WO2020051014A1

WO2020051014A1 - Processes for the preparation of tenapanor and intermediates thereof

Info

Publication number: WO2020051014A1
Application number: PCT/US2019/048226
Authority: WO
Inventors: Parven Kumar Luthra; Suhail Ahmad; Debashis Das; Satnam Singh; Anchal SINGH
Original assignee: Teva Pharmaceuticals International Gmbh; Teva Pharmaceuticals Usa, Inc
Priority date: 2018-09-04
Filing date: 2019-08-27
Publication date: 2020-03-12

Abstract

The present invention provides new procedures and intermediates for the preparation of Tenapanor, Tenapanor dihydrochloride and solid state forms thereof.

Description

PROCESSES FOR THE PREPARATION OF TENAPANOR AND INTERMEDIATES

THEREOF

Technical Field

[0001] The present invention provides new procedures and intermediates for the preparation of Tenapanor, Tenapanor dihydrochloride and solid state forms thereof.

Background

[0002] Tenapanor which has the chemical name N,N'-(l0,l7-dioxo-3,6,2l,24-tetraoxa- 9,l l,l6,l8-tetraazahexacosane-l,26-diyl)bis(3-(6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)benzenesulfonamide) is a selective inhibitor of NHE3 (sodium hydrogen exchanger 3) for the oral treatment of constipation- predominant irritable bowel syndrome (IBS-C) and for the management of fluid overload, dietary sodium restriction and hyperphosphatemia in kidney disease.

[0003] As described in U.S. Patent No. 8,969,377 and U.S. Patent No. 8,541,448 Tenapanor has the following chemical structure:

[0004] Tenapanor and Tenapanor dihydrochloride are not described to show polymorphs. However, Tenapanor is known to exist in crystalline form and Tenapanor di hydrochloride in an amorphous form, as described in the International Patent Application No. WO

2014/169094. Recently, crystalline Tenapanor base was published in the International Patent Application No. WO 2019/091503.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule, like Tenapanor, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis -“TGA”, or differential scanning calorimetry -“DSC”), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. [0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Tenapanor.

[0008] Tenapanor preparation and intermediates thereof is disclosed in U. S. Patent No. 8,969,377. Tenapanor as a Trifluoroacetic acid salt (TFA salt) was prepared by coupling N- (2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin- 4-yl)benzenesulfonamide (referred to herein as (S)-Compound A) and l,4-diisocyanatobutane as demonstrated in the following scheme A (U.S. Patent No. 8,969,377 example 236). The calculated yield for this process according to the reported weights is about 36.7%. Scheme A:

[0009] The synthetic procedure for preparation of N-(2-(2-(2-aminoethoxy)

ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)

benzenesulfonamide (compound A) is described in U.S. Patent No. 8,969,377 (example 168.2).

[0010] The preparation of Tenapanor di-hydrochloride salt, (S or R)— N,N'-(10,17- dioxo-3,6,2l,24-tetraoxa-9,l l,l6,l8-tetraazahexacosane-l,26-diyl)bis(3-((S)-6,8-dichloro-2- methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide)bis-hydrochloride salt, is described in U.S. Patent No. 8,969,377 (example 202) , as demonstrated by the following scheme B.

Scheme B:

Compound A Trifluoroacetate salt

[0011] According to scheme B, (S) or (R)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8- dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide bis(2,2,2- trifluoroacetate), referred to herein as (R) or (S)-Compound A trifluoroacetate salt, triethylamine, and l,4-diisocyanatobutane were added to obtain the crude Tenapanor product that was further purified by HPLC. Hydrochloric acid was added to the purified product and the obtained solution was lyophilized to obtain Tenapanor di -hydrochloride (reported yield: 59%).

[0012] The processes described above in U.S. Patent No. 8,969,377 have significant disadvantage obtaining low yield due to the use of l,4-diisocyanatobutane which is a very reactive and non-selective reagent. Using such reagent results in the production of various impurities and by-products which eventually affects the yield of the process and the purity of the product. Also, purification procedures such as preparative HPLC for instance, must be used in order to obtain Tenapanor with an acceptable purity level. However, this purification procedure cannot be used in large scale commercial production. It would therefore be highly desirable to provide a process which avoids such disadvantages. In particular, it would be desirable to avoid the use of the problematic reagent, l,4-diisocyanatobutane, as employed the prior art synthesis, in order to achieve the synthesis of Tenapanor in high yield and with high purity for use in the pharmaceutical industry.

[0013] Thus, an object of the present invention is to provide methods of synthesizing Tenapanor or a salt thereof, preferably Tenapanor dihydrochloride, that avoids one or more of the disadvantages associated with the procedures described in the prior art. Hence, there is a need for procedure which provides Tenapanor in high yield and quality that can be utilized in industrial scale. Furthermore, there is a need for stable crystalline Tenapanor dihydrochloride for use in the preparation of pharmaceutical compositions and/or formulations for treatment described above.

Summary of the Disclosure

[0014] The present disclosure provides new procedures and intermediates for the preparation of Tenapanor or a salt thereof.

[0015] The present disclosure also provides intermediates, their preparation and their use in the preparation of Tenapanor or a salt thereof.

[0016] According to one aspect, the present invention relates to a process including the use of (S)-Compound A and N,N'-(butane-l,4-diyl)bis(lH-imidazole-l-carboxamide), referred to herein as formula (1), for the preparation of Tenapanor or a salt thereof.

Formula (1)

[0017] According to another aspect, the present disclosure provides a compound of formula (1) that can be used in the preparation of Tenapanor or a salt thereof.

[0018] In another aspect the present disclosure provides the use of compound of formula (1) in the preparation of Tenapanor or a salt thereof.

[0019] In yet another embodiment the disclosure relates to a process for preparation of Tenapanor or a salt thereof including reacting (S)-Compound A with compound of formula (1)^.

[0020] In an aspect, the present disclosure provides a process for preparation of Tenapanor or a salt thereof, including:

i) reacting (S)-Compound A with a compound of formula (1) to form Tenapanor; and optionally

ii) converting Tenapanor to a salt thereof, preferably Tenapanor di -hydrochloride salt.

[0021] The above described process can be summarized by the following scheme C.

Scheme C:

Tenapanor

[0022] In another aspect the compound of formula (1) can be prepared by reacting 1,1 carbonyl diimidazole with 1,4 diamino butane as described in the following scheme.

Formula (1)

[0023] According yet to another aspect the present disclosure relates to a process for preparation of Tenapanor or a salt thereof including reacting (S)-Compound A, 1, 1 -carbonyl diimidazole and 1,4 diaminobutane.

[0024] In yet another embodiment the disclosure relates to a process for preparing Tenapanor or a salt thereof including:

a) reacting (S)-Compound A with 1, 1 -carbonyl diimidazole to produce (S)-N-(2-(2-(2- ((3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- yl)phenyl)sulfonamido)ethoxy)ethoxy)ethyl)-lH-imidazole-l-carboxamide, referred to herein as formula (2)

Formula (2)

; and

b) adding 1,4 diaminobutane to form Tenapanor

; and optionally

c) converting Tenapanor to a salt thereof, preferably Tenapanor di -hydrochloride.

[0025] According to one another aspect, the present disclosure provides a compound of formula (2) that can be used in the preparation of Tenapanor.

[0026] In another aspect the present disclosure provides the use of compound of formula (2) in the preparation of Tenapanor or a salt thereof.

