Method for preparing a PDE4 inhibitor

Abstract

The present invention relates to a method for preparing a compound having phosphodiesterase (PDE4) inhibitory activity of formula (I). The present invention also relates to a method for separation by crystallization of compound (I) and its use in combination with a suitable carrier or vehicle for the preparation of a pharmaceutical composition for inhalation. The present invention also relates to solvates and crystal forms of the compound of formula (I). The synthetic product is suitable for pharmaceutical use, for example for the treatment of respiratory diseases.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of October 17, 2014, an application number of 201910622800.X, and an invention title of "Method for Preparing PDE4 Inhibitors". Technical Field

[0002] The present invention relates to a method for preparing a compound having phosphodiesterase (PDE4) inhibitory activity of formula (I). The present invention also relates to a method for separation by crystallization of compound (I) and its use in combination with a suitable carrier or vehicle for preparing a pharmaceutical composition for inhalation. The present invention also relates to solvates and crystal forms of the compound of formula (I). The synthesized product is suitable for pharmaceutical use, for example, for treating respiratory diseases. Background Art

[0003] The compound of formula (I) obtained according to the present invention, wherein n is 0 or 1

[0004]

[0005] Having the chemical names (S)-3-cyclopropylmethoxy-4-methylsulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethyl ester and (S)-3-cyclopropylmethoxy-4-methylsulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyridin-4-yl)-ethyl ester can be used for prophylactic purposes or for symptom relief of a wide range of conditions, including respiratory disorders such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), all types of asthma, and allergic disease states such as atopic dermatitis and allergic rhinitis.

[0006] The compound is disclosed in WO 2010 / 089107 as an effective PDE4 inhibitor with excellent LPDE4 selectivity.

[0007] WO 2010 / 089107 also discloses a method for preparing the compound of formula (I) (wherein n is 0 or 1) and its analogs. Summary of the Invention

[0008] The present invention relates to a method for preparing a compound of formula (I).

[0009] Specifically, the present invention relates to a method for preparing a compound of formula (I), wherein n is 0 or 1, and the chiral carbon atom marked with an asterisk in the following formula shows the (S) configuration.

[0010]

[0011] The compounds are therapeutically useful because their action as PDE4 inhibitors allows pharmaceutical compositions containing them to be used for the prevention and treatment of respiratory diseases such as COPD (chronic bronchitis and emphysema), asthma, allergic rhinitis and atopic dermatitis; allergic disease states, inflammatory arthritis; Crohn's disease; myocardial and cerebral reperfusion injury; cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, fever, diabetes, pneumoconiosis, toxic and allergic contact eczema; systemic lupus erythematosus, follicular and extensive pustular dermatosis, endogenous and exogenous acne, rosacea, Beghet's disease, allergic purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases; neurological and psychiatric disorders; stroke and spinal cord injury.

[0012] The present invention relates to a particularly effective method for preparing the compounds of formula (I), which is an alternative to the methods disclosed in the prior art documents cited above.

[0013] The method is particularly advantageous compared to known methods because it provides simpler and safer operations, with improved control over process parameters and reproducibility, reduced numbers of synthetic steps and intermediate separations, higher atom efficiency, reduced solvent amounts, higher product formation yields and reduced impurities.

[0014] The method is also particularly suitable for industrial-scale preparation.

[0015] The method according to the invention can give a thermodynamically stable crystalline form of the compound of formula (I) (where n is 1), which will hereinafter be referred to as Form A, which is characterized by a high level of chemical purity and crystallinity and good handling properties for pharmaceutical use.

[0016] According to the part detailed below, by using appropriate solvents and operating conditions for crystallization, the crystalline form A of the present invention can be selectively produced, giving it characteristic peaks and a melting point range in its X-ray powder diffraction (XRPD) pattern.

[0017] Therefore, the present invention also relates to a method for preparing said Form A, said method comprising crystallization or recrystallization under selected conditions.

[0018] Since said crystalline form A can be used for prophylactic or therapeutic purposes, the present invention also includes the use of crystalline form A of the compound of formula (I) (where n is 1) in the preparation of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0019] In another aspect, the present invention includes a method for preventing and / or treating an inflammatory or obstructive respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD), the method comprising inhaled administration of an effective amount of polymorph A.

[0020] By manipulation with a suitable solvent, solvates of the compound of formula (I) in which n is 1 are also obtained.

[0021] Accordingly, the present invention also relates to a method for preparing said solvates.

[0022] Specifically, the solvate of the compound of formula (I) is obtained from ethanol and can be identified based on its characteristic peaks in an X-ray powder diffraction (XRPD) pattern and its characteristic melting point range.

[0023] Definitions

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs.

[0025] The term 'high level of chemical purity' refers to a polymorph in which the total amount of readily detectable impurities determined by standard analytical methods such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) is less than 5%, preferably less than 2.5%, even less than 1.0, or more preferably even less than 0.5% w / w.

[0026] The term "high level of crystallinity" refers to a polymorph in which the percentage of crystallinity determined by standard analytical methods such as X-ray powder diffraction or microcalorimetry is equal to or higher than 90%, preferably higher than 95% w / w. Brief Description of the Drawings

[0027] Figure 1 is a differential scanning calorimetry (DSC) thermogram of the ethanol solvate of the compound of formula (I) in which n is 1.

[0028] Figure 2 is a Raman spectrum of the ethanol solvate of the compound of formula (I) in which n is 1.

[0029] Figure 3 is an XRPD pattern of the ethanol solvate of the compound of formula (I) in which n is 1.

[0030] Figure 4 is a differential scanning calorimetry (DSC) thermogram of polymorph A from ethyl acetate / n-heptane.

[0031] Figure 5 is a Raman spectrum of polymorph A from ethyl acetate / n-heptane.

[0032] Figure 6 is the XRPD pattern of crystalline form A from ethyl acetate / n - heptane, which was recorded on a Bruker D8 Advance with an X - ray diffraction tube model KFL Cu 2k.

[0033] Figure 7 is the XRPD pattern of crystalline form A from isopropyl acetate. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention provides a method for preparing a compound of formula (I) (wherein n is 0 or 1),

[0036]

[0037] The method comprises:

[0038] a) reacting a compound of formula (II)

[0039]

[0040] wherein n is 0 or 1, with a compound of formula (III)

[0041]

[0042] wherein X is selected from - NHSO2Me and - NO2, and Z is selected from - OH, chlorine, bromine, straight - chain or branched (C1 - C6) alkoxy, aryloxy, arylalkoxy, (C1 - C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1 - C6) alkylcarbonyloxy, to obtain a compound of formula (I) (wherein n is 0 or 1) or a compound of formula (IV)

[0043]

[0044] wherein n has the meaning reported above; and, when a compound of formula (IV) is obtained in step (a):

[0045] b) reducing it to the corresponding compound of formula (V)

[0046]

[0047] wherein n is 0 or 1 and reacting it with a mesyl halide to obtain a compound of formula (I), wherein n has the meaning reported above;

[0048] and wherein the compound of formula (II) in step (a) is obtained as follows according to any one of alternative steps (c1) or (c2) or (c3):

[0049] c1) oxidizing a compound of formula (VI)

[0050]

[0051] where n is 0 or 1 to obtain the compound of formula (VII)

[0052]

[0053] where n is 0 or 1, and subsequently enantioselectively reducing it to obtain the compound of formula (II), where n has the meaning reported above; or

[0054] c2) separating the compound of formula (VI), where n is 0 or 1, by chromatography to obtain the compound of formula (II) and the compound of formula (VIII)

[0055]

[0056] where n has the meaning reported above;

[0057] and optionally oxidizing the compound of formula (VIII) obtained in step (c2) to the corresponding compound of formula (VII), which is subsequently reduced to the compound of formula (VI) (where n is 0 or 1) and reprocessed in the following chromatographic separation method; or

[0058] c3) reacting the intermediate of formula B''

[0059]

[0060] with the intermediate of formula D

[0061]

[0062] where R is a straight-chain or branched (C1-C6) alkyl or arylalkyl and n has the meaning reported above, to directly obtain the compound of formula (VII) and subsequently enantioselectively reducing it to obtain the compound of formula (II), where n has the meaning reported above;

[0063] and wherein all compounds of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) (where n is 1) can be obtained by oxidizing the corresponding compound (where n is 0).

