Process for the preparation of sparsentan

Abstract

The present invention relates to a process for the preparation of sparsentan comprising the steps of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV); b1) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A), or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A); c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B); using the compound (B) for the preparation of sparsentan. Therefore, the process according to the present invention is very simple, effective and industrially applicable, and particularly cost-effective.

Description

[0001] PROCESS FOR THE PREPARATION OF SPARSENTAN

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a process for the preparation of a key intermediate of formula (B) for the preparation of sparsentan.

[0005] BACKGROUND ART

[0006] Sparsentan compound is an active ingredient being approved by the Food and Drug Administration (FDA) and used to treat IgA nephropathy, also called Berger's disease, a rare kidney disease characterized by the accumulation of immunoglobulin A, a protein in the kidneys which helps the body fighting infections.

[0007] Sparsentan is an experimental molecule provided with a double action, as it acts as an antagonist of type A endothelin receptor and type 1 angiotensin II receptor, and has the following chemical formula (I):

[0008] The known methods for the preparation thereof use boronic acids as synthesis intermediates, suitably protected at the sulfonamide group, and having chemical formula (II) and (III) or the pinacol boronates thereof having chemical formula (IV) and

[0009] (II) PG = MEM (IV) PG = MEM

[0010] (III) PG = MOM (V) PG = MOM

[0011] MEM= methoxyethoxymethyl ether

[0012] MOM=methoxymethyl ether

[0013] Such compounds are then reacted by Suzuki reaction with compound (VI) so as to obtain compounds (VII) or (VIII) which, following acid treatment, allow obtaining sparsentan (I) in accordance with what is shown in Reaction Scheme 1 :

[0014] (II) X = OH, PG = MEM M (VII) PG = M

[0015] (III) X = OH, PG = MO EM

[0016] (IV) X = Pinacol, PG = MEM (VIII) PG = MOM

[0017] (V) X = Pinacol, PG = MOM

[0018] Reaction Schemel

[0019] WO9833780 describes the preparation of compound (II), while W02002032884 describes the synthetic sequence for the preparation of compound (III). Both synthetic processes are depicted in Reaction Scheme 2 and include a sulfonation reaction between the heterocycle (IX) and the sulfonyl chloride (X). The sulfonamide (XI) thus obtained is then alkylated until alkyl sulfonamides (XII) or (XIII) are obtained. The protected sulfonamides thus obtained are treated with Butyl Lithium and trimethyl borate to obtain boronic acids (II) and (III).

[0020] Reaction Scheme 2

[0021] The lithiation and subsequent borylation step is carried out in both cases at temperatures close to -100°C. Such temperatures are very difficult to reach, with consequent technological gaps to be filled before these steps can be carried out on an industrial scale.

[0022] The use of compounds (II) and (II I) for the production of sparsentan (I) is also described in W02000001389 and WO2001044239.

[0023] W02002032884 instead describes the preparation of compound (V), as shown in Reaction Scheme 3, which includes an esterification of boronic acid by using pinacol. The removal of water through reflux distillation in toluene promotes conversion.

[0024] Pinacol toluene

[0025] Reaction Scheme

[0026] However, this methodology adds a further synthetic step to the entire process, without solving the problem of low temperatures in the borylation step.

[0027] CN110283136 describes an alternative method for the preparation of compound (IV), starting directly from compound (XII), as shown in Reaction Scheme 4:

[0028] Reaction Scheme 4

[0029] Such methodology includes a Miyaura reaction between compound (XII) and bis(pinacolato)diboron catalyzed by a palladium-based species in the presence of potassium acetate in 1-4 dioxane at high temperatures.

[0030] While this method solves the problem of low temperatures in the borylation step, on the other hand it has considerable criticalities, such as the use of a reagent such as bis(pinacolato)diboron with a considerably higher cost with respect to trialkyl borates; the use of a Palladium-based catalyst, a precious metal with a high cost and finally the use of 1-4 dioxane, a highly toxic solvent.

[0031] In addition, the process described in CN110283136 includes the use of compound (X), a reagent with high cost and low availability on the market. The reagent (X) is also used in the other processes described in the prior art.

[0032] It is the object of the present invention to provide an efficient process for the synthesis of the compounds of formula (IV) and (V) which overcomes the drawbacks of the prior art, and which is at the same time advantageous from an industrial point of view.

[0033] SUMMARY OF THE INVENTION

[0034] The purpose indicated above has been achieved by means of a process which allows obtaining the compounds of formula (B), comprising compounds (IV) and (V) of the prior art, starting from low-cost raw materials, avoiding synthesis steps at critical temperatures and without adding further synthesis steps with respect to the known processes.

[0035] In a first aspect thereof, therefore, the present invention relates to a process for the preparation of sparsentan, comprising the steps of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV) bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A) or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A) c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B) d) reacting the compound of formula (B) with the compound of formula (VI) in the presence of a palladium-based species to obtain the compound of formula (C) e) treating the compound of formula (C) with HCI, water and ethanol to obtain the compound (I).

[0036] (C) in which PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3, and

[0037] R is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

[0038] Surprisingly, the process of the present invention allows avoiding the use of critical temperatures in the borylation step provided according to the processes of the prior art, and necessary for obtaining the compounds of formula (B), key intermediates for the synthesis of sparsentan.

[0039] Advantageously, according to the present invention, step c) of borylation of the compounds of formula (A) to obtain the compounds of formula (B), can be carried out by direct lithiation at a temperature of -45°C; such a temperature is significantly lower and easier to manage from an industrial viewpoint with respect to a temperature of -95°C, as described in the prior art. In addition, the ortho assistance of the sulfonamide group is capable of guiding the direct lithiation in the ortho position (highly regioselective reaction), avoiding the presence of a halogen group in such a position to carry out the bromine / lithium exchange. This allows using the compound (XIV) as the starting raw material, which is considerably less expensive with respect to the brominated analogue (X), resulting in advantageous and high economic savings. Therefore, the process according to the present invention is very simple, effective and industrially applicable, and particularly cost-effective.