[0027] In another aspect the present disclosure provides compound of formula (2) for use in the preparation of Tenapanor or a salt thereof.

[0028] The above described process can be summarized by the following scheme D. Scheme D:

Tenapanor

[0029] In any embodiment of the invention as described herein, the process may further include combining the Tenapanor or salt thereof with one or more pharmaceutically acceptable excipients to produce a pharmaceutical composition or a dosage form.

[0030] In another aspect Tenapanor or a salt thereof is prepared according to the processes described herein.

[0031] In another aspect substantially pure Tenapanor or a salt thereof can be obtained by crystallization

[0032] In further aspect Tenapanor or a salt thereof prepared according to present disclosure is substantially pure.

[0033] In further aspect Tenapanor dihydrochloride prepared according to present disclosure is having low chloride content.

[0034] In further aspect Tenapanor or a salt thereof prepared according to present disclosure is having low hydroxy impurity level.

[0035] The present disclosure provides crystalline Tenapanor dihydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof. [0036] The present disclosure also encompasses the use of the Tenapanor or a salt thereof prepared by the processes of the present disclosure for the preparation of pharmaceutical compositions of Tenapanor.

[0037] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining the Tenapanor or a salt thereof prepared by the processes of the present disclosure with at least one pharmaceutically acceptable excipient.

[0038] Tenapanor or a salt thereof prepared by the processes of the present disclosure and the pharmaceutical compositions of Tenapanor or a salt thereof prepared by the processes of the present disclosure can be used as medicaments, particularly for the treatment of constipation-predominant irritable bowel syndrome (IBS-C), chronic kidney disease and hypertension.

[0039] The present disclosure also provides methods for the treatment of IBS-C, chronic kidney disease and hypertension, including administering a therapeutically effective amount of Tenapanor or a salt thereof prepared by the processes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.

Brief Description of the Figures

[0040] Figure 1 shows an X-ray powder diffractogram (XRPD) of Tenapanor free base.

[0041] Figure 2 shows an XRPD of crystalline Tenapanor dihydrochloride.

Detailed Description of the Disclosure

[0042] The present disclosure provides new procedures and intermediates for the preparation of Tenapanor or a salt thereof.

[0043] In another aspect, the present disclosure provides novel intermediates, their preparation and their use in the preparation of Tenapanor or a salt thereof.

[0044] The present invention describes new processes for providing Tenapanor or a salt thereof in high yield and high purity that can be adapted to production in an industrial scale, i.e., greater than 1 kilogram scale.

[0045] As defined herein, "high purity" refers to chemical purity of more than about 98%, more than about 99% or more than about 99.5% Tenapanor, which can be measured by any technique described in the literature e.g. by HPLC.

[0046] As defined herein, the "hydroxy impurity" refers to the compound described in Formula (3).

Formula (3)

[0047] As defined herein, "low hydroxy impurity" content refers to less than 0.05% more preferably less than 0.02% w/w hydroxy impurity.

[0048] As defined herein, "low chloride" content refers to 5.7% to 6.2% w/w, preferably 5.9% to 6.1% w/w chloride in Tenapanor dihydrochloride (theoretical chloride content in Tenapanor dihydrochloride is 5.99%).

[0049] Preparation of Tenapanor dihydrochloride with high chloride content is not favorable since excess of chloride induced impurity increment and formation. Therefore, low chloride content is highly desirable. Low chloride content prevents the formation of impurities, preferably the formation of hydroxy impurity (formula 3) which increases during stability, as described by Table 1 (experimental section), and therefore should be avoided.

[0050] As used herein, and unless indicated otherwise, the term "isolated" in reference to the intermediates of the present disclosure, their solid state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.

[0051] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0052] The processes or steps may be referred to herein as being carried out "overnight." This refers to time intervals, e.g., for the processes or steps, that span the time during the night, when the processes or steps may not be actively observed. The time intervals are from about 8 to about 20 hours, or about 10 to about 18 hours, or about 16 hours.

[0053] As used herein, and unless indicated otherwise, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.

[0054] The amount of solvent employed in chemical processes, e.g., reactions or crystallizations, may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0055] As used herein, the term "isolated" in reference to a crystalline polymorph of the present disclosure corresponds the crystalline polymorph that is physically separated from the reaction mixture in which it is formed.

[0056] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.54060 A. XRPD peaks reported herein are measured using CuK a radiation, l = 1.54060 A, at a temperature of 25 ± 3°C.

[0057] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" or“polymorphically pure” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Tenapanor dihydrochloride described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Tenapanor dihydrochloride. In some embodiments of the disclosure, the described crystalline polymorph of Tenapanor dihydrochloride may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Tenapanor dihydrochloride.

[0058] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data“as depicted in” or“as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Tenapanor dihydrochloride referred to herein as being characterized by graphical data“as depicted in” or“as substantially depicted in” a Figure will thus be understood to include any crystal forms of Tenapanor

dihydrochloride characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0059] As used herein, and unless stated otherwise, the term“anhydrous” in relation to crystalline forms of Tenapanor dihydrochloride, relates to a crystalline form of Tenapanor dihydrochloride which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an“anhydrous” form would typically not contain more than 1% (w/w), of either water or organic solvents as measured for example by

TGA.

[0060] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0061] In another aspect, the present disclosure provides novel intermediates, their preparation and their use in the preparation of Tenapanor or a salt thereof.

[0062] In another aspect Tenapanor or a salt thereof is prepared according to the process describes herein.

[0063] According yet to another aspect the present invention relates to a process for the preparation of Tenapanor or a salt thereof including reacting (S)-Compound A and N-N'- (butane-l,4-diyl)bis(lH-imidazole-l-carboxamide), referred to herein as formula (1):

Formula (1)

[0064] According to one another aspect, the present disclosure provides a compound of formula (1) that can be used in the preparation of Tenapanor or a salt thereof. [0065] In another aspect the present disclosure provides the use of the compound of formula (1) in the preparation of Tenapanor or a salt thereof.

[0066] In another aspect the present disclosure provides compound of formula (1) for use in the preparation of Tenapanor or a salt thereof.

[0067] In yet another embodiment the disclosure relates to a process for preparation of Tenapanor or a salt thereof including coupling (S)-Compound A with compound of formula (1)^.

[0068] In preferred aspect, the present disclosure provides a process for preparation of Tenapanor or a salt thereof including:

i) reacting (S)-Compound A with the compound of formula (1) to afford Tenapanor

; and optionally

[0069] In preferred aspect, the present disclosure provides a process for preparation of Tenapanor or a salt thereof, including coupling of (S)-Compound A with formula (1) according to the following scheme:

Tenapanor

[0070] Suitably solvents used in the above coupling procedure can be selected from polar aprotic solvents, preferably selected from dimethylsulfoxide (DMSO), N,N- dimethylformamide (DMF), N,N-Dimethyl acetamide (DMA), dichlorom ethane, ethyl acetate, isopropyl acetate, acetonitrile, 2-methyl tetrahydrofuran (2-Me-THF),

tetrahydrofuran (THF), methylisobutylketone (MIBK), acetone, methylethylketone (MEK), and/or toluene. In embodiments, the solvent is acetonitrile.

[0071] Preferably (S)-Compound A is first dissolved at temperature range of 40-70°C, preferably at 40-60°C, more preferably at 50-55°C. [0072] Typically, 10-60 vol of solvent, preferably 15-30 vol of solvent, more preferably 15-20 vol of solvent is used.