[0064] In the present specification, and unless otherwise provided, the bond with the symbol in formula (VI) indicates a racemic mixture of the two enantiomers (R) and (S).

[0065] The bond with the symbol in formulas (I) and (II) indicates the enantiomer (S), while the bond with the symbol in formula (VIII) The key indicates the enantiomer (R).

[0066] The term straight-chain or branched (C1-C6) alkyl represents a straight-chain or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0067] The term (C1-C6) arylalkyl represents a (C1-C6) alkyl group further substituted by an aryl group.

[0068] The term straight-chain or branched (C1-C6) alkoxy refers to any alkyl-oxy chain, where the alkyl represents a straight-chain or branched alkyl group having 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc., preferably methoxy.

[0069] The term aryloxy refers to any aryl group connected to the rest of the molecule through an oxygen atom, i.e., the aryl-O- group. Within this scope, and unless otherwise provided, the aryl represents an aromatic carbocyclic or aromatic heterocyclic ring, such as a 5- or 6-membered ring containing 1-3 heteroatoms or heteroatom groups selected from N, NH, O, or S. Phenoxy is preferred.

[0070] The term arylalkoxy refers to any (C1-C6) alkoxy group substituted by one or more aryl groups as defined above. Benzyloxy is preferred.

[0071] The term arylalkylcarbonyloxy refers to any (C1-C6) alkylcarbonyloxy group substituted by one or more aryl groups as defined above, preferably benzylcarbonyloxy.

[0072] When representing methanesulfonyl halide in step (b) of the method of the present invention, the term halide refers to chloride and bromide.

[0073] In a preferred embodiment, the present invention provides a method for preparing a compound of formula (I) (where n is 0 or 1), the method comprising, in step (a), reacting a compound of formula (II) (where n has the meaning reported above) with a compound of formula (III) (where X is NHSO2Me and Z has the meaning reported above).

[0074] According to an alternative preferred embodiment, the present invention provides a method for preparing a compound of formula (I) (where n is 0 or 1), the method comprising, in step (a), reacting a compound of formula (II) (where n has the meaning reported above) with a compound of formula (III) (where X is -NO2 and Z has the meaning reported above).

[0075] According to a further preferred embodiment, the present invention provides a process for preparing a compound of formula (I) wherein n is 0 or 1, said process comprising reacting the compound of formula (II) obtained according to step (c1): oxidizing the compound of formula (VI) to a compound of formula (VII), and enantioselectively reducing the latter compound to a compound of formula (II), wherein n has the meaning reported above.

[0076] According to a further preferred embodiment, the present invention provides a process for preparing a compound of formula (I) wherein n is 0 or 1, said process comprising reacting the compound of formula (II) obtained according to step (c2): chromatographically separating the compound of formula (VI) to obtain a compound of formula (II) and a compound of formula (VIII), wherein n has the meaning reported above.

[0077] Even more preferably, according to the latter embodiment, the present invention provides a process for preparing a compound of formula (I) wherein n is 0 or 1, said process comprising reacting the compound of formula (II) obtained according to step (c2): chromatographically separating the compound of formula (VI) to obtain a compound of formula (II) and a compound of formula (VIII), wherein n has the meaning reported above, and then oxidizing the compound of formula (VIII) to the corresponding compound of formula (VII), which is subsequently reduced to a compound of formula (VI) that can be recycled in another chromatographic separation.

[0078] According to a further preferred embodiment, the present invention provides a process for preparing a compound of formula (I) wherein n is 0 or 1, said process comprising reacting the compound of formula (II) obtained according to step (c3): reacting the intermediate of formula B”

[0079]

[0080] with the intermediate of formula D

[0081]

[0082] to directly obtain the compound of formula (VII) and subsequently enantioselectively reducing it to obtain the compound of formula (II), wherein n has the meaning reported above.

[0083] According to another preferred embodiment, the present invention provides a process for preparing a compound of formula (I) wherein n is 1, said process comprising oxidizing the compound of formula (I) wherein n is 0.

[0084] Alternatively, the present invention provides a method for preparing a compound of formula (I) (wherein n is 1) starting from a compound of formula (II) (wherein n is 1), said compound of formula (II) being obtained by oxidizing the corresponding compound of formula (II) (wherein n is 0).

[0085] Alternatively, the present invention provides a method for preparing a compound of formula (I) (wherein n is 1) starting from a compound of formula (IV) (wherein n is 1), said compound of formula (IV) being obtained by oxidizing the corresponding compound of formula (IV) (wherein n is 0).

[0086] Alternatively, the present invention provides a method for preparing a compound of formula (I) (wherein n is 1) starting from a compound of formula (V) (wherein n is 1), said compound of formula (V) being obtained by oxidizing the corresponding compound of formula (V) (wherein n is 0).

[0087] Alternatively, the present invention provides a method for preparing a compound of formula (I) (wherein n is 1) starting from a compound of formula (VI) (wherein n is 1), said compound of formula (VI) being obtained by oxidizing the corresponding compound of formula (VI) (wherein n is 0).

[0088] Alternatively, the present invention provides a method for preparing a compound of formula (I) (wherein n is 1) starting from a compound of formula (VII) (wherein n is 1), said compound of formula (VII) being obtained by oxidizing the corresponding compound of formula (VII) (wherein n is 0).

[0089] According to step (a) of the present invention, the method provides for the preparation of a compound of formula (I) or a compound of formula (IV) by reacting a compound of formula (II) with a compound of formula (III) (wherein n, X and Z have the meanings reported above).

[0090] More specifically, when using a compound of formula (III) (where Z is -OH), in the presence of a coupling agent selected from DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, EDCI, with or without HOBt, with or without an organic base such as TEA, DIPEA, NMM, DBU, DBO, pyridine and DMAP, in a solvent selected from dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, the reaction is carried out.

[0091] When the compound of formula (III) is an acyl chloride or acyl bromide, or an activated ester and mixed anhydride, the reaction is carried out as described above in the absence of a coupling agent.

[0092] Preferably, the above reaction with the compound of formula (III) wherein X is -NHSO2Me is carried out in ethyl acetate with CDI and DBU.

[0093] In an alternative preferred embodiment, when carrying out the reaction with the compound of formula (III) wherein X is -NO2 to produce the compound of formula (IV), the above reaction is carried out in DMF with EDCI and DMAP.

[0094] According to step (b) of the method, in order to optionally start from the compound of formula (III) wherein X is -NO2 in step (a), the compound of formula (IV) wherein n has the meaning reported above is first reduced to the corresponding amino derivative of formula (V), and then appropriately reacted with methanesulfonyl halide to obtain the compound of formula (I).

[0095] Preferably, the reduction step is carried out with a reducing agent selected from hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, stannous chloride, tin, nickel chloride, nickel, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and sodium dithionite.

[0096] In a more preferred embodiment, when carrying out the reaction with hydrogen, cyclohexadiene, ammonium formate and formic acid, then the reaction is carried out in the presence of a catalyst selected from palladium-based, platinum-based or nickel-based catalysts, or it is selected from palladium on carbon, palladium on barium sulfate and palladium on calcium carbonate.

[0097] In an even more preferred embodiment, when using formic acid, the reaction is carried out in the presence of ammonia or an amine, preferably triethylamine.

[0098] Suitable solvents for the above reduction step are selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, THF, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile and mixtures thereof.

[0099] More preferably, the reaction is carried out with palladium on carbon and hydrogen in ethyl acetate.

[0100] Subsequently, the reaction of the compound of formula (V) with methanesulfonyl halide is carried out in the presence of a suitable solvent (such as toluene, benzene, xylene, tetrahydrofuran, di It is carried out in the presence of an alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene and their mixtures) and a base, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBO (1,4-diazabicyclo[2.2.2]octane), pyridine and DMAP (4-dimethylaminopyridine); in the case of excessive use of pyridine, other solvents can be avoided.