[0040] In a second aspect, the present invention relates to a process for the preparation of the compound of formula (XV) comprising the step of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV)

[0041] In a third aspect, the present invention relates to a process for the preparation of the compound of formula (A) comprising the step of: bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A) or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A) . in which PG represents a protecting group selected from the group consisting of - CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and - CH2OCH2CH2CH2CH3, and

[0042] R is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

[0043] In a fourth aspect, the present invention relates to a process for the preparation of the compound of formula (B), comprising the step of: c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B)

[0044] (A! (Bi in which PG represents a protecting group selected from the group consisting of

[0045] -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3.

[0046] As indicated above, advantageously step c) of borylation of compound (A) to obtain the compound of formula (B), can be carried out by direct lithiation at a temperature of -45°C, significantly lower and easier to manage from an industrial viewpoint with respect to a temperature of -95°C necessary to carry out the borylation of compounds (XII) or (XIII) of the prior art.

[0047] In another aspect, the present invention relates to the compound of formula (XV) and the use of compound (XV) for the preparation of sparsentan.

[0048] In another aspect, the present invention relates to the compound of formula (A) in which PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3. and the use of the compounds of formula (A) for the preparation of sparsentan.

[0049] DESCRIPTION OF THE DRAWINGS Figure 1 shows the1H-NMR spectrum of the compound of formula (XV).

[0050] Figure 2 shows the UPLC profile of compound (XV) obtained according to the process described in step a). UPLC analysis of the crude obtained following the process described in Example 1 , where compound XII (retention time 1 ,083 min) is present with high UV purity without the need for further purification.

[0051] Figure 3 shows the1H-NMR spectrum of the compound of formula (XVI).

[0052] Figure 4 shows the UPLC profile of compound (XVI) obtained according to the process described in step b1 ). UPLC analysis of the crude obtained following the process described in the experimental section, where compound XII (retention time 1 ,379 min) is present with high UV purity following purification.

[0053] Figure 5 shows the1H-NMR spectrum of the compound of formula (IV).

[0054] Figure 6 shows the UPLC profile of the compound of formula (B) in which PG is -CH2OCH2CH2OCH3 (MEM) obtained according to the process described in step bl). Example of UPLC analysis of the crude obtained following the process described in the experimental section where the compound of formula (B) in which PG is -CH2OCH2CH2OCH3 (MEM) (retention time l,659min) is present with 95% UV purity without the need for further purification. The impurity with retention time l,377min is no more than 5% of the unreacted compound (XVI).

[0055] Figure 7 shows the1H-NMR spectrum of the compound of formula (C) in which PG is -CH2OCH2CH2OCH3 (MEM).

[0056] Figure 8 shows the UPLC profile of the compound of formula (C) in which PG is -CH2OCH2CH2OCH3 (MEM) obtained according to the process described in step d). Figure 9 shows the1H-NMR spectrum of the compound of formula (I).

[0057] Figure 10 shows the UPLC profile of compound (I) obtained according to the process described in step e).

[0058] Figure 11 shows the UPLC profile of compound (XVII) obtained according to the process described in step b2). Example of UPLC analysis of the crude obtained following the process described in the experimental section where compound XVII (retention time 1.399 min) is present with high UV purity without the need for further purification.

[0059] Figure 12 shows the UPLC profile of compound (XVIII) obtained according to the process of step b2). Example of UPLC analysis of the crude obtained following the process described in the experimental section where compound XVII (retention time 1.480 min) is present with high UV purity without the need for further purification. DETAILED DESCRIPTION OF THE INVENTION

[0060] In a first aspect, the present invention relates to a process for the preparation of sparsentan comprising the steps of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV) bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A) or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A) add, soivent

[0061] (XVj £A) c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B)

[0062] (A) IS) d) reacting the compound of formula (B) with the compound of formula (VI) in the presence of a palladium-based species to obtain the compound of formula (C) e) treating the compound of formula (C) with HCI, water and ethanol to obtain the compound

[0063] (I).

[0064] (C) in which PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3, and

[0065] R is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

[0066] In the step a) thereof, the invention includes reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV).

[0067] Step a) is preferably carried out using from 0.9 to 1.5 equivalents of the compound of formula (XIV), more preferably from 1.0 to 1.3 equivalents, even more preferably from 1.03 to 1.18 equivalents.

[0068] The reaction of step a) occurs in the presence of an organic solvent. According to a preferred embodiment of the invention, the organic solvent of step a) is selected from the group consisting of acetonitrile, acetone, THF, 2-methyltetrahydrofuran, ethyl acetate and a combination thereof. Preferably the organic solvent is acetonitrile.

[0069] The base used in step a) is preferably a tertiary amine selected from the group consisting of pyridine, lutidine, collidine. Preferably, the base of step a) is pyridine.

[0070] The base of step a) is preferably used in a ratio from 1.50 to 4.00 equivalents with respect to compound (IX), preferably from 1.50 to 3.00 equivalents.

[0071] According to a preferred embodiment of the invention, the reaction of step a) can optionally occur in the presence of a catalyst. Preferably, the catalyst of step a) is N,N dimethylaminopyridine (DMAP).

[0072] The catalyst of step a) is used in a ratio from 0.01 to 0.20 equivalents with respect to the compound of formula (IX).

[0073] Step a) preferably occurs at a temperature in the range from -20°C to 60°C, more preferably from -10°C to 50°C, even more preferably from -5°C to 25°C.

[0074] In the step bl) thereof, the invention includes reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A).

[0075] Preferably, the compound PG-CI is selected from the group consisting of 2- Methoxyethoxymethyl chloride (MEMCI), 2-Methoxymethyl chloride (MOMCI),(chloromethoxy)ethane, l-(chloromethoxy)propane, and l-(chloromethoxy)butane to obtain compounds of formula (XVI) or (XVII) or (XVIII) or (XIX) or (XX), respectively

[0076] (XVI) PG = -CH2OCH2CH2OCH3 (MEM)

[0077] (XVII) PG = -CH2OCH3(MOM)

[0078] (XVIII) PG = -CH2OCH2CH3

[0079] (XIX) PG = -CH2OCH2CH2CH3

[0080] (XX) PG = -CH2OCH2CH2CH2CH3

[0081] Step bl) is carried out using from 1.0 to 2.0 equivalents of 2-methoxyethoxymethyl chloride (MEMCI) or 2-methoxymethyl chloride (MOMCI) or (chloromethoxy)ethane or 1- (chloromethoxy)propane or l-(chloromethoxy)butane, more preferably from 1.05 to 1.25 equivalents.