[0073] In preferred embodiment the compound of formula (1) is added to (S)-Compound A solution.

[0074] In preferred embodiment the %w/w ratio between (S)-Compound A and compound of formula (1) is about 78-81% of (S)-Compound A per gram of formula (1).

[0075] Optionally the compound of formula (1) is added in lots (portions), optionally the solution is further stirred for 0.5-4 hours, more preferably for 1-3 hours, more preferably for 2 hours.

[0076] Optionally Tenapanor is isolated by filtration and washing, preferably washing with a solvent, preferably a reaction solvent as described above, and more preferably with acetonitrile.

[0077] Optionally Tenapanor can be converted to a salt thereof, preferably Tenapanor di hydrochloride salt.

[0078] In another aspect the compound of formula (1) can be prepared by reacting 1,1- carbonyl diimidazole with 1, 4-diamino butane according to the following scheme:

Formula (1)

[0079] In embodiments, the compound of formula (1) is prepared in solvent system including aprotic organic solvent. Preferably the solvent is selected from DMSO, DMF, dimethyl acetamide, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, 2-methyl THF, THF, MIBK, acetone, MEK and toluene; more preferably the solvent includes di chl orom ethane .

[0080] Typically, 5-50 vol of solvent (with reference to 1,1 carbonyl diimidazole) , preferably 5-30 vol of solvent, more preferably 10-20 vol of solvent is used for preparing compound of formula (1).

[0081] In another aspect the ratio between 1,1 carbonyl diimidazole and 1,4 diamino butane is 78-88 %w/w, preferably 78-84 w/w % more preferably 81-82 %w/w ratio per gram of 1,4 diamino butane.

[0082] Preferably the solution is kept at -20 to -l0°C more preferably at -20 to -l5°C for about 10-60 min, preferably for 10-40 min, more preferably for 30 min, optionally with stirring. [0083] Preferably, the temperature of the solution is subsequently raised to -5 °C to l0°C, preferably at -5 °C to 5°C, more preferably to 0°C.

[0084] Optionally compound of formula (1) is isolated by filtration and washing, preferably washing with the reaction solvent, and more preferably with dichloromethane.

[0085] According yet to another aspect the present invention relates to process for preparation of Tenapanor including reacting (S)-Compound A, l,l-carbonyl diimidazole and 1,4 diaminobutane, and optionally converting the Tenapanor to a salt thereof, preferably Tenapanor dihydrochloride.

[0086] In yet another embodiment the disclosure relates to a process for preparation of Tenapanor or a salt thereof, including:

a) reacting (S)-Compound A, with l,l-carbonyl diimidazole to produce (S)-N-(2-(2-(2-((3- (6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)

sulfonamido)ethoxy)ethoxy)ethyl)-lH-imidazole-l-carboxamide [formula (2)]:

; and

b) adding 1,4 diaminobutane to form Tenapanor

; and optionally

c) converting Tenapanor to a salt thereof, preferably Tenapanor di -hydrochloride salt.

[0087] According to another aspect, the present disclosure provides a compound of formula (2) that can be used in the preparation of Tenapanor or a salt thereof.

[0088] In another aspect the present disclosure provides the use of compound of formula (2) in the preparation of Tenapanor or a salt thereof.

[0089] Preferably the compound of formula (2) is not isolated during the reaction.

[0090] In preferred aspect, the present disclosure provides a process for preparation of Tenapanor or a salt thereof including coupling of (S)-Compound A, with 1,1 -carbonyl diimidazole following by addition of l,4-diaminobutane according to the following scheme:

Tenapanor

[0091] Preferably, the process detailed above is carried out in a solvent system including a solvent selected from the group consisting of ethers, polar aprotic solvents, chlorinated solvents, hydrocarbons or ketones. Preferably the solvent is selected from DMF, DMSO, acetonitrile (ACN) or ethyl acetate, and more preferably the solvent includes ethyl acetate.

[0092] Typically, 5-75 vol of solvent (in relation to (S)-Compound A), preferably 10-40 vol, more preferably 15-20 vol of solvent is used.

[0093] Typically, (S)-Compound A and 1,1 -carbonyl diimidazole are added to the solvent system, to produce the compound of formula (2).

[0094] In preferred embodiment the w/w% ratio between (S)-Compound A and 1,1 carbonyl diimidazole is about 2.4 to 3.1 %w/w, preferably 2.6 to 3.0%w/w, more preferably 2.9%w/w per gram of 1,1 carbonyl diimidazole.

[0095] Typically, the obtained solution mixture is kept at -5 °C to 40°C, preferably 10-30 °C, more preferably at 20 °C-30°C, preferably for 0.5-3 hours, preferably for 1-2 hours, optionally with stirring.

[0096] 1,4 -diaminobutane is subsequently added to the mixture to obtain Tenapanor.

[0097] In another embodiment the ratio between (S)-Compound A and 1, 4

diaminobutane is 90-95 %w/w, preferably 92-93 %w/w per gram of 1, 4 diaminobutane. [0098] In another embodiment the solution is heated to 35-80°C, preferably to 35-60°C, more preferably to 40-50°C for 3-10 hours, preferably for 4-6 hours, optionally with stirring.

[0099] In another embodiment Tenapanor may be isolated by filtration and washing with the reaction solvent system, preferably with acetonitrile or ethyl acetate, more preferably with ethyl acetate.

[00100] Tenapanor can be prepared by a process including crystallizing from solvent mixture including acetonitrile, methanol and water.

[00101] Typically, the crystallization includes dissolving Tenapanor in the solvent mixture including acetonitrile, methanol and water, and precipitating Tenapanor to obtain a

suspension.

[00102] Typically, about 15 vol. of acetonitrile, about 5 vol. of methanol and about 2 vol. of water are used for preparing Tenapanor solution.

[00103] Preferably, Tenapanor solution is heated to temperature of about 45°C -70°C, preferably, about 45°C -60°C, more preferably about 50°C -55°C.

[00104] Preferably, Tenapanor solution is heated until clear solution is obtained, optionally, activated carbon can be added before cooling. The activated carbon can be removed by filtration.

[00105] Preferably, precipitation is done by cooling the said solution to obtain a

suspension including Tenapanor, preferably, cooling to -5°C to about 25°C, or l0°C to about 25°C, and preferably about 20°C to 25°C for about 1-20 hours, preferably 15-20 hours, more preferably 4-5 hours.

[00106] Optionally, the above crystallization procedure can be repeated twice.

[00107] In a further aspect Tenapanor or a salt thereof prepared according to present disclosure is substantially pure.

[00108] In further aspect Tenapanor or a salt thereof prepared according to present disclosure is substantially pure wherein at least about more than 98% or more than about 99%, or more than about 99.9% Tenapanor or a salt thereof is measured by any technique described in the literature e.g. by HPLC.

[00109] In further aspect Tenapanor prepared according to processes described herein shows low hydroxy impurity. Preferably less than 0.05%, more preferably less than 0.02% w/w hydroxy impurity of Formula (3):

Formula (3).

[00110] The present disclosure provides crystalline Tenapanor dihydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof.

[00111] In another aspect, the present disclosure includes a crystalline form of Tenapanor dihydrochloride. The crystalline Tenapanor dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.1, 21.1, 21.6, 22.7 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in figure 2; or combinations of these data.