[0101] Preferably, the reaction is carried out with triethylamine in dichloromethane.

[0102] According to step (c1) for preparing the compound of formula (II), the compound of formula (VI) is first oxidized to the corresponding ketone derivative of formula (VII), and then enantioselectively reduced to the compound of formula (II).

[0103] Preferably in the presence of an oxidizing agent (selected from metal oxides such as MnO2, hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, DMSO-based oxidizing agent (Swern) such as sulfur trioxide pyridine complex) in a solvent (selected from water, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, THF, di alkane and their mixtures) for oxidation.

[0104] Even more preferably, the reaction is carried out with MnO2 in toluene or with the Swern oxidizing agent in DMSO.

[0105] As described in WO 2010 / 089107, the intermediate of formula B

[0106]

[0107] and the intermediate of formula D (where n = 0)

[0108]

[0109] are used to prepare the compound of formula (VI).

[0110] According to step (c3) for preparing the compound of formula (II), the intermediate of formula B' is as follows

[0111]

[0112] Intermediate for "converted to Formula B"

[0113]

[0114] In methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, with or without other solvents, react with thionyl chloride, hydrochloric acid, sulfuric acid; or in the presence of a suitable solvent (such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di alkane, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof) and a base with the relevant alkyl halide, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), pyridine.

[0115] More preferably, the above reaction is carried out with potassium carbonate in dimethylformamide or dimethylacetamide.

[0116] By reacting in the presence of a suitable solvent such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di alkane, 2-methoxyethyl ether, isopropyl acetate, acetonitrile, and mixtures thereof, using an oxidizing agent selected from hydrogen peroxide, organic peracids such as peracetic acid or m-chloroperbenzoic acid or inorganic peracids such as persulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4) to oxidize Intermediate B, Intermediate B' can be obtained. More preferably, use to carry out the above reaction in methanol.

[0117] Alternatively, Intermediate B" can be directly prepared from Intermediate B by oxidation in the corresponding alkyl alcohol as the solvent using oxidation.

[0118] Alternatively, Intermediate B" can be prepared as follows: carry out a Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as the solvent to convert Intermediate C' to Intermediate C",

[0119]

[0120] subsequently in the presence of a suitable solvent (such as toluene, benzene, xylene, tetrahydrofuran, di The cyclopropyl bromide is alkylated in the presence of an alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof) and a base, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBO (1,4-diazabicyclo[2.2.2]octane), pyridine, and DMAP (4-dimethylaminopyridine).

[0121] The intermediate B" is then converted to the corresponding ketone derivative of formula (VII) as follows: in the presence of a suitable solvent such as toluene, benzene, xylene, tetrahydrofuran, methyl-tetrahydrofuran, di alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, and mixtures thereof, in the presence of a base, and reacted with intermediate D, and the base is preferably selected from lithium diisopropylamide (LDA), butyllithium, hexyllithium, pentyllithium, lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide, and potassium tert-butoxide.

[0122] More preferably, the above reaction is carried out with LHMDS in THF.

[0123] The subsequent enantioselective reduction step is preferably carried out with a reducing agent selected from hydrogen in the presence of a preformed or in-situ formed heavy metal chiral complex. In-situ formation can occur as follows: reacting a Ru-, Rh-, or Ir-complex such as RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCI2(Cp*)]2, or [IrCI2(Cp*)]2 with a chiral ligand such as SL-N004-1 ((S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl] oxazoline), SL-N003-1 ((R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl] oxazoline), (S,S)-Ts-DPEN ((1S,2S)-(-)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine), (S,S)-Ms-DPEN ((1S,2S)-(-)-N-methanesulfonyl-1,2-diphenylethylenediamine), (R)-DAIPEN ((2R)-(-)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), (1R,2S)-1-amino-2-indanol.

[0124] The above reduction reaction is preferably carried out in the presence of a base, and the base is preferably selected from sodium hydroxide, sodium carbonate, C1-C4 sodium alkoxide, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C1-C4 potassium alkoxide, potassium bicarbonate, lithium hydroxide, lithium carbonate, C1-C4 lithium alkoxide, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, pyridine and 4-dimethylaminopyridine.

[0125] In an even more preferred embodiment, the reaction is carried out in toluene and in the presence of an aqueous sodium hydroxide solution with a complex formed in situ by reacting RuCl2(PPh3)3 with the chiral ligand SL-N004-1.

[0126] Alternatively, the compounds of formula (II) and (VIII) can be separated by preparative chiral chromatography; batch operation can be employed: the chiral column is loaded several times with a solution of the racemate (VI), and the elution fractions of the separated enantiomers are collected. Simulated moving bed (SMB) operation should be considered for separating large amounts of material.

[0127] Advantageously, according to an alternative embodiment of the method of the present invention, once the compounds of formula (II) and (VIII) have been separated by preparative chiral HPLC techniques, the compound of formula (VIII) can be conveniently reconverted into the compound of formula (VI) as follows: oxidized to the corresponding derivative of formula (VII), and then reduced and reprocessed in the following chromatographic separation methods as reported previously.

[0128] The reduction can be carried out with lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride in solvents such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, THF, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof.

[0129] It should be understood that by oxidizing with an oxidizing agent selected from hydrogen peroxide, organic peracids such as peracetic acid or m-chloroperbenzoic acid or inorganic peracids such as peroxysulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4) in a solvent selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di (KHSO5*1 / 2KHSO4*1 / 2K2SO4), all the compounds of the present invention (where n is 0) can be converted into the corresponding compounds (where n is 1).

[0130] More preferably, the above reaction is carried out with This is accomplished on (I) or on (II) wherein n is 0 in water and methanol.

[0131] It is obvious from all the above that when preparing compounds of formula (I) according to any one of the aforementioned process variants, optional functional groups in the starting materials or their intermediates that may produce undesirable side reactions need to be appropriately protected according to conventional techniques. Likewise, the conversion of these protected compounds to free deprotected compounds can be carried out according to known operations.

[0132] The intermediate compounds of formula (IV) and (V) (and wherein n is 0 or 1) are novel and therefore represent another object of the present invention.

[0133]

[0134] The compounds of formula (VI) as starting materials for the present process are known or can be prepared according to known methods.

[0135] As an example, compounds of formula (VI) and their preparation are disclosed in WO 2010 / 089107.

[0136] Compounds of formula (III) wherein X is -NHSO2Me and Z is -OH represent another object of the present invention.

[0137] Other starting materials of formula (III) are known or readily prepared according to known methods.

[0138] As another example, compounds of formula (III) wherein X is -NHSO2Me can be prepared from the corresponding derivatives wherein X is -NO2 by reducing said derivatives to the amino derivatives and subsequently reacting them with methanesulfonyl halide, essentially as reported previously.

[0139] Likewise, the preparation of compounds of formula (III) wherein Z is -OH can be obtained by conventional hydrolysis of the corresponding ester derivatives.

[0140] In this regard, the hydrolysis reaction (e.g., occurring on a compound of formula (III) wherein Z is methoxy) can be readily carried out in the presence of a suitable base selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate; the solvent being selected from water alone or in admixture with methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, dimethicone, methyl ether ... Alkanes and mixtures thereof.

[0141] More preferably, the hydrolysis of the ester to the free acid (wherein Z is -OH) is carried out with NaOH in THF and water.

[0142] Similarly, the compounds of formula (III) in which Z is not -OH can be prepared according to well-known esterification or transesterification techniques or starting from the relevant esters of 3-hydroxy-4-nitrobenzoic acid.

[0143] The present invention also provides a process for preparing further compounds of formula (IX) which carry additional R1 and R2 groups at the positions of the cyclopropylmethyl and difluoromethyl groups of formula (I) relative to the above compounds of formula (I).

[0144] The compounds of formula (IX) can be used for prophylactic purposes or for the relief of symptoms of a wide range of disorders including respiratory disorders such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), all types of asthma and allergic disease states such as atopic dermatitis and allergic rhinitis.