[0082] The reaction of step bl) occurs in the presence of an organic solvent. According to a preferred embodiment of the invention, the organic solvent of step bl) is selected from the group consisting of acetonitrile, acetone, THF, 2-methyl tetra hydrofuran, DMF and DMSO. Preferably the organic solvent is DMF.

[0083] The base used in step bl) is selected from the group consisting of sodium hydride, tert-butylate of Li, Na, K, carbonate of Li, Na, K, Cs. Preferably the base of step b) is Cs carbonate.

[0084] The base of step bl) is used in a ratio from 1.00 to 3.00 equivalents with respect to compound (XV).

[0085] Step bl) preferably occurs at a temperature in the range from -20°C to 60°C, more preferably from -10°C to 40°C, even more preferably from 0°C to 30°C.

[0086] Alternatively, in the step b2), the invention includes reacting the compound of formula (XV) with the compound RO-PG to obtain the compound of formula (A).

[0087] Preferably, R is selected from the group consisting of in -CH2CH2OCH3, methyl, ethyl, propyl or butyl, to obtain the compounds of formula (XVI), (XVII), (XVIII), (XIX) or (XX), respectively.

[0088] Step b2) is carried out using from 1.00 to 10.00 equivalents of the compound RO-PG with respect to the compound XV. Preferably from 3.00 to 7.00 equivalents with respect to compound XV.

[0089] The reaction of step b2) occurs in the presence of a solvent. According to a preferred embodiment of the invention, the solvent of step b2) is selected from the group consisting of dichloromethane, dichloroethane, cyclopentyl methyl ether, toluene, xylene. Preferably the organic solvent is toluene.

[0090] Step b2) can occur in the presence of an acid or in the presence of only P2O5 or both.

[0091] The acid used in step b2) is selected from the group consisting of iron trichloride, sulfuric acid, para-toluenesulfonic acid, methanesulfonic acid. Preferably the acid is selected from paratoluenesulfonic acid and methanesulfonic acid.

[0092] The acid of step b2) is used in a ratio from 0.0 to 1.00 equivalents with respect to compound (XV), preferably 0.30 to 0.50 equivalents with respect to compound (XV).

[0093] The reaction of step b2) occurs in the presence of P2O5 used in a ratio from 0.0 to 1.00 equivalents with respect to compound (XV), preferably from 0.30 to 0.50 equivalents with respect to compound (XV).

[0094] Step b2) preferably occurs at a temperature in the range from 20 to 70°C, preferably between 40 and 50°C.

[0095] The reaction of step b2) preferably lasts from 4 to 48 hours.

[0096] In the step c) thereof, the invention includes reacting the compound of formula (A) with a butyl lithium solution and treating the suspension obtained with isopropyl pinacol borate.

[0097] Step c) is preferably carried out using from 1 to 3 equivalents of butyl lithium, more preferably from 1.5 to 2.5 equivalents, even more preferably from 1.8 to 2.2 equivalents.

[0098] Preferably, the butyl lithium solution comprises a hydrocarbon solvent. Preferably the hydrocarbon solvent is hexane. The reaction of step c) preferably includes the addition of the isopropyl pinacol borate compound in amounts ranging from 1 to 3 equivalents, more preferably from 1.5 to 2.5 equivalents, even more preferably from 1.8 to 2.2 equivalents.

[0099] Step c) occurs in the presence of an ether solvent, preferably selected from the group consisting of tetra hydrofuran and 2-methyltetrahydrofuran. More preferably, the ether solvent is tetra hydrofuran.

[0100] Step c) is preferably carried out at a temperature in the range from -70°C to 0°C, more preferably between -60°C and -10°C, even more preferably between -50°C and -30°C.

[0101] Advantageously, step c) of borylation of the compound of formula (A) to obtain compound (B), can be carried out by direct lithiation at a temperature of -45°C; such a temperature is significantly lower and easier to manage from an industrial viewpoint with respect to a temperature of -95°C, necessary to carry out the borylation of compounds (XII) or (XIII) of the prior art, as described for example in WO9833780 and W02002032884.

[0102] In addition, the ortho assistance of the sulfonamide group is capable of guiding the direct lithiation in the ortho position (highly regioselective reaction), avoiding the presence of a halogen group in such a position to carry out the bromine / lithium exchange. This allowed using the compound (XIV) as the starting raw material, which is considerably less expensive with respect to the brominated analogue (X), resulting in advantageous and high economic savings. In step d) of the present invention, the compound of formula (B) is reacted with the compound of formula (VI) in the presence of a palladium-based species to obtain the compound of formula (C), which upon acid treatment leads to obtaining the compound (I), according to the process described in example 11 of W02010135350.

[0103] The compound of formula (VI) of step d) is prepared as described in W02010135350.

[0104] In a second aspect, the present invention relates to a process for the preparation of the compound of formula (XV) including the step of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV) In a third aspect, the present invention relates to a process for the preparation of the compound of formula (A) comprising the step of: bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A) or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A) in which PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and

[0105] -CH2OCH2CH2CH2CH3, and

[0106] R is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

[0107] In a fourth aspect, the present invention relates to a process for the preparation of the compound of formula (B), including the step of: c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B) in which PG represents a protecting group selected from the group consisting of

[0108] -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and

[0109] -CH2OCH2CH2CH2CH3. As indicated above, advantageously step c) of borylation of the compound of formula (A) to obtain the compound of formula (B), can be carried out by direct lithiation at a temperature of -45°C, significantly lower and easier to manage from an industrial viewpoint with respect to a temperature of -95°C necessary to carry out the borylation of compounds (XII) or (XIII) of the prior art.

[0110] In another aspect, the present invention relates to the compound of formula (XV) and the use of compound (XV) for the preparation of sparsentan. The compound of formula (XV) is also defined as intermediate of formula (XV).