[00112] Crystalline Tenapanor dihydrochloride may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.1, 21.1, 21.6, 22.7 and 24.0 degrees two theta ± 0.2 degrees two-theta; and also having one, two, three, four, five or six additional peaks selected from 13.4, 16.8, 17.4, 18.3, 19.2 and 19.7 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[00113] Crystalline Tenapanor di hydrochloride may alternatively be characterized by an XRPD pattern having peaks at 11.1, 13.4, 16.8, 17.4, 18.3, 19.2, 19.7, 21.1, 21.6, 22.7 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

[00114] Crystalline Tenapanor di hydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 11.1, 21.1, 21.6, 22.7 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[00115] In another embodiment crystalline Tenapanor dihydrochloride may be characterized as anhydrous form.

[00116] In another embodiment of the present disclosure, crystalline Tenapanor dihydrochloride is polymorphically pure, preferably as defined above.

[00117] In one embodiment of the present disclosure, crystalline Tenapanor

dihydrochloride is isolated.

[00118] As discussed above, depending on which other solid state it is compared with, crystalline Tenapanor dihydrochloride according to the present disclosure may have advantageous properties. Crystalline Tenapanor dihydrochloride, described in this application, shows unexpected higher stability, better handling and improved flowability properties compared to known amorphous Tenapanor dihydrochloride obtained by following the procedure described in US patent publication no. 8,969,377.

[00119] According to a further aspect of the invention, the above crystalline Tenapanor dihydrochloride can be prepared by a process including suspending Tenapanor in a solution of hydrogen chloride in isopropyl acetate or ethyl acetate in Isopropyl acetate.

[00120] Typically, 10-50 vol of Isopropyl acetate, preferably 15-25 vol, more preferably 18-22 vol of Isopropyl acetate is used for preparing Tenapanor suspension.

[00121] Preferably the temperature of Tenapanor suspension is about 10- 40°C, or about 15 to about 35°C. More preferably the suspension is at room temperature, and most preferably about 20 to about 30°C.

[00122] Preferably, the suspension is kept at room temperature, preferably at 20°C-30°C for about 10 to 60 minutes, preferably for about 10 to 30 minutes, more preferably for about 10 to 15 minutes, optionally with stirring.

[00123] Typically, the suspension is cooled to temperature of about -5°C to l0°C, preferably about -5°C to 5°C, more preferably about 0°C to 5°C.

[00124] Typically, hydrochloric acid solution in Isopropyl acetate is added to Tenapanor suspension.

[00125] Preferably, 1.9-2.2 mol eq of HC1, preferably 1.95-2.15 mol equivalents of HC1, preferably 2-2.10 mol eq of hydrochloric acid in Isopropyl acetate.

[00126] Typically, the suspension is kept for about 30 minutes to 180 minutes, preferably for about 30 minutes to 120 minutes, more preferably for about 60 to 90 minutes, optionally with stirring at the same temperature.

[00127] Typically, isolation of the said crystalline form may be done for example by filtering the suspension, optionally washing and optionally drying.

[00128] Preferably, drying is done by vacuum. Preferably, drying is performed at a temperature of about 20-50°C, preferably about 25°C-45°C, and more preferably about 40°C.

[00129] The process for preparing crystalline Tenapanor dihydrochloride according to any of the embodiments disclosed herein may further include a step of combining the crystalline Tenapanor dihydrochloride with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or a pharmaceutical formulation.

[00130] In one embodiment crystalline Tenapanor dihydrochloride prepared according to processes described herein shows low chloride content. Preferably about 5.7% to 6.2% w/w and more preferably 5.9% to 6.1% w/w chloride. Hence the crystalline Tenapanor dihydrochoride prepared according to the disclosed processes contain only low or negligible excess chloride impurity.

[00131] In another embodiment, crystalline Tenapanor dihydrochloride produced according to processes described herein shows low hydroxy impurity. Preferably, less than 0.05%, more preferably less than 0.02% w/w hydroxy impurity.

[00132] In another aspect, the present disclosure encompasses Tenapanor or a salt thereof prepared by the processes of the present disclosure for use in the preparation of

pharmaceutical compositions and/or formulations.

[00133] In another aspect, the present disclosure encompasses the above described solid state forms of Tenapanor and Tenapanor dihydrochloride for use in the preparation of pharmaceutical compositions and/or formulations.

[00134] The present disclosure also encompasses the use of the Tenapanor or a salt thereof prepared by the processes of the present disclosure for the preparation of pharmaceutical compositions and/or formulations of Tenapanor or a salt thereof.

[00135] In another aspect, the present disclosure encompasses the use of the above described solid state forms of Tenapanor and Tenapanor dihydrochloride for the preparation of pharmaceutical compositions and/or formulations of Tenapanor or a salt thereof.

[00136] In yet another embodiment, the present disclosure encompasses pharmaceutical compositions including any one or a mixture of the solid state forms of Tenapanor and Tenapanor dihydrochloride and solid state form thereof.

[00137] In specific embodiment, the present disclosure encompasses pharmaceutical formulations including any one or a mixture of the solid state forms of Tenapanor and Tenapanor dihydrochloride and solid state form thereof and at least one pharmaceutically acceptable excipient.

[00138] The present disclosure further encompasses processes to prepare said

pharmaceutical formulations of Tenapanor and/or Tenapanor di hydrochloride, by combining any one or a mixture of the above described salt and solid state forms of Tenapanor, or pharmaceutical compositions including them, and at least one pharmaceutically acceptable excipient.

[00139] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining the Tenapanor or Tenapanor dihydrochloride prepared by the processes of the present disclosure with at least one pharmaceutically acceptable excipient. [00140] Pharmaceutical formulations of the present invention contain any one or a combination of the solid state forms of Tenapanor and Tenapanor dihydrochloride of the present disclosure, particularly crystalline Tenapanor dihydrochloride. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[00141] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00142] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical

compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[00143] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.

Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[00144] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. [00145] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil,

polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[00146] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00147] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00148] In liquid pharmaceutical compositions of the present disclosure, active ingredient and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00149] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00150] Liquid pharmaceutical compositions of the present disclosure can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose,

ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum. [00151] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00152] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00153] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00154] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the administration route is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00155] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[00156] The dosage form of the present disclosure can be a capsule containing the composition, in embodiments a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contains a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[00157] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00158] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00159] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00160] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00161] A capsule filling of the present invention can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00162] A pharmaceutical formulation of Tenapanor can be administered. Tenapanor may be formulated for administration to a mammal, such as a human, by injection. Tenapanor can be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00163] Tenapanor or a salt thereof, including Tenapanor dihydrochloride prepared by the processes of the present disclosure and the pharmaceutical compositions of Tenapanor or a salt thereof, including Tenapanor dihydrochloride prepared by the processes of the present disclosure can be used as medicaments, particularly for the treatment of the treatment of constipation-predominant irritable bowel syndrome (IBS-C), chronic kidney disease and hypertension.

[00164] The present disclosure also provides the uses of Tenapanor or a salt thereof, including Tenapanor dihydrochloride prepared by the processes of the present disclosure and the pharmaceutical compositions of Tenapanor or a salt thereof for the manufacture of medicaments for the treatment of the treatment of constipation-predominant irritable bowel syndrome (IBS-C), chronic kidney disease and hypertension. [00165] The present disclosure also provides methods for the treatment of IBS-C, chronic kidney disease and hypertension, including administering a therapeutically effective amount of Tenapanor prepared by the processes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.

