of analytic methods used for the quality control of sacubitril of formula 1 and its sodium or calcium salt, which may be optionally prepared by an intramolecular cyclization reaction based on the amine of formula 3, or the protonated form of the amine 3, after the addition of a base, preferably lithium hydroxide.

35. A pharmaceutically acceptable form of sacubitril, preferably the free acid, sodium salt or calcium salt, characterized in that the content of the lactone of formula 10 is up to 0.15%, preferably up to 0.10%.

36. Use of the solid form of the free acid of sacubitril according to any one of claims 1 to 4 for the preparation of pharmaceutically acceptable salts of sacubitril, preferably any crystalline salt, more preferably the sodium or calcium crystalline salt.

37. Use of the solid form of the free acid of sacubitril according to any one of claims 1 to 4 or the solid form of the sodium salt of sacubitril according to claims 25 to 29 for the preparation of a drug for the treatment of hypertension and heart failure.

38. Use of the solid form of the potassium salt of sacubitril according to claims 31 or 32 for the preparation of other pharmaceutically acceptable salts of sacubitril, preferably any crystalline salt, more preferably the sodium or calcium crystalline salt.

39. Use of the solid form of the potassium salt of sacubitril according to claims 31 or 32 for the preparation of a drug for the treatment of hypertension and heart failure.