[0111] In another aspect, the present invention relates to the compound of formula (A) in which PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and

[0112] -CH2OCH2CH2CH2CH3. and the use of the compounds of formula (A) for the preparation of sparsentan. The compounds of formula (A) also referred to as intermediates of formula (A).

[0113] EXPERIMENTAL SECTION

[0114] The invention is now shown by means of some examples to be understood for illustrative and non-limiting purposes thereof.

[0115] Abbreviations - Meaning

[0116] DMAP: N,N, dimethylaminopyridine

[0117] ACN: Acetonitrile

[0118] EtOAc: ethyl acetate

[0119] HCI: hydrochloric acid NaHCCh: sodium bicarbonate

[0120] NaCI: sodium chloride

[0121] CS2CO3: cesium carbonate

[0122] DMF: N,N, dimethylformamide

[0123] MEMCI: 2-methoxyethoxymethyl chloride

[0124] MOMCI: 2-methoxymethyl chloride

[0125] DCM: dichloromethane

[0126] CPME: cyclopentyl methyl ether

[0127] FeCI3: iron trichloride

[0128] IPAC: isopropyl acetate

[0129] K2CO3: potassium carbonate

[0130] KOtBu: potassium tert-butoxide

[0131] NaOtBu: sodium tert-butoxide

[0132] DMSO: dimethylsulfoxide

[0133] NaH: sodium hydride

[0134] THF: tetra hydrofuran

[0135] MTBE: tertbutyl methyl ether

[0136] BuLi: butyllithium

[0137] Pd (dppfjCL: Bis(diphenylphosphino)ferrocene] palladium dichloride

[0138] Na2CO3: sodium carbonate

[0139] TEA: triethyl amine

[0140] AcOH: acetic acid

[0141] HPLC analysis

[0142] For carrying out the analysis on any reaction mixture, 50 pL of said mixture was withdrawn under stirring and diluted in 2 mL of a solution consisting of 80 parts by volume of acetonitrile and 20 parts by volume of a 0.1% solution of formic acid in water.

[0143] For carrying out the analysis on each of the intermediates obtained, an aliquot of the intermediate was dissolved in a solution consisting of 80 parts by volume of acetonitrile and 20 parts by volume of a 0.1% solution of formic acid in water at a concentration of 2 mg / mL.

[0144] In both cases, the solution obtained was then analyzed according to the following methodology: IIPLC chromatograph with UV detector;

[0145] Column: Waters ACQUITY UPLC BEH C18 1.7pm, 2.1 x 50mm

[0146] Column temperature: 40°C

[0147] Eluent: Mobile phase A = Ultra-pure water + 0.1% Formic Acid; Mobile phase B =

[0148] Acetonitrile + 0.1% Formic Acid;

[0149] Gradient: from 99 / 1 to 0 : 100 A / B in 2 minutes;

[0150] Eluent Flow: 0.8 mL / min;

[0151] Injected volume 0.2 microliters;

[0152] UV detection wavelength: 210 nm.

[0153] 1H NMR

[0154] NMR spectra were recorded with a BROKER AV400 instrument using CDCI3 or CD3CN as solvent.

[0155] In many of the spectra, dimethyl sulfone was used as an analytical standard so as to provide a titer of the product obtained.

[0156] Examples

[0157] Example 1: Preparation of compound (XV)

[0158] Benzenesulfonyl chloride (XIV) (43.31 g, 245.25 mmol, 1.1 eq) was added over 120 minutes while maintaining the temperature between 0 and 10°C to a mixture of compound (IX) (25 g,

[0159] 222.95 mmol, 1.0 eq), pyridine (52.90 g, 668.86 mmol, 3.0 eq), and DMAP (1.37 g, 11.15 mmol,

[0160] 0.05 eq) in acetonitrile (300mL). At the end of the addition, the reaction mixture was stirred at 10°C for 12 hours until the disappearance of compound VII monitored by UPLC, as shown in

[0161] Figure 2. The mixture was concentrated to remove the acetonitrile present and diluted with an EtOAc / water mixture. The pH was brought to 1-1.5 by addition of concentrated HCI and the two phases were separated. The organic phase was subsequently washed with water, with a saturated solution of NaHCOs and finally with a saturated solution of NaCI. The organic phase is partially concentrated under reduced pressure until a suspension is obtained. The mixture thus obtained was cooled to 0°C and filtered to obtain 38.2 g of compound (XV) as a white solid, used in the next step without further purification (yield 68%).

[0162] 1H NMR (400 MHz, CD3CN): 1.83 (s, 3H), 2.24 (s, 3H), 7.60 (t, 2H), 7.69 (t, 1H), 7.95 (d, 2H),

[0163] 8.12 (bs, 1H).

[0164] Figure 1 shows the1H-NMR spectrum of compound (XV).

[0165] Figure 2 shows the IIPLC profile of compound (XV). Example 2: Preparation of compound (XV)

[0166] Benzenesulfonyl chloride (XIV) (3.94 g, 22.3 mmol, 1.0 eq) was added over 120 minutes maintaining the temperature between 0 and 10°C to a mixture of compound (IX) (2.5 g, 22.3 mmol, 1.0 eq), lutidine (7.16 g, 669 mmol, 3.0 eq), and DMAP (0.28 g, 2.2 mmol, 0.1 eq) in THE

[0167] (30mL). At the end of the addition, the reaction mixture was stirred at 10°C until the disappearance of compound (VII) monitored by LIPLC. The mixture was diluted with water and partially concentrated to remove the THE present. The mixture was diluted with EtOAc, the pH was brought to 1-1.5 by addition of concentrated HCI and the two phases were separated. The organic phase was subsequently washed with water, with a saturated solution of NaHCOg and finally with a saturated solution of NaCI. The organic phase is partially concentrated under reduced pressure until a suspension is obtained. The mixture thus obtained was cooled to 0°C and filtered until 3.3 g of compound (XV) were obtained as a white solid, used in the next step without further purification (yield 60%). The1H NMR spectrum is analogous to that of the product obtained in Example 1.