[00166] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.

Analytical Method

[00167] Powder X-Ray Diffraction (XRD) Method

X-ray diffraction was performed on X-Ray powder diffractometer: Bruker D8 Advance; CuK radiation (l = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring.

Examples

[00168] (S)-Compound A, the starting material used herein, can be prepared according to the procedure described in U.S. Patent No. 8,969,377 (example for compound 168.2) and according to example 1 described herein.

Example 1. Preparation of (S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2- methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide [(S)-Compound A]

[00169] To tert-butyl (S)-(2-(2-(2-((3-(6,8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)phenyl) sulfonamide) ethoxy) ethoxy) ethyl) carbamate hydrochloride (100 gr) (this intermediate can be prepared according to procedure described in example 10) was added methanol (350 ml) and aq Hydrochloric Acid ( 30%) (150 ml) and stirred at 45-50°C for 1-3 hours. The obtained reaction mass was concentrated under vacuum while it is possible to continue without any concentration but to continue with addition of Demineralized water (350 ml) and Isopropyl Acetate (350 ml). Solution was stirred and layers were separated. To the aqueous layer was added isopropyl acetate (350 ml) and adjusted pH to 10-11 with sodium hydroxide solution. Stirred and separate layers and distilled off organic layer under vacuum to get oily mass which converted to solid residue upon standing at RT for about overnight. Alternatively, addition of Isopropyl acetate to the oily mass followed by seeding with pure (S)-Compound A and stirring, leads to solid isolation within only 1-2 hours. Isopropyl acetate or ethyl acetate is further added and stirred for about 5-6 hours. Solution mass was filtered the solid and washed with solvent to get pure (S)-N-(2-(2-(2-aminoethoxy) ethoxy) ethyl)-3-(6,8-dichloro-2-methyl-l, 2, 3, 4- tetrahydroisoquinolin-4-yl) benzenesulfonamide ((S)-Compound A, 40-50 gr, >99% purity by HPLC). Alternatively (S)-N-(2-(2-(2-aminoethoxy) ethoxy) ethyl)-3-(6,8-dichloro-2- methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide oil (20 gr) was taken in ethyl acetate (20 ml) and added heptane (20 ml) to isolate solid (S)-Compound A (14-15 gr, >99% purity by HPLC).

Example 2: Preparation of N,N'-(butane-l,4-diyl)bis(lH-imidazole-l-carboxamide), [Formula (1)]

[00170] To dichloromethane (400 ml) was added 1,1 carbonyl diimidazole (92 gr) and stirred by cooling to -20°C. Added 1,4 diamino butane (20 gr), dropwise at -20 to -l5°C. Stirred for 30 minutes and raised temperature to 0°C. Stirred for 1 hour, filtered under vacuum and washed with dichloromethane (80 ml) and dried under vacuum to get N,N'- (butane-l,4-diyl)bis(lH-imidazole-l-carboxamide) (55-60 gr of formula (1))

Example 3: Preparation of, Tenapanor via formula (1)

[00171] To acetonitrile (40 ml) was added (S)-N-(2-(2-(2-aminoethoxy) ethoxy) ethyl)-3- (6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide, (2 gr, (S)- Compound A and heated to 50-55°C. N,N'-(butane-l,4-diyl)bis(lH-imidazole-l- carboxamide), formula (1), prepared in previous stage (0.49 gr), was added in lots (in portions) and stirred for 2 hours. Isolated product was filtered under vacuum and washed with acetonitrile (5 ml) to get 3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N- (26-((3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa-9, 11,16,18-tetraazahexacosyl)benzenesulfonamide

(Tenapanor purity: 96-98%, Yield: 85-90% ). XRD confirms crystalline Tenapanor, as shown in figure 1. Example 4: preparation of Tenapanor via Formula (2)

[00172] To Ethyl acetate (100 ml) was added (S)-N-(2-(2-(2-aminoethoxy) ethoxy) ethyl)- 3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide ((S)- Compound A, 10 gr). Added carbonyl diimidazole (4.2 gr) and stirred at 20-30°C for about 1- 2 hours. Added 1, 4 diaminobutane (0.88 gr) and stirred at 40-50°C for about 5-6 hours, filter the isolated solid and wash with ethyl acetate (20 ml) to get -((S)-6,8-dichloro-2-methyl- l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa-9, 11,16,18- tetraazahexacosyl)benzenesulfonamide (Tenapanor purity: 95-96%, yield: 85-90%). XRD confirms crystalline Tenapanor, as shown in figure 1.

Example 5: Crystallization of Tenapanor

[00173] Tenapanor was purified by crystallization in mixture of acetonitrile (15 vol.) methanol (5 vol.) and water (2 vol.) and heated to 50-55°C to get a clear solution. To the solution activated carbon was added and stirred. Filtration was further used to remove the carbon. The filtrated solution was cooled to 20-25°C and stirred for 4-5 hours to crystallize the product and can be further stirred for additional 15-20 hours before filtration to insure complete crystallization. The filtered solid can optionally recrystallized again from a mixture of acetonitrile (15 vol.), methanol (5 vol.) and water (2 vol.) to get pure 3-((S)-6,8-dichloro- 2-methyl-l, 2,3, 4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa-9, 11,16,18- tetraazahexacosyl)benzenesulfonamide (purity: 99. 5%. Yield 70-75%). The obtained product was analyzed by XRD (figure 1).

Example 6. Preparation of Amorphous Tenapanor

[00174] To 3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3- ((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-l0,l7- dioxo-3,6,2l,24-tetraoxa-9,l l,l6,l8-tetraazahexacosyl)benzenesulfonamide (Tenapanor, 5.0 gr) was added methanol (1250 ml) and stirred to get a clear solution. Evaporated the solution under reduced pressure (<50 mm Hg at 50-55°C) on rotary evaporator to get amorphous Tenapanor (5.0 gr). XRD confirms amorphous.

Example 7. Preparation of Tenapanor di- hydrochloride

[00175] To 3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3- ((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-l0,l7- dioxo-3,6,2l,24-tetraoxa-9,l l,l6,l8-tetraazahexacosyl)benzenesulfonamide (Tenapanor, 25.0 gr) was added water (250 ml), methanol (250 ml) and 2N HC1 (25 ml) to get a clear solution at 20-30°C. Distilled out the solution completely under vacuum (<50 mmHg, 50-55°C) to get 3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro- 2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24- tetraoxa-9,l l,l6,l8-tetraazahexacosyl)benzenesulfonamide bis hydrochloride as foamy solid. XRD confirms amorphous Tenapanor di -hydrochloride salt.

Example 8. Preparation of Tenapanor di- h drochloride

[00176] To 3-((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3- ((S)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-l0,l7- dioxo-3,6,2l,24-tetraoxa-9,l l,l6,l8-tetraazahexacosyl)benzenesulfonamide (Tenapanor, 15 gr) added methanol (112 ml) and stirred. Added HC1 solution in methanol (5.70% w/w)

(17.20 gr) at 20-30°C over 5-10 minutes to get clear solution. Distilled out the solution completely under vacuum (<50 mmHg, 50-55°C) followed by addition of cyclohexane (150 ml) and stirred for 1-2 hours at 20-30°C. Filtered the solid and washed with cyclohexane (30 ml) and dried under vacuum (<50 mmHg, 50-55°C) to obtain 3-((S)-6,8-dichloro-2-methyl-

1.2.3.4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa-9, 11,16,18- tetraazahexacosyl)benzenesulfonamide bis hydrochloride (Tenapanor di -hydrochloride, 14.5 gr). XRD confirms amorphous content.