[0145] Accordingly, the present invention also provides a process for preparing a compound of formula (XI)

[0146]

[0147] wherein n is 0 or 1;

[0148] and R1 and R2 are independently selected from H, straight-chain or branched (C1-C6) alkyl, said (C1-C6) alkyl being optionally substituted by one or more substituents selected from halogen atoms, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, straight-chain or branched (C2-C6) alkenyl, aryl(C2-C6) alkenyl and straight-chain or branched (C2-C6) alkynyl, the process comprising:

[0149] a) reacting a compound of formula (X)

[0150]

[0151] wherein n is 0 or 1, with a compound of formula (III)

[0152]

[0153] wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6) alkylcarbonyloxy, to obtain a compound of formula (XI) (wherein n is 0 or 1) or a compound of formula (XII)

[0154]

[0155] wherein R1, R2 and n have the meanings reported above; and, when obtaining the compound of formula (XII) in step (a):

[0156] b) reducing it to the corresponding compound of formula (XIII)

[0157]

[0158] wherein R1, R2 and n have the meanings reported above and reacting it with a mesyl halide to obtain a compound of formula (XI), wherein n has the meaning reported above;

[0159] and wherein the compound of formula (X) in step (a) is obtained as follows according to either alternative step (c1) or (c2):

[0160] c1) oxidizing the compound of formula (XIV)

[0161]

[0162] wherein n is 0 or 1 to obtain a compound of formula (XV)

[0163]

[0164] wherein n is 0 or 1 and subsequently enantioselectively reducing it to obtain a compound of formula (X), wherein n has the meaning reported above; or

[0165] c2) chromatographically separating the compound of formula (XIV), wherein n is 0 or 1, to obtain a compound of formula (X) and a compound of formula (XVI)

[0166]

[0167] wherein n has the meaning reported above;

[0168] and optionally oxidizing the compound of formula (XVI) obtained in step (c2) to the corresponding compound of formula (XV), which is subsequently reduced to the compound of formula (XIV) (wherein n is 0 or 1) and reprocessed in the following chromatographic separation method;

[0169] and wherein all compounds of formula (XI), (X), (XII), (XIII), (XIV), (XV) or (XVI) wherein n is 1 can be obtained by oxidizing the corresponding compound wherein n is 0.

[0170] From all of the above it is evident that the operating conditions of the foregoing steps of the process useful for preparing the compound of formula (I) can equally be applied to the preparation of the compound of formula (XI).

[0171] The intermediate compounds of formula (XII) and (XIII) (wherein n is 0 or 1) are new and thus represent another object of the present invention

[0172]

[0173] The starting materials of formula (X) are known or can be readily prepared according to known methods.

[0174] In another even more preferred embodiment, when obtaining compound (I) (where n is 0 or 1), it can be purified by crystallization or trituration from one or more solvents, preferably selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, aliphatic or aromatic hydrocarbons, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or mixtures thereof.

[0175] The reaction is preferably carried out in ethyl acetate with n-heptane.

[0176] In another preferred embodiment, the present invention relates to a method of separation by crystallization of compound (I) and to its use in combination with a suitable carrier or vehicle for the preparation of a pharmaceutical composition for inhalation.

[0177] In another preferred embodiment, the present invention relates to a method for preparing polymorph A from ethyl acetate and n-heptane, characterized by the following characteristic XRPD peaks: 7.48; 7.93; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 18.08; 18.53; 18.94; 8.55; 17.79; 19.89; 19.1; 20.2; 21.37; 22.96; 23.63; 24.87; 26.51; 28.09; 28.61 and 25.82 ± 0.2 degrees / 2θ.

[0178] In another preferred embodiment, the present invention relates to the use of polymorph A for the prevention and / or treatment of inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0179] In another aspect, the present invention relates to a method for the prevention and / or treatment of inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), the method comprising inhalatory administration of an effective amount of polymorph A.

[0180] In another preferred embodiment, the present invention relates to a method for preparing a solvate of a compound of formula (I).

[0181] In another preferred embodiment, the present invention relates to a method for preparing a solvate of a compound of formula (I) from ethanol, characterized by the following characteristic XRPD peaks: 7.45; 7.87; 8.51; 10.12; 10.28; 12.66; 13.29; 13.45; 14.95; 16.14; 16.34; 17.05; 17.74; 18.05; 18.48; 18.88; 19.05; 19.33; 19.85; 20.18; 20.65; 21.3; 22.96; 23.55; 23.87; 24.41; 24.66; 24.88; 25.62; 25.82; 26.45; 28.12 and 28.53 ± 0.2 degrees / 2θ.

[0182] A pharmaceutical composition can be prepared by mixing a compound of formula (I) (wherein n is 0 or 1) prepared according to the present invention and one or more pharmaceutically acceptable excipients. Depending on the nature of the medical disease or condition to be treated and the type of patient, the pharmaceutical composition can be formulated for delivery by any suitable route, including oral, intravenous, parenteral, inhalation, intranasal, topical, subcutaneous, intramuscular, rectal, vaginal routes. Suitable dosage forms include known formulations such as tablets, capsules, powders, sustained release formulations, ointments, gels, creams, suppositories, eye drops, transdermal patches, syrups, solutions, suspensions, aerosols, solutions for nebulizers, nasal sprays, etc. In a preferred embodiment, the composition is formulated for delivery by inhalation or intranasal route, for example in an aerosol solution or suspension, as a dry powder for inhalation, or in a nasal spray.

[0183] Suitable excipients include carriers, diluents, wetting agents, emulsifiers, binders, coating agents, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffering substances, etc. Examples of excipients and their uses are provided in Handbook of Pharmaceutical Excipients, 5th Edition (2006), edited by Rowe et al., Pharmaceutical Press.

[0184] The dosage of the compounds of the present invention can depend on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of dosage intervals, the specific compound used, the potency of the compound, the toxicological properties and the pharmacokinetic properties.

[0185] Advantageously, the compounds of formula (I) (wherein n is 0 or 1) can be administered, for example, in a dose comprised within the following ranges: between 0.001 and 1000 mg / day, preferably between 0.1 and 500 mg / day, even more preferably between 0.2 and 2000 mg / day, and even more preferably between 0.1 and 4000 mg / day.

[0186] The compounds of formula (I) (wherein n is 0 or 1) obtained according to the present invention can be used for prophylactic purposes or for the relief of symptoms of a wide range of disorders, including: respiratory disorders such as chronic bronchitis, chronic obstructive pulmonary disease (COPD) and all types of asthma. However, the compounds of formula (I) (wherein n is 0 or 1) can be administered for the prevention and / or treatment of any disease or disease state mediated by PDE4 activity (e.g., a disease state in which PDE4 is overexpressed or hyperactive) in which the activity of the PDE4 receptor is involved and in which it is desired to inhibit the activity of the PDE4 receptor. Examples of such diseases include: allergic disease states such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, fever, diabetes, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the anal and genital areas, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and extensive areas of pyoderma, endogenous and exogenous acne, rosacea, Behçet's disease, allergic purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases, etc.

[0187] They also include neurological and psychiatric disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, depression, stroke and spinal cord injury.

[0188] In one embodiment, the present invention provides the use of a compound of formula (I) (wherein n is 0 or 1) prepared by any method according to the present invention in the preparation of a medicament for the prevention or treatment of any one of chronic bronchitis, chronic obstructive pulmonary disease (COPD), all types of asthma, atopic dermatitis and allergic rhinitis.

[0189] In another embodiment, the present invention provides a method for preventing or treating any one of chronic bronchitis, chronic obstructive pulmonary disease (COPD), all types of asthma, atopic dermatitis, and allergic rhinitis in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) prepared by any method according to the present invention, wherein n is 0 or 1.

[0190] A "therapeutically effective amount" of a substance is defined herein as an amount that results in a detectable improvement in one or more clinical symptoms of the treated disorder, or measurably decreases the likelihood of development of the disease condition or its symptoms.

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] Detailed Description

[0197] The present invention provides a method for preparing a compound of general formula (I) (wherein n is 0 or 1) according to the following steps.