[0168] Example 3: Preparation of compound (XV)

[0169] Benzenesulfonyl chloride (XIV) (3.94 g, 22.3 mmol, 1.0 eq) was added over 120 minutes, keeping the temperature between 0 and 10°C, to a mixture of compound (IX) (2.5 g, 22.3 mmol, 1.0 eq), syn-collidine (8.10 g, 66.9 mmol, 3.0 eq) in acetone (30mL). At the end of the addition, the reaction mixture was stirred at 10°C until the disappearance of compound (VII) monitored by UPLC. The mixture was diluted with water and partially concentrated to remove the acetone present. The mixture was diluted with EtOAc, the pH was brought to 1-1.5 by addition of concentrated HCI and the two phases were separated. The organic phase was subsequently washed with water, with a saturated solution of NaHCOg and finally with a saturated solution of NaCI. The organic phase is partially concentrated under reduced pressure until a suspension is obtained. The mixture thus obtained was cooled to 0°C and filtered until

[0170] 2.9 g of compound (XV) were obtained as a white solid, used in the next step without further purification (yield 52%). The1H NMR spectrum is analogous to that of the product obtained in

[0171] Example 1.

[0172] Example 4: Preparation of compound (XVI)

[0173] CS2CO3 (35.64 g, 109.4 mmol, 1.38 eq) was added portion-wise to a solution of compound (XV)

[0174] (20.0 g, 79.27 mmol, 1.0 eq) in DMF (140mL) without exceeding 28°C. The mixture was stirred at 25°C for 30 minutes, then MEMCI (11.46 g, 92.02 mmol, 1.15 eq) was added over 2 hours, keeping the temperature below 30°C. At the end of the addition, the mixture was stirred at

[0175] 25°C for 4 hours. The mixture was quenched by slow addition of water, kept stirring for 20 minutes and subsequently diluted with IPAC. The two phases were separated, and the organic phase washed twice with water and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 23.0 g of compound (XVI) (yield 81%).

[0176] 1H NMR (400 MHz, CD3CI): 2.02 (s, 3H), 2.36 (s, 3H), 3.34 (s, 3H),3.48 (t, 2H), 3.77 (t, 2H), 5.08

[0177] (s, 2H), 7.53 (m, 2H), 7.61 (m, 1H), 7.87(d, 2H).

[0178] Figure 3 shows the1H-NMR spectrum of compound (XVI). The singlet at 3.0 ppm is relative to the dimethyl sulfone used as standard.

[0179] Figure 4 shows the UPLC profile of compound (XVI)

[0180] Example 5: Preparation of compound (XVI)

[0181] K2CO3 (2.56 g, 18.5 mmol, 1.5 eq) was added to a solution of compound (XV) (3.1 g, 12.3 mmol,

[0182] 1.0 eq) in DMF (25mL) without exceeding 28°C. The mixture was stirred at 25°C for 30 minutes, then MEMCI (1.78g, 14.3mmol, 1.16eq) was added over 30 minutes keeping the temperature below 30°C. At the end of the addition, the mixture was stirred at 25°C for 4 hours before being cooled to 20°C. The mixture was quenched by slow addition of water and kept stirring for 20 minutes and subsequently diluted with IPAC. The two phases were separated, and the organic phase washed twice with water and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 2.5g of compound (XVI) (yield 60%). The1H NMR spectrum is analogous to that of the product obtained in Example 4.

[0183] Example 6: Preparation of compound (XVI)

[0184] 60% NaH in mineral oil (1.33 g, 33.34 mmol, 1.2 eq) was added portion-wise to a solution of compound (XV) (7.0 g, 27.9 mmol, 1.0 eq) in DMF (70mL) without exceeding 5°C. The mixture was then heated to 20°C and stirred for 30 minutes before being cooled again to 0°C. MEMCI

[0185] (4.33g, 34.72 mmol, 1.2eq) was added over 2 hours, keeping the temperature below 5°C. At the end of the addition, the mixture was stirred at the same temperature for 2 hours and for further 2 hours at 20°C. The mixture was quenched by slow addition of water, stirred for 20 minutes and then diluted with IPAC. The two phases were separated, and the organic phase washed twice with water and finally with a saturated NaCI solution. The organic phase is concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 8.3 g of compound (XVI) (yield 88%). The1H NMR spectrum is similar to that of the product obtained in Example 4

[0186] Example 7: Preparation of compound (XVI)

[0187] K2CO3 (2.56g, 18.5mmol, 1.5eq) was added to a solution of compound (XV) (3.1g, 12.3mmol, l.Oeq) in acetone (30mL). MEMCI (1.78g, 14.3mmol, 1.16eq) was added over 10 minutes, keeping the temperature below 30°C. At the end of the addition, the mixture was heated to

[0188] 55°C and stirred at the same temperature for 24 hours before being cooled to 20°C. The mixture was quenched by slow addition of water, kept stirring for 20 minutes, partially concentrated to remove the organic solvent and finally diluted with IPAC. The two phases were separated, and the organic phase washed twice with water and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 2.0g of compound (XVI) (yield 50%). The1H NMR spectrum is analogous to that of the product obtained in Example 4.

[0189] Example 8: Preparation of compound (XVI)

[0190] 60% NaH in mineral oil (145 mg, 3.62 mmol, 1.2 eq) was added portion-wise to a solution of compound (XV) (1.0 g, 3.0 mmol, 1.0 eq) in THE (20mL) without exceeding 10°C. The mixture was then heated to 20°C and stirred for 30 minutes before being cooled again to 0°C. MEMCI

[0191] (470mg, 34.72 mmol, 1.2eq) was added over 10 min, maintaining the temperature below 5°C.

[0192] At the end of the addition, the mixture was stirred at 25°C for 6 hours. The mixture was quenched by slow addition of a saturated aqueous solution of ammonium chloride. The two phases were separated, and the organic phase washed with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 735 mg of compound (XVI) (yield 72%). The1H

[0193] NMR spectrum is analogous to that of the product obtained in Example 4.