Example 9. Preparation of crystalline Tenapanor di-hydrochloride

[00177] To isopropyl acetate (60 ml) was added 3-((S)-6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6, 8-dichloro-2-m ethyl- 1, 2,3,4- tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa-9, 11,16,18- tetraazahexacosyl)benzenesulfonamide (Tenapanor, 3 gr) at 20-30°C with stirring. The slurry was cooled to 0-5°C. Added a solution of HC1 in Isopropyl acetate (7.95%w/w, 2.07 mol eq) 2.87 ml at 0-5°C and stirred for 60-90 minutes. Filtered the solid under vacuum and washed with isopropyl acetate (20 ml). Dried the solid under vacuum at 40°C to obtain 3-((S)-6,8- dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-

1.2.3.4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)- 10, 17-dioxo-3 ,6,21 ,24-tetraoxa- 9,l l,l6,l8-tetraazahexacosyl)benzenesulfonamide di hydrochloride (Tenapanor bis HC1, 2.9 gr). XRD measurement described in figure 2 confirms crystalline Tenapanor bis HC1.

Example 10. Preparation of tert-butyl (S)-(2-(2-(2-((3-(6,8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)phenyl) sulfonamide) ethoxy) ethoxy) ethyl) carbamate

[00178] This intermediate used in example 1 for the preparation of Compound A can be prepared according to the following synthetic procedures (steps a-d). Step a. Preparation of (S)-4-(3-(benzylthio) phenyl)-6,8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinoline

To (S)-4-(3-bromophenyl)-6, 8-dichloro-2-methyl-l, 2, 3, 4-tetrahydroisoquinoline (100 gr, can be prepared according to W02010/078449) was added toluene (1000 ml) under nitrogen purging and stirring. Added Xantphos (3.89 gr) and Pd2(dba)3 (3.94 gr) and stirred. Added Benzyl mercaptan (44.0 gr) and diisopropyl ethyl amine (52.0 gr) and heated to 90-l00°C for 1-2 hours. Cooled the reaction mass, added DM water (200 ml) and separated layer. Washed organic layer with water (200 ml) and concentrated completely under vacuum to get (S)-4-(3- (benzylthio) phenyl)-6,8-dichloro-2-m ethyl- 1, 2, 3, 4-tetrahydroisoquinoline as oil (110-125 gr, purity 86%).

Step b. Purification of (S)-4-(3-(benzylthio) phenyl)-6,8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinoline

To (S)-4-(3-(benzylthio) phenyl)-6,8-dichloro-2-methyl-l, 2, 3, 4-tetrahydroisoquinoline oily mass obtained in previous stage (25.5 gr) was added ethyl acetate (125 ml) and stirred. Added concentrated HC1 (35%, 1.37 mol eq) and stirred for 2-3 hours at 25-30°C. Filtered the solid and washed with ethyl acetate (25 ml). Solid is dried under vacuum at 45°C to get (S)-4-(3- (benzylthio) phenyl)-6,8-dichloro-2-m ethyl- 1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (23.0 gr, purity >97%).

Step c. Preparation of -(S)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- yl)benzenesulfonyl chloride hydrochloride

To (S)-4-(3-(benzylthio) phenyl)-6,8-dichloro-2-methyl-l, 2, 3, 4-tetrahydroisoquinoline hydrochloride, obtained from previous stage (100 gr) was added ethyl acetate (700 ml) and stirred. Water (40 ml) was added followed by addition of N-chloro succinimide (115 gr) in lots at 40-45°C. Product is filtered under vacuum and washed with ethyl acetate 300 ml. Dried the solid in vacuum oven to get (S)-3-(6, 8- dichloro-2-methyl-l, 2, 3, 4- tetrahydroisoquinolin-4-yl) benzene sulfonyl chloride hydrochloride (70-90 gr).

Alternatively, in this procedure, instead of adding ethyl acetate, DCM and Isopropyl acetate can also be used.

Step d. Preparation of tert-butyl (S)-(2-(2-(2-((3-(6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquino lin-4-yl)phenyl)sulfonamido)ethoxy)ethoxy)ethyl)carbamate

To isopropyl acetate (500 ml) was added tert-butyl (2-(2-(2-aminoethoxy) ethoxy) ethyl) carbamate (58 gr) and cooled to 0-5°C. Added Triethyl amine (71.0 gr) followed by lot wise addition of (S)-3-(6, 8-dichloro-2-methyl-l, 2, 3, 4-tetrahydroisoquinolin-4-yl) benzene sulfonyl chloride hydrochloride obtained in previous stage (100 gr). Stirred for 1-2 hours. Added DM water (300 ml) slowly and stirred. Layers were separated and to the organic layer water was added (200ml) and adjusted pH to 3-4 with aqueous HC1 and separated layers. Distilled off organic layer under vacuum to get tert-butyl (S)-(2-(2-(2-((3-(6, 8-dichloro-2- methyl-l, 2, 3, 4-tetrahydroisoquinolin-4- yl) phenyl) sulfonamido) ethoxy) ethoxy) Ethyl) carbamate hydrochloride (110-120 gr) as oil.

In this procedure, instead of adding isopropyl acetate, alternatively DCM and ethyl acetate can also be used.

[00179] The table below demonstrates the correlation between chloride content and the hydroxy impurity level in Tenapanor dihydrochloride samples. Two Tenapanor

dihydrochloride samples having 8.38% and 5.95% chloride were kept under stability for 1 month at 5°C and 25°C (same humidity was used: 60% ± 5%). It is clearly shown that hydroxy impurity is not produced during stability when the chloride content is 5.95%.

However, sample having 8.38% chloride shows increase in the hydroxyl impurity level during stability.

[00180] Table 1. Level of hydroxy impurity in Tenapanor dihydrochloride having different levels of chloride content (measured at time zero "initial" and after 1 month kept at 5°C and 25°C).

n.d.= not

Claims

1. A process for preparation of Tenapanor or a salt thereof, comprising reacting (S)- Compound A with compound of formula (1):

· _and optionally converting

Tenapanor to a salt thereof, preferably Tenapanor dihydrochloride salt.

2. A process according to Claim 1, comprising adding the compound of Formula (1) to a solution of (S)-Compound A, preferably wherein the solution of (S)-Compound A is in a polar aprotic solvent, preferably wherein the solvent comprises: dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-Dimethyl acetamide (DMA), dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, 2-methyl tetrahydrofuran (2-Me-THF),

tetrahydrofuran (THF), methylisobutylketone (MIBK), acetone, methylethylketone (MEK), toluene, or combinations thereof, and preferably wherein the solvent comprises acetonitrile.

3. A process according to Claim 1 or Claim 2, wherein the molar ratio between (S)- Compound A and compound of formula (1) is: about 3: 1 to about 2: 1, preferably about 2.5: 1 to about 2: 1, more preferably about 2.3: 1 to about 2: 1, and most preferably about 2.25: 1.

4. A process according to Claim 2 or Claim 3, wherein the solution of (S)-Compound A is heated to a temperature of about 40°C to about 70°C, more preferably at about 40°C to about 60°C, and particularly at about 50°C to about 55°C.