[0198] Route A - Oxidizing intermediate (VI) (wherein n is 0 or 1) obtained according to the procedure described in Example 1 of WO 2010 / 089107 to (VII) (wherein n is 0 or 1) in the presence of an oxidizing agent, said oxidizing agent being selected from metal oxides such as MnO2, hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, DMSO-based oxidizing agents (Swern) such as sulfur trioxide pyridine complex. The synthesis is preferably carried out in a solvent selected from water, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, tetrahydrofuran (THF), di alkane and mixtures thereof. The reaction is preferably carried out with MnO2 in toluene or with the Swern oxidizing agent in DMSO.

[0199] Alternatively, the compound of formula (VII) can be obtained as follows: in the presence of a base (preferably selected from lithium diisopropylamide (LDA), butyllithium, hexyllithium, pentyllithium, lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide, potassium tert-butoxide), in the presence of a suitable solvent (such as toluene, benzene, xylene, tetrahydrofuran, methyl-tetrahydrofuran, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof), reacting an intermediate of formula B”

[0200]

[0201] wherein R is a straight-chain or branched (C1-C6) alkyl or arylalkyl, with an intermediate of formula D

[0202]

[0203] wherein n has the meaning reported above.

[0204] More preferably, R is methyl, and the above reaction is carried out with LHMDS in THF.

[0205] Compound B” can be obtained from compound B’ as follows: in methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, with or without other solvents, reacting with thionyl chloride, hydrochloric acid, sulfuric acid; or in the presence of a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di ane, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof and a base, reacting with a relevant alkyl halide, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), pyridine.

[0206] More preferably, the above reaction is carried out with potassium carbonate in dimethylformamide or dimethylacetamide.

[0207] In the presence of a suitable solvent such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di ane, 2-methoxyethyl ether, isopropyl acetate, acetonitrile, and mixtures thereof, using a peroxide selected from hydrogen peroxide, an organic peracid such as peracetic acid or meta-chloroperbenzoic acid, or an inorganic peracid such as peroxydisulfuric acid or An oxidizing agent of (KHSO5·1 / 2KHSO4·1 / 2K2SO4) can obtain compound B' from compound B. More preferably, the above reaction is carried out with in methanol.

[0208] Alternatively, by alkylating with bromomethyl cyclopropane in the presence of a base and in a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof, an intermediate of formula B'' can be obtained from an intermediate of formula C'', and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), pyridine, DBU, DBO, DMAP. More preferably, the above reaction is achieved with potassium carbonate in dimethylformamide.

[0209] By carrying out the Pinner reaction in the presence of an alcohol and a Lewis acid with or without a suitable solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, tetrahydrofuran, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof, intermediate C'' can be obtained from intermediate C', and the Lewis acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, alkane sulfonic acids such as methanesulfonic acid, aryl sulfonic acids such as benzenesulfonic acid, aluminum tribromide, aluminum trichloride, titanium(IV) chloride, titanium(IV) isopropoxide, tin(IV) chloride, boron trifluoride, boron trichloride, iron(III) chloride, iron(III) bromide, aluminum isopropoxide, thionyl chloride, oxalyl chloride, trimethylsilyl chloride (TMSCl), trimethylsilyl trifluoromethanesulfonate (Me3SiOTf). More preferably, the above reaction is achieved with sulfuric acid in methanol.

[0210] (VII) (where n is 0 or 1) subsequent enantioselective reduction will provide a single enantiomer (II), where n is 0 or 1.

[0211] The reducing agent is selected from hydrogen, in the presence of a preformed or in-situ formed heavy metal chiral complex, reacting a Ru-, Rh- or Ir-complex such as RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCI2(Cp*)]2 or [IrCI2(Cp*)]2 with a chiral ligand such as SL-N004-1 ((S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl] oxazoline), SL-N003-1 ((R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl] oxazoline), (S,S)-Ts-DPEN ((1S,2S)-(-)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine), (S,S)-Ms-DPEN ((1S,2S)-(-)-N-methanesulfonyl-1,2-diphenylethylenediamine), (R)-DAIPEN ((2R)-(-)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), (1R,2S)-1-amino-2-indanol. The reaction is carried out in the presence of a base, and the base is preferably selected from sodium hydroxide, sodium carbonate, C1-C4 sodium alkoxides, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C1-C4 potassium alkoxides, potassium bicarbonate, lithium hydroxide, lithium carbonate, C1-C4 lithium alkoxides, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, pyridine and 4-dimethylaminopyridine.

[0212] The synthesis is preferably carried out in a solvent selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, THF, di ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile and mixtures thereof.

[0213] The reaction is preferably carried out in toluene in the presence of an aqueous sodium hydroxide solution through a complex formed in situ by reacting RuCl2(PPh3)3 with the chiral ligand SL-N004-1.

[0214] Alternatively, (II) (where n is 1) is obtained by oxidizing (II) (where n is 0) with an oxidizing agent selected from hydrogen peroxide, organic peracids such as peracetic acid or m-chloroperbenzoic acid, or inorganic peracids such as peroxymonosulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4). The reaction solvent is selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di ane, ethyl acetate, isopropyl acetate, acetonitrile, acetic acid and mixtures thereof. The reaction is preferably carried out in water and methanol.

[0215] Route B - As an alternative to Route A, intermediate (II) and (VIII) (where n is 0 or 1) are obtained from intermediate (VI) (where n is 0 or 1) by preparative chiral HPLC separation of the enantiomers.

[0216] Batch operations can be employed: the chiral column is loaded several times with a solution of the racemate (VI), and the elution fractions of the separated enantiomers are collected. Simulated moving bed (SMB) operations should be considered for the separation of large quantities of material.

[0217] Once the compounds of formula (II) and (VIII) have been separated by preparative chiral HPLC techniques, the compound of formula (VIII) can be conveniently reconverted into the compound of formula (VI) as follows: oxidized to the corresponding derivative of formula (VII), and then reduced and reprocessed in a chromatographic separation method, as reported previously.

[0218] In this way, by recycling (VIII), the final yield of the compound of formula (I) can be further increased.

[0219] In intermediate (III), where X is -NHSO2Me and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy, and aryl(C1-C6) alkylcarbonyloxy, Z is a protecting group that can be introduced and removed using standard procedures according to Theodora W. Greene's "Protective Groups in Organic Synthesis" (Wiley-Interscience, New York, 1981) and J.F.W. McOmie's "Protective Groups in Organic Chemistry" (Plenum Press, London, 1973).

[0220] Thus, intermediate (III), where X is -NHSO2Me and Z is as defined above, can be obtained starting from methyl 3-cyclopropylmethoxy-4-methanesulfonylamino-benzoate (obtained as described in WO2007 / 089107, Example 18) under well-known conditions, or starting from the relevant ester of 3-hydroxy-4-nitrobenzoic acid according to the same synthetic route.

[0221] Intermediate (III) (where X is -NHSO2Me and Z is as defined above) is converted into (III) (where Z is -OH) by hydrolysis in a base, which is preferably selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, and cesium carbonate; the solvent is selected from water alone or water mixed with: methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, di- Alkanes and their mixtures. In a preferred embodiment, the reaction is carried out with NaOH in THF and water.

[0222] Route C - Compound (I) (where n is 0 or 1) is obtained as follows: in the presence of a coupling agent selected from CDI (1,1'-carbonyldiimidazole), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate), HBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea tetrafluoroborate), DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride), COMU ((1-cyano-2-ethoxy-2-oxoethylenediaminooxy)dimethylamino-morpholino-carbon hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) and DCC (N,N′-dicyclohexylcarbodiimide), with or without HOBt (1-hydroxybenzotriazole), with or without an organic base such as TEA, DIPEA, NMM, DBU, DBO, pyridine and DMAP, in a solvent selected from dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di ethane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, the intermediate (III) (where X is -NHSO2Me and Z is -OH) is condensed with the intermediate (II) (where n is 0 or 1).

[0223] When the compound of formula (III) is an acyl chloride or acyl bromide or an activated ester and a mixed anhydride, the reaction is carried out as described above in the absence of a coupling agent.

