EP3386945A1 - Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation - Google Patents

Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation

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Publication number
EP3386945A1
EP3386945A1 EP16818971.0A EP16818971A EP3386945A1 EP 3386945 A1 EP3386945 A1 EP 3386945A1 EP 16818971 A EP16818971 A EP 16818971A EP 3386945 A1 EP3386945 A1 EP 3386945A1
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EP
European Patent Office
Prior art keywords
sacubitril
salt
acid
crystalline
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP16818971.0A
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German (de)
English (en)
Inventor
Ales Halama
Pavel ZVATORA
Michal Voslar
Jan Stach
Michal Zapadlo
Ondrej Dammer
Lukas KREJCIK
Lenka DVORAKOVA
Marketa REZANKOVA
Rostislav VYSLOUZIL
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Zentiva KS
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Zentiva KS
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Priority claimed from CZ2015-891A external-priority patent/CZ2015891A3/cs
Priority claimed from CZ2015-896A external-priority patent/CZ2015896A3/cs
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3386945A1 publication Critical patent/EP3386945A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a specific, maximum acceptable limit usually expressed in the ppm units
  • solvents with a low toxic potential are classified and the maximum acceptable limit for every such solvent is generally defined as 5000 ppm.
  • HPLC High Performance Liquid Chromatography
  • 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 are called relative retention times (rrt).
  • 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.
  • active substances are tested for the content of residual solvents by means of gas chromatography, abbreviated as GC.
  • 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.
  • the industrial scale involves considerably stricter requirements for safety or environmental aspects of the process, so there is e.g.
  • 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° 2 ⁇ ), 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.
  • 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.
  • 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.
  • 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, R 2 , R 3 independently stand for hydrogen or a C1-C7 alkyl, preferably isolation of the crystalline salt with cyclohexylamine, tert-butylamine or wo-propylamine.
  • 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.
  • 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:
  • 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.
  • the invention provides a preparation method of the acid of sacubitril using a procedure that comprises the following steps:
  • 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.
  • 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.
  • a mineral acid preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid
  • 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
  • R 1? R 2 , 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.
  • the separated crystalline salt is isolated, more preferably by filtration.
  • 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.
  • a good crystallization capability of ammonium salts of sacubitril is not a general characteristic of all ammonium salts.
  • 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.
  • 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.
  • a crystalline product is often stable, it is easier to obtain in the pure form and it dissolves more slowly.
  • 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).
  • spectral methods e.g. X-ray Powder Diffraction (XRPD)
  • thermoanalytical methods e.g. Differential Scanning Calorimetry (DSC).
  • 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.
  • a suitable agent as the source of a metal cation, which may be the sodium or calcium cation
  • 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.
  • an inorganic or organic salt, oxide, alcoholate, hydride or metal hydroxide which may be sodium or calcium
  • sodium reagents selected from the group: sodium hydroxide, sodium methanolate, sodium ethanolate, sodium zso-propoxide, sodium tert-butylate or sodium acetate
  • sodium reagents selected from the group sodium 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.
  • 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
  • Liquid esters of carboxylic acids 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.
  • 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.
  • the sodium salt of sacubitril can be prepared using the procedure consisting of the following steps with a number of benefits:
  • 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.
  • the discovered process exhibits a high yield, usually over 90%
  • the obtained product is crystalline and is characterized with a high chemical purity of 99.5% and higher, preferably 99.9% and higher,
  • 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° 2 ⁇ ), 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 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:
  • 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,
  • 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,
  • 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).
  • 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.
  • R 3 independently stand for a C1-C6 alkyl or hydrogen the crystalline form of sacubitril free acid
  • Another object of this invention is a solid form of the potassium salt of sacubitril of formula 8, preferably in a crystalline form.
  • 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 mineral acid preferably hydrochloric, hydrobromic, sulfuric or phosphoric acid
  • 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 CH 3 COOH or K 2 S0 3 and CH 3 COOH, possibly KHC0 3 and CH 3 COOH;
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • DIPEA N,N-diisopropyl-ethylamine
  • 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 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).
  • 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.
  • 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.
  • a crystalline product 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.
  • 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).
  • spectral methods e.g. X-ray Powder Diffraction (XRPD)
  • thermoanalytical methods e.g. Differential Scanning Calorimetry (DSC).
  • 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.
  • 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.
  • 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 R 2 , R 3 independently stand for hydrogen or a C1-C7 alkyl, subsequently crystallizes.
  • the crystalline salts with cyclohexylamine, tert-butylamine or zso-propylamine are advantageous.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Ar-C 129.78 (ArCH); 128.85 (ArCH); 127.11 (ArCH); 123.42 (ArCH); 126.26 (ArCH); 59.60 (CH 3 -CH 2 -0); 47.99 (NH-CH); 40.59 (CH 2 -Ar); 37.65 (CH-CH 2 -CH); 35.91 (CH 3 - CH); 33.11 (CH 2 -COOK or CH 2 -CONH); 32.82 (CH 2 -COOK or CH 2 -CONH); 23.49 (CH 3 acetate); 17.91 (CH 3 -CH); 13.97 (CH 3 -CH 2 -0)
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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. 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. 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
  • 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.
  • EXAMPLE 3a (general procedure of preparation and isolation of salts of sacubitril with amines)
  • 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.
  • Rz' R 3 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 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).
  • 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.
  • 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 l H 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
  • 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.).
  • 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 (SOCl 2 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).
  • SOCl 2 1.5 eq thionyl chloride
  • 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 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • gaseous hydrogen chloride approximately 20 g of HC1, i.e. 3 eq.
  • 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 150 ml of a 9% aqueous solution of sulfuric acid is added and the emulsion is stirred for approx. 15 minutes at RT.
  • 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.
  • 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.
  • HPLC chromatograms were measured using a UHPLC system Agilent 1290 Infinity LC.
  • 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 ⁇ .
  • As the mobile phase a mixture of acetonitrile (30%) and HC10 4 was used (70%, lml of HC10 4 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.
  • 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.
  • Table 4 Values of characteristic diffraction angles 2 ⁇ , interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline calcium salt of sacubitril of formula 6.
  • the 1H NMR spectra were measured using a Bruker Avance 500 spectrometer with the measuring frequency of 500.131 MHz.
  • 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 ⁇ ,) 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 N 2 was used at the flow of 20 ml/min.
  • the melting points of the crystalline substances were measured on a Kofler block at the sample heating rate of 4- 10°C per minute.
  • 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.