5. A process according to any of Claims 2-4, wherein the solvent is used in an amount of about 10 to about 60 vol of solvent, preferably about 15 to about 30 vol of solvent, and more preferably about 15 to about 25 vol of solvent, and most preferably about 20 vol, relative to (S)-Compound (A).

6. A process according to any of Claims 2-5 , wherein the compound of formula (1) is added to the solution of (S)-Compound A portionwise, and more preferably wherein the addition is carried out over a period of about 2-5 hours, preferably 3-4 hours.

7. A process according to any of Claims 2-6, wherein the reaction mixture is stirred for about 0.5 to about 4 hours, more preferably about 1 to about 3 hours, more preferably about 2 hours.

8. A process according to any of Claims 1-7, wherein Tenapanor is isolated by filtration and washing, preferably washing with a solvent, preferably a reaction solvent as described above, and more preferably with acetonitrile.

9. A process according to any of Claims 1-8, wherein the Tenapanor is converted to a salt thereof, preferably Tenapanor dihydrochloride salt, and more preferably crystalline Tenapanor dihydrochloride as defined in any of Claims 43-46.

10. A process according to any of Claims 1-9, further comprising combining the

Tenapanor or salt thereof, with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

11. A process for preparing a compound of formula (1) comprising reacting 1,1 -carbonyl diimidazole with 1, 4-diamino butane:

Formula (1)

12. A process according to Claim 11, wherein the molar ratio of 1, 1 carbonyl diimidazole to 1,4 diamino butane is: about 3.5: 1 to about 2: 1, preferably about 2.8: 1 to about 2: 1, more preferably about 2.7: 1 to about 2.3: 1, and most preferably about 2.5: 1.

13. A process according to Claim 11 or Claim 12, comprising adding 1, 4-amino butane to a solution of 1,1 -carbonyl diimidazole in a solvent.

14. A process according to Claim 13, wherein the solvent is selected from the group consisting of dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethyl acetamide, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, 2- methyltetrahydrofuran (MeTHF), THF, MIBK, acetone, MEK and toluene, or combinations thereof; and more preferably the solvent comprises dichloromethane.

15. A process according to Claim 13 or Claim 14, wherein the reaction is carried in an amount of solvent of: about 1 to about 50 vol of solvent, about 1 to about 30 vol of solvent, preferably about 2 to about 20 vol, and more preferably about 2-10 vol of solvent, with reference to 1,1 -carbonyl diimidazole..

16. A process according to any of Claims 11-15, wherein the reaction is carried out at temperature of about -20 to about -l0°C more preferably at about -20 to -l5°C, preferably at a reaction time of: about 10 to about 60 min, preferably about 10 to about 40 min, more preferably about 30 min, optionally with stirring.

17. A process according to Claim 16, wherein the reaction mixture is raised to a temperature of about -5°C to about l0°C, preferably at about -5 to about 5°C, and more preferably to about 0°C.

18. A process according to any of Claims 11-17, further comprising isolating the compound of formula (1) by filtration and washing, preferably washing with the reaction solvent, and more preferably with dichloromethane.

19. A process for the preparation of Tenapanor or a salt thereof, comprising reacting (S)- Compound A, 1,1 -carbonyl diimidazole and 1,4 diaminobutane, and optionally converting the Tenapanor to a salt thereof, preferably Tenapanor dihydrochloride.

20. A process according to Claim 19, comprising:

(i) reacting (S)-Compound A, with 1,1 -carbonyl diimidazole to prepare a compound of Formula (2):

; and

(ii) reacting the compound of Formula (2) with l,4-diaminobutane to form Tenapanor.

21. A process according to Claim 20, wherein step (ii) is carried out without isolation of the compound of Formula (2).

22. A process according to Claim 20 or Claim 21, wherein step (i) and step (ii) are carried out in a solvent, preferably the same solvent, wherein the solvent comprises an ether, a polar aprotic solvent, a chlorinated solvent, a hydrocarbon or a ketone, or a combination thereof, preferably wherein the solvent comprises DMF, DMSO, acetonitrile (ACN) or ethyl acetate, and more preferably wherein the solvent comprises ethyl acetate.

23. A process according to Claim 22, wherein the solvent is used in an amount of: about 5 to about 75 vol, about 10 to about 40 vol, or preferably about 15 to about 20 vol. of solvent, relative to (S)-Compound A.

24. A process according to any of Claims 20-23, wherein step (i) comprises adding (S)- Compound A and 1,1 -carbonyl diimidazole to the solvent system, to produce the compound of formula (2).

25. A process according to any of Claims 19-24, wherein the molar ratio of (S)- Compound A to 1,1 carbonyl diimidazole is: about 1 : 1.2 to about 1 :2.5, preferably about 1 : 1.4 to about 1 :2, and more preferably about 1 : 1.5 to about 1 : 1.6.

26. A process according to any of Claims 19-25, wherein the molar ratio of 1, 1 -carbonyl diimidazole to l,4-diaminobutane is: about 4: 1 to about 2: 1, preferably about 3: 1 to about 2: 1, and more preferably about 2.8 : 1 to about 2.5: 1.

27. A process according to any of Claims 19-26, wherein the molar ratio of (S)- Compound A and 1, 4 diaminobutane is: about 2: 1 to about 1 : 1, preferably about 1.8: 1 to about 1.4: 1, and more preferably about 1.7: 1 to about 1.6: 1.

28. A process according to any of Claims 20-27, wherein the reaction mixture in step (i) is maintained at: about -5 to about 40°C, preferably about 10 to about 30 °C, more preferably about 20 to about 30°C; and preferably for a time period of: about 0.5 to about 3 hours, more preferably for about 1 to about 2 hours, optionally with stirring.

29. A process according to any of Claims 20-28, wherein step (ii) comprises the addition of l,4-diaminobutane to the reaction mixture of step (i) to obtain Tenapanor.

30. A process according to any of Claims 20-29, wherein the reaction mixture in step (ii) is heated to about 35 to about 80°C, preferably about 35 to about 60°C, more preferably about 40 to about 50°C; and preferably for a time period of: about 3 to about 10 hours, , about 4 to about 8 hours, and most preferably about 5 to about 6 hours, optionally with stirring.

31. A process according to any of Claims 19-30, further comprising isolating the

Tenapanor, preferably by filtration, optionally washing with the reaction solvent system, preferably with acetonitrile or ethyl acetate, more preferably with ethyl acetate.

32. A process according to any of Claims 19-31, wherein the Tenapanor is converted to a salt thereof, preferably Tenapanor dihydrochloride salt, and more preferably crystalline Tenapanor dihydrochloride salt as defined in any of Claims 43-46.

33. A process according to any of Claims 19-32, further comprising combining the Tenapanor or salt thereof, with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

34. A process for preparing a compound of Formula (2):

comprising reacting (S)-Compound A, with l,l-carbonyl di imidazole_^

35. A process according to Claim 34, comprising adding l,l-carbonyl diimidazole to a mixture comprising (S)-Compound A in the solvent.

36. A process according to Claim 34 or Claim 35, wherein the reaction is carried out in a solvent, wherein the solvent comprises an ether, a polar aprotic solvent, a chlorinated solvent, a hydrocarbon or a ketone, or a combination thereof, preferably wherein the solvent comprises DMF, DMSO, acetonitrile (ACN) or ethyl acetate, and more preferably wherein the solvent comprises ethyl acetate.