[0194] Example 9: Preparation of compound (XVI)

[0195] KOtBu (406mg, 3.62mmol, 1.2eq) was added to a solution of compound (XV) (1.0 g, 3.0 mmol,

[0196] 1.0 eq) in THE (20mL) without exceeding 30°C. The mixture was then stirred for 30 minutes before being cooled to 0°C. MEMCI (470mg, 34.72 mmol, 1.2eq) was added over 10 min, maintaining the temperature below 5°C. At the end of the addition, the mixture was stirred at

[0197] 25°C for 6 hours. The mixture was quenched by slow addition of a saturated aqueous solution of ammonium chloride. The two phases were separated, and the organic phase washed with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 580 mg of compound (XVI) (yield 59%). The1H NMR spectrum is analogous to that of the product obtained in Example 4.

[0198] Example 10: Preparation of compound (XVI)

[0199] NaOtBu (348 mg, 3.62 mmol, 1.2 eq) was added to a solution of compound (XV) (1.0 g, 3.0 mmol, 1.0 eq) in DMSO (lOmL) without exceeding 30°C. The mixture was then stirred for 30 minutes before being cooled to 20°C. MEMCI (470mg, 34.72 mmol, 1.2eq) was added over 20 min, maintaining the temperature below 20°C. At the end of the addition, the mixture was stirred at 25°C for 6 hours. The mixture was quenched by slow addition of water, stirred for 20 minutes and then diluted with IPAC. The two phases were separated, and the organic phase washed twice with water and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure and the obtained oil purified on silica gel: eluent heptane / EtOAc 6 : 4 so as to obtain 770 mg of compound (XVI) (yield 75%). The1H NMR spectrum is analogous to that of the product obtained in Example 4.

[0200] Using 2-Methoxymethyl chloride (MOMCI), or (chloromethoxy)ethane, or 1- (chloromethoxy)propane or l-(chloromethoxy)butane instead of MEMCI, adopting the same operating conditions, it was possible to obtain compounds (XVII) or (XVIII) or (XIX) or (XX), respectively, with similar yields.

[0201] Example 11: Preparation of compound (XVII)

[0202] Methylal (CH3OCH2OCH3) (6.0mL, 68.3mmol, 8.5eq) was added, followed by P2O5 (1.0g, 7.1mmol, 0.9eq), to a solution of compound XV (2.0g, 7.93 mmol, l.Oeq) in DCM (40mL). The mixture was then heated to 38°C and stirred for 36 hours. The mixture was quenched by slow addition of an aqueous solution of K2CO3 and partially concentrated to remove the low-boiling solvents. The mixture was diluted with toluene and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 2.3 g of compound (XVII) were obtained as a yellowish oil (92% yield).

[0203] 1H NMR (400 MHz, CDCI3) 2.02 (s, 3H), 2.36 (s, 3H), 3.39 (s, 3H), 4.97 (s, 2H), 7.52 (t, 2H), 7.60 (m, 1H), 7.85 (d, 1H).

[0204] Figure 11 shows the UPLC profile of compound (XVII).

[0205] Example 12: Preparation of compound (XVII)

[0206] Methylal (CH3OCH2OCH3) (20.0 mL, 200 mmol, 10 eq) was added, followed by methanesulfonic acid (MsOH, 0.13 mL, 2.0 mmol, 1.0 eq), to a suspension of compound XV (5.0 g, 19.9 mmol, 1.0 eq) in toluene (100 mL). The mixture was then heated to 45°C and stirred for 8 hours. The mixture was quenched by slow addition of an aqueous solution of NaOH and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 4.3 g of compound (XVII) were obtained as a yellowish oil (75% yield).

[0207] The1H NMR spectrum is analogous to that of the product obtained in Example 11.

[0208] Example 13: Preparation of compound (XVII)

[0209] Methylal (CH3OCH2OCH3) (20.0 mL, 200 mmol, 10 eq) was added, followed by FeCh (1.0 g, 6.7 mmol, 0.3 eq), to a suspension of compound XV (5.0 g, 19.9 mmol, 1.0 eq) in DCM (100 mL). The mixture was stirred for 48 hours. The mixture was quenched by slow addition of an aqueous solution of NaOH and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 3.7 g of compound (XVII) were obtained as a yellowish oil (yield 55%).

[0210] The1H NMR spectrum is analogous to that of the product obtained in Example 11.

[0211] Example 14: Preparation of compound (XVIII)

[0212] Ethylal (CH3CH2OCH2OCH2CH3) (25.0 mL, 200 mmol, 10 eq) was added, followed by paratoluenesulfonic acid monohydrate (PTSA, 1.80 g, l.Ommol, 0.5 eq), to a suspension of compound XV (5.0 g, 19.9 mmol, 1.0 eq) in toluene (lOOmL). The mixture was then heated to 65°C and stirred for 8 hours. The mixture was quenched by slow addition of an aqueous solution of NaOH and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 6.0 g of a yellowish oil were obtained. The oil was crystallized with a DIPE / heptane mixture, providing 4.2 g of compound XVIII (64% yield).

[0213] 2H NMR (400 MHz, CD3CN) 1.08 (t, 3H), 1.92 (s, 3H), 2.36 (s, 3H), 3.56 (q, 2H), 5.02 (s, 2H), 7.60 (t, 2H), 7.65 (m, 1H), 7.88 (d, 1H).

[0214] Figure 12 shows the UPLC profile of compound (XVIII).

[0215] Using propylal or butylal in the ethylal place, adopting the same operating conditions, it was possible to obtain compound (XI) and compound (XX), respectively, with similar yields.

[0216] Example 15: Preparation of compound (XVIII)

[0217] Ethylal (CH3CH2OCH2OCH2CH3) (60.0 mL, 479 mmol, 7.5 eq) was added, followed by methanesulfonic acid (MsOH, 2.1 mL, 32.59 mmol, 0.5 eq), to a suspension of compound XV (16.42g, 60.9 mmol, 1.0 eq) in toluene (250 mL). The mixture was then heated to 50°C and stirred for 8 hours. The mixture was quenched by slow addition of an aqueous solution of NaOH and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 6.0 g of a yellowish oil were obtained. The oil was crystallized with a MTBE / heptane mixture, providing 14.2 g of compound XVIII (70% yield).

[0218] The1H NMR spectrum is analogous to that of the product obtained in Example 14.

[0219] Using propylal or butylal in the ethylal place, adopting the same operating conditions, it was possible to obtain compound (XI) and compound (XX), respectively, with similar yields.