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Abstract

L'invention concerne des formes solides d'acide libre de sacubitril de formule 1, notamment une forme cristalline, un procédé d'élimination des impuretés chimiques de l'acide libre de sacubitril brut qui est caractérisé par l'utilisation de la cristallisation des sels de sacubitril avec des amines de formule 9, où R1, R2, R3 représentent indépendamment un atome d'hydrogène ou un alkyle C1-C7, de préférence du sel avec la cyclohexylamine, la tert-butylamine ou l'iso-propylamine. L'invention concerne également une nouvelle forme cristalline solide de sacubitril (8) - l'hémisolvate du sel de potassium de sacubitril, notamment un procédé de préparation direct, très efficace et utilisable à l'échelle industrielle d'une forme solide d'acide libre de sacubitril et de ses sels pharmaceutiquement acceptables, notamment le sel de sodium cristallin de formule 5, le sel de calcium de sacubitril de formule 6 et l'hémisolvate du sel de potassium de sacubitril de formule 8.
EP16818971.0A 2015-12-11 2016-12-12 Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation Withdrawn EP3386945A1 (fr)

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CZ2015-891A CZ2015891A3 (cs) 2015-12-11 2015-12-11 Krystalická forma draselné soli ethylesteru (2R,4S)-5-(bifenyl-4-yl)-4-[(3-karboxypropionyl)amino]-2-methylpentanové kyseliny a průmyslově použitelný způsob její přípravy
CZ2015-896A CZ2015896A3 (cs) 2015-12-14 2015-12-14 Pevné formy ethyl esteru (2R,4S)-5-(bifenyl-4-yl)-4-[3-karboxypropionyl)amino]-2--methylpentanové kyseliny, její sole a způsob přípravy
PCT/CZ2016/000130 WO2017097275A1 (fr) 2015-12-11 2016-12-12 Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation

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WO2018069833A1 (fr) 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
AU2017349757A1 (en) 2016-10-28 2019-05-30 Biocon Limited Amorphous trisodium sacubitril valsartan and process for its preparation
CN107311909A (zh) * 2017-06-22 2017-11-03 东南大学 一种lcz696杂质对照品的制备方法
PL3658122T3 (pl) 2017-07-28 2021-10-18 Synthon B.V. Kompozycja farmaceutyczna zawierająca sakubitryl i walsartan
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MX2018007129A (es) 2018-11-09

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