[0224] In a preferred embodiment, the reaction is achieved with CDI and DBU in ethyl acetate.

[0225] Under the same conditions as described above for the condensation of (III) (where X is -NHSO2Me) with (II), the intermediate (IV) (where n is 0 or 1) is obtained by the condensation of (III) (where X is -NO2) with (II) (where n is 0 or 1). In a preferred embodiment, the reaction is carried out with EDCI and DMAP in DMF.

[0226] The intermediate (V) (where n is 0 or 1) is obtained by reducing (IV) (where n is 0 or 1) with a reducing agent selected from hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, stannous chloride, tin, nickel chloride, nickel, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, and sodium dithionite. In the case of using hydrogen, cyclohexadiene, ammonium formate, and formic acid, the reaction is carried out in the presence of a catalyst, which is preferably based on palladium, platinum, or nickel, and more preferably selected from palladium on carbon, palladium on barium sulfate, and palladium on calcium carbonate. In the case of using formic acid, the reaction is carried out in the presence of ammonia or an amine, preferably triethylamine.

[0227] Suitable solvents for the above reduction step are selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, THF, di ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, and mixtures thereof. In a preferred embodiment, the reaction is carried out with hydrogen using 5% palladium on activated carbon powder (type A103038, sulfided in ethyl acetate).

[0228] In another preferred embodiment, the reaction is carried out with hydrogen using platinum on carbon in ethyl acetate.

[0229] Compound (I) (where n is 0 or 1) is obtained by reacting (V) (where n is 0 or 1) with methanesulfonyl chloride in the presence of a suitable solvent and a base selected from toluene, benzene, xylene, tetrahydrofuran, di ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA (triethylamine), DIPEA (Hünig's base, diisopropylethylamine), NMM (N-methylmorpholine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBO (1,4-diazabicyclo[2.2.2]octane), pyridine, and DMAP (4-dimethylaminopyridine), pyridine; in the case of using an excess of pyridine, other solvents can be avoided.

[0230] The reaction is preferably carried out with triethylamine in dichloromethane.

[0231] As described above for the oxidation of compound (II) where n is 0 to compound (II) where n is 1, all compounds of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) where n is 1 can be obtained by oxidizing the corresponding compound where n is 0.

[0232] When compound (I) where n is 0 or 1 is obtained, it can be purified by crystallization or trituration from one or more solvents, which are preferably selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, aliphatic or aromatic hydrocarbons, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or mixtures thereof. The reaction is preferably carried out in ethyl acetate with n-heptane.

[0233] Thus, for example, crystalline form A can be prepared in the presence of ethyl acetate / heptane or isopropyl acetate.

[0234] The reaction can be carried out in a reactor, where a compound of formula (I) is loaded together with one or more solvents selected from the above list, and the suspension can be stirred while heating to a temperature between 50 - 90 °C until the solid is completely dissolved. The suspension can be cooled between 0 - 5 °C for 1 - 5 hours, filtered and dried.

[0235] When crystallization is carried out in the presence of ethanol, a solvate of the compound of formula (I) can be obtained.

[0236] The reaction can be carried out starting from a compound of formula (I) in one or more solvents selected from pentane, hexane, heptane, cyclohexane, methylcyclohexane and dichloromethane to obtain a solution, which can be concentrated and then added together with ethanol. The solution can be concentrated, and the resulting suspension can be cooled and stirred at a temperature between 0 - 10 °C for 1 - 5 hours. The solid is filtered, washed with ethanol, and dried at a temperature between 25 - 55 °C for 10 - 30 hours.

[0237] The present invention will be illustrated in more detail in the following examples.

[0238] Example 1

[0239] Preparation of 3-(Cyclopropylmethoxy)-4-(methylsulfonamido)benzoic acid (Intermediate (III), X = -NHSO2Me, Z = -OH)

[0240]

[0241] (III), X = -NHSO2Me , Z = -OMe (III), X = -NHSO2Me, Z = -OH

[0242] (III) was obtained as described in WO 2010 / 08910, Example 18, where X is -NHSO2Me and Z is -OMe. It (6.0 kg) and 18 L of THF were charged into a reactor. Separately, 6.6 kg of 35% w / w sodium hydroxide and 21 L of purified water were mixed and transferred into the reactor, and the mixture was heated to 65 °C while distilling off all the THF. After the hydrolysis reaction was completed, the alkaline solution was slowly transferred into another reactor containing a solution of 24 L of purified water and 7.2 kg of 37% w / w hydrochloric acid, keeping the temperature below 40 °C and stirring for 15 minutes. The resulting solid was filtered and washed with 24 L of water. The wet solid (III) (16.6 kg wet weight) was recharged into the reactor together with 60 L of ethyl acetate, and then heated to reflux to distill off 30 L of the solvent. 12.6 L of heptane was charged into the reactor, and the mixture was kept under stirring for 15 - 30 minutes. Then it was cooled to 5 °C and kept under stirring for 2 hours. The resulting solid was filtered, and the reactor and the filter cake were washed with 12 L of heptane. The wet solid was dried in a static tray drier under vacuum. 6235 g of a white solid was obtained (93.9% yield).

[0243] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br.s., 1H), 9.03 (s, 1H), 7.40 - 7.71 (m, 2H), 7.35 (d, J = 8.16 Hz, 1H), 3.91 (d, J = 6.84 Hz, 2H), 3.07 (s, 3H), 1.11 - 1.42 (m, 1H), 0.50 - 0.67 (m, 2H), 0.18 - 0.41 (m, 2H).

[0244] Example 2

[0245] Preparation of 1-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone (Intermediate (VII), n = 0)

[0246] The intermediate (VI) where n is 0 was obtained according to the preparation operation described in WO 2010 / 089107, Example 1.

[0247]

[0248] Alternative operation for obtaining intermediate (VII) (n = 0):

[0249] Operation using MnO2

[0250] Dissolve 5 kg of (VI) where n is 0 in 30 L of toluene in a reactor; add 3.15 kg of activated MnO2 to the organic mixture and heat the suspension to reflux for 3 hours. Cool the mixture to 50 °C and filter out the MnO2 through a diatomaceous earth pad. Load the organic solution into the reactor and distill off the toluene until 3 residual volumes. Add 20 L of 2-propanol to the reactor and concentrate again until 2 residual volumes to remove the total amount of toluene. Load another 20 L of 2-propanol and distill off the solvent partially to have 4 residual volumes in the reactor. Cool the suspension and keep it at 10 °C overnight with stirring. Filter the solid and dry the wet solid in a vacuum drying oven at T = 50 °C for 12 hours to obtain a white solid (4.12 kg, 82.8% yield).

[0251] The product characterization was described in WO 2009018909, Example 2 (Intermediate 1b).

[0252] Swern operation

[0253] Under stirring at 25 °C, add triethylamine (4.5 mL, 32 mmol) dropwise to a solution of alcohol (VI) where n is 0 (5.0 g, 12.4 mmol) in DMSO (15 mL). Add the pyridine.SO3 complex (5.0 g, 31 mmol) portionwise over about 1 hour such that the internal batch temperature does not rise above 35 °C. Stir the reaction mixture at 25 °C for 4 hours and then quench with water (60 mL) and 10% aqueous H2SO4 solution (10 mL). Stir the resulting mixture at 25 °C, filter out the solid and dry it under reduced pressure at 50 °C to obtain 4.6 g (92% yield) of pure ketone (VII) as a colorless solid.

[0254] Operation using IBX

[0255] (VI) (where n is 0) (1.0 g, 2.5 mmol) was added in one portion to a suspension of 2-iodoxybenzoic acid (IBX) (0.9 g, 3.2 mmol) prepared according to the literature (JOC 1999, page 4537) in DMSO (5 mL). The resulting mixture was stirred at 25 °C for 1 h and then heated to 50 °C for 2 h. After cooling to 25 °C, the reaction was quenched with 10% aqueous potassium carbonate solution (40 mL), and the solid was filtered off to give the ketone (VII) in quantitative yield.