[0220] Example 16: Preparation of compound (XVIII)

[0221] Ethylal (CH3CH2OCH2OCH2CH3) (44.8 mL, 357 mmol, 6.0 eq) was added, followed by methanesulfonic acid (MsOH 2.86 g, 29.8 mmol, 0.5 eq) and P2O5 (3.4 g, 24.0 mmol, 0.4 eq) to a suspension of compound XV (15.0 g, 59.46 mmol, 1.0 eq) in toluene (225 mL). The mixture was then heated to 50°C and stirred for 5 hours. The mixture was quenched by slow addition of an aqueous solution of NaOH and the two phases were separated. The organic phase was subsequently washed with water, and finally with a saturated NaCI solution. The organic phase was concentrated under reduced pressure until 6.0 g of a yellowish oil were obtained. The oil was crystallized with a CPME / heptane mixture, providing 14.2 g of compound XVIII (77% yield). The1H NMR spectrum is analogous to that of the product obtained in Example 14.

[0222] Using propylal or butylal in the ethylal place, adopting the same operating conditions, it was possible to obtain compound (XI) and compound (XX), respectively, with similar yields.

[0223] Example 17: Preparation of the compound of formula (B) in which PG is -CH2OCH2CH2OCH3 (MEM)

[0224] In a 25-mL 3-neck flask, 1.0 g of compound (XVI) (2.94 mmol, 1.0 equivalent) was dissolved in 8 mL of THE and the temperature brought to -50°C. Once the temperature was reached, a solution of 1.6M n-butyl lithium in hexane (3.7 mL, 5.88 mmol, 2.0 equivalents) was added in thirty minutes, keeping the temperature below -40°C. At the end of the addition, the mixture was stirred at the same temperature for further thirty minutes; the mixture was then quenched by the addition of isopropyl pinacol borate (1.23mL, 6.0mmol, 2.05eq). At the end of the addition, the mixture was stirred at the same temperature for sixty minutes and then brought to 0°C in 30 minutes and quenched by slowly adding a IM solution of aqueous H2SO4. At the end of the addition, the two phases were separated. The aqueous phase was counterextracted with MTBE and the two organic phases were combined. The obtained organic phase was washed with a saturated NaCI solution and concentrated under reduced pressure. Compound (IV) was obtained as an oil used in the next step, without further purification.

[0225] 1H NMR (400 MHz, CD3CI): 1.38 (s, 12H), 1.94 (s, 3H), 2.34 (s, 3H), 3.33 (s, 3H), 3.51 (t, 2H), 3.82 (5.14, s, 2H), 7.49 (m, 3H), 7.72 (d, 1H).

[0226] Figure 5 shows the1H-NMR spectrum of compound (IV) contaminated by 5% of unreacted compound (XVI).

[0227] Figure 6 shows the UPLC profile of the compound of formula (B) in which PG is -CH2OCH2CH2OCH3 (MEM).

[0228] Using the other compounds of formula (A), adopting the same operating conditions it was possible to obtain the respective compounds of formula (B) with similar yields.

[0229] Example 18: Preparation of the compound of formula (C) in which PG is -CH2OCH2CH2OCH3 (MEM).

[0230] The compound of formula (VI) (1.5 g, 3.55 mmol, 1.18 equivalents) prepared according to the process described in patent application W02010135350, Na2CO3 (969mg, 3.0eq) and Pd(dppf)CI2 (78 mg, 0.04 eq) were weighed in a 100 mL flask. The flask was placed under nitrogen flow and subjected to vacuum / nitrogen cycles to make the reaction environment inert. Simultaneously, a solution of the compound of formula (B) in which PG is -CH2OCH2CH2OCH3 (MEM), previously obtained (2.94 mmol theoretical, 1.0 eq) in 30mL of toluene was prepared.

[0231] Such a solution was stirred and degassed and / or vacuum / nitrogen cycled to make the prepared solution inert. The solution was added to the previously weighed solids followed by lOmL of water, also previously degassed.

[0232] The mixture was stirred at 75°C for 16 hours after which the reaction mixture was cooled to 20 to 30°C and diluted with water and EtOAc. The two phases were separated and the organic phase containing the product washed with a saturated solution of NaHCCh, with water and finally with a saturated solution of NaCI. The organic phase was finally concentrated under reduced pressure and the obtained oil purified by chromatography using hepta ne / EtOAc / TEA as eluent mixture to generate 1.10 g of compound (VII) (yield 55% over two steps).

[0233] 1H NMR (400 MHz, CD3CI): 0.90 (t, 3H), 1.11 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 1.84 - 2,00 (m, 11H), 2.29 (s, 3H), 2.37 (t, 2H), 3.30 - 3.50 (m, 7H), 3,62 (m, 1H), 3.72 (m, 1H), 4.15 (d, 1H), 4.35 (m, 2H), 4.46 (d, 1H), 4.75 (s, 2H), 7.06 (d, 1H), 7.20 - 7.30 (m, 2H), 7.38 (s, 1H), 7.45 (t,

[0234] 1H), 7.57 (t, 1H), 8.00 (d, 1H).

[0235] Figure 1 shows the 1H-NMR spectrum of the compound of formula (C) in which PG is

[0236] -CH2OCH2CH2OCH3 (MEM).

[0237] Figure 8 shows the UPLC profile of the compound of formula (C) in which PG is

[0238] -CH2OCH2CH2OCH3 (MEM). Using the other compounds of formula (B), adopting the same operating conditions it was possible to obtain the respective compounds of formula (C) with similar yields.

[0239] Example 19: Preparation of compound (I)

[0240] 10 g of a 20% by weight aqueous solution of hydrochloric acid are added to a solution of the compound of formula (C) in which PG is -CH2OCH2CH2OCH3 (MEM) (680 mg, 1.0 mmol, 1 eq) in lOmL of EtOH. The resulting solution was heated to 70°C and stirred for 4 hours until complete conversion observed via UPLC. The reaction mixture was cooled to 25°C and the pH neutralized by the addition of a 30% by weight aqueous solution of NaOH. The mixture was then partially concentrated to remove residual ethanol and extracted with EtOAc. The organic phase was re-extracted with additional EtOAc and the combined organic phases washed with a saturated aqueous NaCI solution. The organic phases were finally concentrated, and the crude obtained purified on silica gel: eluent heptane / EtOAc / AcOH so as to obtain 470 mg of compound (I) as amorphous solid (yield 80%).