37. A process according to Claim 35 or Claim 36, wherein the solvent is used in an amount of: about 5 to about 75 vol, about 10 to about 40 vol, or preferably about 15 to about 20 vol. of solvent, relative to (S)-Compound A.

38. A process according to any of Claims 34-37, wherein the molar ratio of (S)- Compound A to 1,1 carbonyl diimidazole is: about 1 : 1.2 to about 1 :2.5, preferably about 1 : 1.4 to about 1 :2, and more preferably about 1 : 1.5 to about 1 : 1.6.

39. A process according to any of Claims 34-38, wherein the reaction mixture is maintained at: about -5 °C to about 40 °C, preferably about 10 to about 30 °C, more preferably about 20 °C to about 30°C; and preferably for a time period of: about 0.5 to about 3 hours, more preferably for about 1 to about 2 hours, optionally with stirring.

40. A process according to any of Claims 34-39, further comprising isolating the compound of formula (2).

41. A compound of Formula (1) or Formula (2):

42. Use of a compound of Formula (1) or Formula (2) as defined in Claim 41 in the preparation of Tenapanor, or a salt thereof, preferably Tenapanor dihydrochloride.

43. Crystalline Tenapanor di hydrochloride, preferably wherein the crystalline Tenapanor dihydrochloride is characterized by data selected from one or more of the following:

a. an X-ray powder diffraction pattern having peaks at 11.1, 21.1, 21.6, 22.7 and 24.0 degrees two theta ± 0.2 degrees two-theta;

b. an XRPD pattern as depicted in Figure 2

c. a combination of the above.

44. Crystalline Tenapanor di hydrochloride according to Claim 43, characterized by an XRPD pattern having peaks at 11.1, 21.1, 21.6, 22.7 and 24.0 degrees two theta ± 0.2 degrees two-theta, and also further characterized by one, two, three, four, five or six additional peaks selected from 13.4, 16.8, 17.4, 18.3, 19.2 and 19.7 ± 0.2 degrees two theta.

45. Crystalline Tenapanor di hydrochloride according to Claim 43 or Claim 44, which is substantially free of chloride impurity, preferably wherein the crystalline Tenapanor dihydrochoride contains: about 5.7% to about 6.2% w/w and more preferably about 5.9% to about 6.1% w/w chloride

46. Crystalline Tenapanor di hydrochloride according to any of Claims 43-45, which is substantially free of hydroxy impurity, preferably wherein the crystalline Tenapanor dihydrochloride contains: less than 0.05%, more preferably less than 0.02% w/w hydroxy impurity.

47. A process for preparing crystalline Tenapanor dihydrochloride as defined according to any of Claims 43-46, comprising crystallising Tenapanor dihydrochloride in ethyl acetate or isopropyl acetate, preferably isopropyl acetate.

48. A process according to Claim 47, comprising reacting a suspension of Tenapanor in isopropyl acetate or ethyl acetate with hydrogen chloride.

49. A process according to Claim 48, wherein the isopropyl acetate or ethyl acetate is present in the reaction mixture an amount of: about 10 to about 50 vol, about 15 to about 25 vol, or about 18-22 vol relative to the Tenapanor.

50. A process according to Claim 48 or Claim 49, wherein the Tenapanor suspension is at a temperature of: about l0°C to about 40°C, about l5°C to about 35°C, and preferably wherein the suspension is at room temperature, and most preferably about 20°C to about 30°C.

51. A process according to any of Claims 48-50, wherein the Tenapanor suspension is maintained at room temperature, preferably at about 20°C to about 30°C for about 10 to 60 minutes, preferably for about 10 to 30 minutes, more preferably for about 10 to 15 minutes, optionally with stirring.

52. A process according to any of Claims 48-51, wherein the Tenapanor suspension is cooled to temperature of about -5°C to about l0°C, preferably about -5°C to about 5°C, and more preferably about 0°C to about 5°C.

53. A process according to any of Claims 48-52, wherein a solution of hydrogen chloride in ethyl acetate or isopropyl acetate is added to the suspension of Tenapanor, preferably wherein the HC1 is present in an amount of: about 1.9 to about 2.2 mol eq of HC1, preferably about 1.95 to about 2.15 mol equivalents of HC1, and preferably about 2-2.10 mol eq of HC1 in isopropyl acetate or ethyl acetate.

54. A process according any of Claims 48-53, wherein the reaction mixture is maintained for about 30 minutes to 180 minutes, preferably for about 30 minutes to 120 minutes, more preferably for about 60 to 90 minutes, optionally with stirring, preferably at a temperature of about -5 to about l0°C, preferably about -5 to about 5°C, and more preferably about 0 to about 5°C.

55. A process according to any of Claims 47-54, wherein the Tenapanor dihydrochloride is isolated, preferably by filtration, optionally washing, and optionally drying.

56. A process according to Claim 55, wherein the drying is carried out under reduced pressure, preferably at a temperature of about 20 to about 50°C, preferably about 25 to about 45°C, and more preferably about 40°C.

57. A process according to any of Claims 47-56, further comprising a step of combining the crystalline Tenapanor dihydrochloride with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or a pharmaceutical formulation.

58. Crystalline Tenapanor di hydrochloride obtainable by a process according to any of Claims 47-57, preferably which is: substantially free of chloride impurity, preferably wherein the crystalline Tenapanor dihydrochoride contains: about 5.7% to about 6.2% w/w and more preferably about 5.9% to about 6.1% w/w chloride; and/or substantially free of hydroxy impurity, preferably wherein the crystalline Tenapanor dihydrochloride contains: less than 0.05%, more preferably less than 0.02% w/w hydroxy impurity.

59. A pharmaceutical composition comprising a crystalline form according to any of Claims 43-44 or 58.

60. Use of a crystalline form according to any of Claims 43-44 or 58 in the manufacture of a pharmaceutical composition and/or formulation.

61. A pharmaceutical formulation comprising a crystalline form according to any of Claims 43-44 or 58, or the pharmaceutical composition of Claim 59, and at least one pharmaceutically acceptable excipient.

62. A process for preparing the pharmaceutical formulation according to Claim 62 comprising combining a crystalline form according to any of Claims 43-44 or 58, or the pharmaceutical composition of Claim 59, with at least one pharmaceutically acceptable excipient.

63. The crystalline form according to any of Claims 43-44 or 58, the pharmaceutical composition according to Claim 59, or the pharmaceutical formulation according to Claim 61, for use as a medicament.

64. The crystalline form, according to any of Claims 43-44 or 58, the pharmaceutical composition according to Claim 59, or the pharmaceutical formulation according to Claim 61, for use in the treatment of constipation-predominant irritable bowel syndrome (IBS-C), chronic kidney disease and hypertension.

65. A method of treating IBS-C, chronic kidney disease and hypertension, comprising administering a therapeutically effective amount of a crystalline form according to any of Claims 43-44 or 58, the pharmaceutical composition according to Claim 59, or the

pharmaceutical formulation according to Claim 61, to a subject suffering from IBS-C, chronic kidney disease and hypertension or otherwise in need of the treatment.

66. The crystalline form, according to any of Claims 43-44 or 58, the pharmaceutical composition according to Claim 59, or the pharmaceutical formulation according to Claim 61, for use in the manufacture of medicament for treatment of IBS-C, chronic kidney disease and hypertension.