[0256] Using the procedure of

[0257] Commercially available ("stabilized IBX", a white powder formulation of IBX consisting of a mixture of benzoic acid (22%), isophthalic acid (29%), and o-iodoxybenzoic acid (49%), obtained from SIMAFEX) (2.0 g, 3.2 mmol) was added in one portion to a solution of (VI) (where n is 0) (1.0 g, 2.5 mmol) in acetone (15 mL). The resulting mixture was refluxed for 2.5 h, cooled to 25 °C, and then quenched with 10% aqueous sodium sulfite solution (10 mL) and 10% aqueous potassium carbonate solution (40 mL). The mixture was stirred at 25 °C for 0.5 h and the solid was filtered off to give the ketone (VII) (where n is 0) in quantitative yield.

[0258] The procedure using DMP

[0259] Dess-Martin periodinane (DMP) (1.3 g, 0.31 mmol) was added in one portion to a solution of alcohol (VI) (where n is 0) (1.0 g, 2.5 mmol) in acetone (5 mL). The reaction mixture was stirred at 25 - 30 °C for 1 h and quenched with 10% aqueous sodium metabisulfite solution (10 mL) and 15% aqueous potassium carbonate solution (30 mL). The mixture was stirred at 25 °C for 0.5 h and the solid was filtered off to give (VII) (where n is 0) in quantitative yield.

[0260] Example 2A

[0261] Preparation of 3,5-dichloro-4-methyl-1-oxo-pyridine (Intermediate A)

[0262]

[0263] 3,5-Dichloro-4-methyl-pyridine (0.5 g, 3.08 mmol) and (1.5 g, 4.62 mmol) was suspended in an 8:3 mixture of methanol and water (5.5 ml) in a 25 ml flask. The suspension was stirred and warmed to 55 °C for 10 - 15 h. The solvent was removed under reduced pressure, and the resulting crude solid was suspended in hot toluene (80 °C) with stirring for 20 min. Then the inhomogeneous hot solution was filtered, and the mother liquor was cooled to room temperature to give a precipitate of solid. After stirring at 0 - 5 °C for 30 min and filtration, the pure product as a white solid (0.43 g, 78% yield) was obtained.

[0264] Example 2B

[0265] Preparation of (R / S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanol (Intermediate (VI), n = 1)

[0266]

[0267] Intermediate A (0.4 g, 2.25 mmol) and Intermediate B (0.78 g, 3.22 mmol) were added under a nitrogen atmosphere to a three-necked 50 ml flask and dissolved in anhydrous THF (5 ml). The stirred solution was cooled to -35 °C. Potassium tert-butoxide (0.3 g, 2.67 mmol) was added portionwise to the solution over 10 min. After reacting at -35 °C for 60 min, the solution was quenched with 25% aqueous NH4Cl solution (10 ml). EtOAc (8 ml) and water (8 ml) were added to the suspension and stirred, the phases were separated, and the organic phase was extracted and washed with 5% aqueous NaCl solution (10 ml). Then the organic solvent was dried over Na2SO4 and removed under reduced pressure to give a crude white solid. It was crystallized from hot toluene to give a white solid (0.40 g, 42% yield).

[0268] Example 3

[0269] Preparation of (R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethanol (Intermediate (II), n = 0)

[0270]

[0271] Dissolve 2.40 kg of (VII) (where n is 0) in 23 L of toluene in a reactor. Degas the reactor with nitrogen. Place the Solvias proprietary ligand SL-N004-1 and RuCl2(PPh3)3 in a 2 L Schlenk round-bottom flask and dry, and add degassed toluene (1.2 L). Heat the mixture to 80 °C for 1 hour and then allow it to reach room temperature (RT). Subsequently, add the catalyst solution and 298 mL of degassed 0.5 M aqueous NaOH solution to the reactor. Close the reactor, degas it with nitrogen, and set it under 10 bar of hydrogen. Heat the mixture to 35 °C under a constant pressure of 10 bar. After a total reaction time of 19 hours, turn off the heater. Cool the reactor to room temperature and remove the aqueous layer. Wash the organic phase twice with 0.5 L of water; back-extract the aqueous phase with 1 L of toluene added to the organic phase. Add 240 g of decolorizing carbon (Norit CAP Super) to the toluene solution and stir the mixture overnight at room temperature. Filter off the carbon and rinse the cake with 1.5 L of ethyl acetate. Concentrate the slightly yellow solution to dryness under reduced pressure to give 2.38 kg of crude wet material. Dissolve it in 1.5 L of isopropyl acetate with stirring at 60 °C, add 9 L of preheated heptane (50 °C), and stir the mixture at 60 °C. Seed the solution and slowly cool it to room temperature with stirring. Continue stirring overnight at room temperature and then cool the mixture to 0 °C for 1 hour. Filter and dry the solid. The yield is 2.1 kg (87% yield, 95.0% ee).

[0272] Example 4

[0273] Separation of (R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanol and (S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanol (Intermediates (VIII) and (II), n = 0)

[0274]

[0275] Chromatographic separation of 3000 g of (VI) (where n is 0) was carried out in batches using a Chiralpak IC 20 μm - 250 * 76 mm column and dichloromethane / ethanol 95 / 5 (v / v) as the mobile phase. A solution of the racemate (VI) was loaded onto the top of the chiral column in several rounds, and the elution fractions of the separated enantiomers collected at the bottom of the column were combined. (II) was crystallized from the concentrated DCM / EtOH elution mixture enriched in ethanol. 1440 g (48% yield) of the desired enantiomer (II) (where n is 0) was obtained, which had an HPLC purity of >99.5% and an HPLC chiral purity of >99.5%. 1470 g (49% yield) of the other enantiomer (VIII) (where n is 0) was also obtained, which had an HPLC purity of >99% and an HPLC chiral purity of >99%.

[0276] Example 4A

[0277] Separation of (R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanol and (S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanol (Intermediates (VIII) and (II), n = 1)

[0278]

[0279] Similarly to Example 4, chromatographic separation of a solution of the racemate (VI) (where n is 1) can be carried out using a Chiralpak IC 20 μm - 250 * 76 mm column and methanol as the mobile phase to obtain the desired enantiomer (II) (where n is 1), which has a high HPLC purity and an HPLC chiral purity. The other enantiomer (VIII) (where n is 1) can also be obtained, which has a high HPLC purity and an HPLC chiral purity.

[0280] Example 5

[0281] Preparation of (S)-3-cyclopropylmethoxy-4-methanesulfonylaminobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethyl ester (Compound (I), n = 0)

[0282]

[0283] 75 g of (III) (where X is -NHSO2Me and Z is -OH) was suspended in 750 ml of DCM; 42.5 g of N,N-carbonyldiimidazole was added portionwise, and the resulting solution was stirred at room temperature for 30 min. 375 ml of toluene was added, followed by 85 g of (II) (where n is 0), and the mixture was heated to reflux. DCM was removed by distillation, and then the suspension was stirred at 100 °C overnight. The resulting solution was cooled to 40 °C, 500 ml of ethyl acetate was added, and it was washed with NaHCO3 solution and brine. The product was isolated by crystallization from ethyl acetate / heptane and recrystallized from the same solvent mixture to give a white solid (129 g recovered, 73% yield).

[0284] Product characterization was described in Example 15 of WO 2010089107.

[0285] Example 6

[0286] Preparation of (S)-3-cyclopropylmethoxy-4-methylsulfonylaminobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxo-pyridin-4-yl)-ethyl ester (Compound (I), n = 1)

[0287]

[0288] Procedure using H2O2 / acetic acid

[0289] 73 g of (I) (where n is 0) was charged into a flask, followed by 150 ml of toluene, 290 ml of acetic acid and 75 ml of 35% H2O2, and the mixture was heated to 80 °C for 8 h. The mixture was cooled to 50 °C, 750 ml of ethyl acetate was added, and the aqueous phase was removed; the organic phase was washed with water and 10% aqueous NaHCO3 solution until alkaline pH, and the solvent was removed by distillation. The crude material was purified by crystallization from 375 ml of ethyl acetate and 225 ml of n-heptane and dried in a static rack dryer to give a white solid (65.1 g recovered, 87.1% yield).