[0241] TH NMR (400 MHz, CD3CI): 0.91 (t, 3H), 1.07 (t, 3H), 1.41 (m, 2H), 1.63 (m, 2H), 1.71 (m, 1H),

[0242] 1.80 (s, 3H), 1.85 (m, 1H), 2.01 (m, 6H), 2.27 (s, 3H), 2.39 (t, 2H), 3.37 (m, 2H), 4.17 (d, 1H),

[0243] 4.27 (d, 1H), 4.76 (s, 2H), 6.78 (bs, 1H), 7.09 (d, 1H), 7.27 (m, 2H), 7.37 (s, 1H), 7.52 (t, 1H), 7.61

[0244] (t, 1H), 8.05 (d, 1H).

[0245] Figure 5 shows the1H-NMR spectrum of compound (I).

[0246] Figure 10 shows the UPLC profile of compound (I).

[0247] Compound (I) was obtained in an analogous manner using the other compounds of formula

[0248] (C).

Claims

CLAIMS1. A process for the preparation of sparsentan, including the steps of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV)bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A)or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A)c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B)d) reacting the compound of formula (B) with the compound of formula (VI) in the presence of a palladium-based species to obtain the compound of formula (C)e) treating the compound of formula (C) with HCI, water and ethanol to obtain the compound(I)(C) wherein PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3, andR is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

2. A process according to claim 1, wherein step a) is carried out using from 0.9 to 1.5 equivalents of the compound of formula (XIV), preferably from 1.0 to 1.3 equivalents, more preferably from 1.03 to 1.18 equivalents.

3. A process according to any one of claims 1 and 2, wherein the organic solvent of step a) is selected from the group consisting of acetonitrile, acetone, THE, 2-methyltetrahydrofuran, ethyl acetate and a combination thereof.

4. A process according to anyone of claims 1 to 3, wherein the base of step a) is a tertiary amine selected from the group consisting of pyridine, lutidine and collidine.

5. A process according to anyone of claims 1 to 4, wherein the catalyst of step a) is N,N dimethylamino pyridine (DMAP).

6. A process of any one of claims 1 to 5, wherein step bl) is carried out using from 1.0 to 2.0 equivalents of the compound PG-CI, preferably from 1.05 to 1.25 equivalents.

7. A process according to claim 6, wherein the PG-CI compound is selected from the group consisting of 2-Methoxyethoxymethyl chloride (MEMCI), 2-Methoxymethyl chloride (MOMCI),(chloromethoxy)ethane, l-(chloromethoxy)propane, l-(chloromethoxy)butane.

8. A process according to any one of claims 1 to 7, wherein the organic solvent of step bl) is selected from the group consisting of acetonitrile, acetone, THF, 2-methyl tetra hydrofuran, DMF and DMSO.

9. A process according to any one of claims 1 to 8, wherein the base of step bl) is selected from the group consisting of sodium hydride, tert-butylate of Li, Na, K, carbonate of Li, Na, K, Cs.

10. A process according to any one of claims 1 to 5, wherein step b2) is carried out using from 1.00 to 10.00 equivalents of the compound RO-PG with respect to the compound XV, preferably from 3.00 to 7.00 equivalents.

11. A process according to claim 10, wherein the acid of step b2) is selected from the group consisting of iron trichloride, sulfuric acid, para-toluenesulfonic acid, methanesulfonic acid.

12. A process according to claims 10 and 11, wherein the solvent of step b2) is selected from the group consisting of dichloromethane, dichloroethane, cyclopentyl methyl ether, toluene, xylene, preferably toluene.

13. A process according to any one of claims 1 to 12, wherein step c) is carried out using from1 to 3 equivalents of butyl lithium, preferably from 1.5 to 2.5 equivalents, more preferably from 1.8 to 2.2 equivalents.

14. A process according to any one of claims 1 to 13, wherein isopropyl pinacol borate compound in step c) is added in an amount from 1 to 3 equivalents, preferably from 1.5 to 2.5 equivalents, more preferably from 1.8 to 2.2 equivalents.

15. A process according to any one of claims 1 to 14, wherein the ether solvent of step c) is selected from the group consisting of ted ra hydrofuran and 2-methyl tetra hydrofuran.

16. A process according to any one of claims 1 to 15, wherein step c) occurs at a temperature in the range from -70°C to 0°C, preferably from -60°C to -10°C, more preferably from -50°C to -30°C.

17. A process for the preparation of the compound of formula (XV), comprising the step of: a) reacting the compound of formula (IX) with the compound (XIV), in the presence of a base and optionally a catalyst to obtain the compound of formula (XV)18. A process for the preparation of the compound of formula (A), comprising the step of: bl) reacting the compound of formula (XV) with the compound PG-CI in the presence of a base to obtain the compound of formula (A)or alternatively b2) reacting the compound of formula (XV) with the compound RO-PG in the presence of P2O5 and / or an acid to obtain the compound of formula (A)wherein PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and-CH2OCH2CH2CH2CH3, andR is selected from the group consisting of -CH2CH2OCH3, methyl, ethyl, propyl and butyl.

19. A process for the preparation of the compound of formula (B), comprising the step of: c) reacting the compound of formula (A) with a butyl lithium solution and treating the obtained suspension with isopropyl pinacol borate to obtain the compound of formula (B)wherein PG represents a protecting group selected from the group consisting of-CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3,-CH2OCH2CH2CH2CH3.

20. A compound of formula (XV)21. A compound of formula (A)wherein PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, and -CH2OCH2CH2CH2CH3.

22. Use of the compound (XV) for the preparation of sparsentan23. Use of the compounds of formula (A) for the preparation of sparsentanwherein PG represents a protecting group selected from the group consisting of -CH2OCH2CH2OCH3 (MEM), -CH2OCH3 (MOM), -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2OCH2CH2CH2CH3.

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