[0290] Product characterization was described in Example 17 of WO 2010089107.

[0291] Example 7

[0292] Preparation of (S)-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxo-pyridin-4-yl)-ethanol (Intermediate (II), n = 1)

[0293]

[0294]

[0295] Operation using H2O2 / acetic acid

[0296] Charge 490 g of (II) (where n is 0) into a reactor together with 1960 ml of glacial acetic acid. Heat the mixture to 50 °C, then gradually add 980 ml of a 30 - 35% solution of hydrogen peroxide in water, and maintain the mixture at the same temperature with stirring for 16 hours. Slowly add 2000 ml of purified water, and (II) (where n = 1) precipitates as a solid. Cool the slurry to 10 °C and maintain it with stirring for 3 hours. Then filter out the solid and wash the resulting solid with 1000 ml of water. Resuspend the wet solid (II) (where n is 1) in 2000 ml of water for 2 hours and then in 2000 ml of diisopropyl ether for 3 hours. Dry the wet solid under vacuum. 433 g of a white solid is obtained (85% yield).

[0297] Product characterization is described in Example 7 of WO 2010089107.

[0298] Using Operation

[0299] Charge 456 g (KHSO5*1 / 2KHSO4*1 / 2K2SO4) and 1.2 L of water into a reactor and stir the mixture at room temperature. Add 400 g of (II) (where n is 0) and 3.2 L of methanol, and heat the mixture to 70 °C for 3 hours. Add an additional 50 g After 1.5 hours, the reaction is complete. Distill off the alcohol, and add 4 L of water and 2 L of ethyl acetate at 50 °C. Drain the aqueous phase, wash the organic phase with 800 ml of water, and concentrate it to 1.5 L under vacuum. Add 4 L of toluene and concentrate the mixture to 2.5 L under vacuum while the product starts to precipitate. Cool the suspension to 10 °C and maintain it with stirring for 1.5 hours. Filter the resulting solid and wash it with 800 ml of toluene. Dry the wet solid under vacuum in a static tray dryer. 288 g of a white solid is obtained (72% yield).

[0300] Product characterization is described in Example 7 of WO 2010089107.

[0301] Example 8

[0302] Preparation of (S)-3-cyclopropylmethoxy-4-methylsulfonylaminobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethyl ester (Compound (I), n = 1)

[0303]

[0304] 100 g of (III) (where X is NHSO2Me and Z is -OH) and 1 L of ethyl acetate were charged into a reactor. 57 g of carbonyldiimidazole was added portionwise with stirring at 40 °C, and then the mixture was stirred for 60 min. 123 g of (II) (where n = 1) and 3.7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, and the mixture was heated to 75 °C and maintained for about 4 h. The organic solution was washed with 500 ml of 1 M aqueous HCl, with 500 ml of 5% aqueous NaHCO3, and with 500 ml of 10% aqueous NaCl. The organic mixture was heated to 70 °C under vacuum and concentrated to 600 ml. The mixture was cooled to 50 °C and 300 ml of n-heptane was added. The solution was seeded, cooled to 5 °C and kept under stirring for 1.5 h. The resulting solid was filtered off and dried under vacuum. 168 g of a crude solid (82% yield) was obtained.

[0305] The product characterization was described in Example 17 of WO 2010089107.

[0306] Example 9

[0307] (S)-3-Cyclopropylmethoxy-4-methylsulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethyl ester (Compound (I), n is 1) Preparation - from ethanol solvation

[0308] A solution of the crude Compound (I) (where n is 1) was charged into a 1 L reactor. DCM (90 ml) and EtOH (300 ml) were added, and the white suspension was stirred and warmed to reflux until completely dissolved. The DCM was distilled off and a white solid started to precipitate. The ethanol solution was further concentrated to 6 - 7 volumes, a portion of EtOH was distilled off, and then it was cooled to 0 - 5 °C and stirred for 120 min. The resulting solid was filtered and washed with 30 ml of EtOH. The wet solid was dried under vacuum in a static shelf dryer. 28.55 g of a white solid (95% yield) was obtained.

[0309] The compound of formula (I) (where n is 1) obtained as a solvate according to Example 9 was studied by the following: differential scanning calorimetry (DSC) (to determine the melting point), Raman spectroscopy (to observe the vibrational, rotational and low-frequency modes), and X-ray powder diffraction (XRPD) pattern.

[0310] It is characterized as follows: a melting point range of 87 °C - 101 °C was determined by DSC at a scanning rate of 10 °C / min;

[0311] X-ray powder diffraction pattern (Bruker D8Advance con XrayDiffraction Tube model KFL CuKα2) characterized by the following XRPD peaks: 7.45; 7.87; 8.51; 10.12; 10.28; 12.66; 13.29; 13.45; 14.95; 16.14; 16.34; 17.05; 17.74; 18.05; 18.48; 18.88; 19.05; 19.33; 19.85; 20.18; 20.65; 21.3; 22.96; 23.55; 23.87; 24.41; 24.66; 24.88; 25.62; 25.82; 26.45; 28.12 and 28.53 ± 0.2 degrees / 2θ.

[0312] Example 10

[0313] Crystalline - form A of compound (I) (where n is 1)

[0314] Procedure from ethyl acetate / heptane

[0315] 5 g of crude (I) (where n is 1) was loaded into a reactor together with 30 ml of ethyl acetate, and the suspension was stirred while heating to 75 °C until the solid was completely dissolved. 15 ml of n - heptane was added, and the solution was brought to room temperature. The suspension was cooled to 5 °C and kept for 2 hours, filtered and dried under vacuum. A white solid was obtained, namely so - called form A (3.6 g, 72% yield).

[0316] The compound of formula (I) (where n is 1) obtained as form A according to Example 10 was studied by the following: differential scanning calorimetry (DSC) (to determine the melting point), Raman spectroscopy (to observe vibrational, rotational and low - frequency modes) and X - ray powder diffraction (XRPD) pattern.

[0317] It is characterized as follows: a melting point range of 144 °C - 147 °C was determined by DSC at a scanning rate of 10 °C / min;

[0318] X-ray powder diffraction pattern (Bruker D8 Advance with X-ray Diffraction Tube model KFL CuKα2) characterized by the following XRPD peaks: 7.48; 7.93; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 18.08; 18.53; 18.94; 8.55; 17.79; 19.89; 19.1; 20.2; 21.37; 22.96; 23.63; 24.87; 26.51; 28.09; 28.61 and 25.82 ± 0.2 degrees / 2θ.

[0319] Procedure from isopropyl acetate

[0320] 5 g of crude product (I) (where n is 1) was loaded into a flask together with 20 ml of isopropyl acetate, and the suspension was heated to reflux until completely dissolved. The mixture was cooled to 0 °C and stirred for 2 hours. The resulting solid was filtered and washed with 10 ml of isopropyl acetate. The wet solid was dried under vacuum. 4.05 g of a white solid, namely crystalline form A (81% yield), was obtained.

[0321] Product characterization is described in Example of WO 2010089107.

[0322] Example 11

[0323] Oxidation of intermediate (VII), n = 0 to 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanone (intermediate (VII), n = 1)

[0324]

[0325] Procedure using H2O2 / acetic acid

[0326] 0.5 g of (VII) (where n is 0) was loaded into a 50 ml flask together with 3 ml of glacial acetic acid. The homogeneous solution was heated to 50 °C, then 1 ml of 30 - 35% aqueous hydrogen peroxide solution was gradually added, and the mixture was kept at the same temperature with stirring for 21 hours. Then the solvent was removed under reduced pressure, and the crude solid was purified by column chromatography using gradient elution (hexane / EtOAc 85 / 15 to 100% EtOAc), yielding the pure product as a white solid (50% yield).

[0327] Using Procedure

[0328] 10 g of (VII) (where n is 0) was combined with 11.44 g 80 ml of methanol and 30 ml of water were loaded into a flask. The mixture was heated to 65 °C for 5 hours and kept at room temperature for 48 hours. The alcohol was distilled off, and 50 ml of water and 100 ml of toluene were added. The mixture was heated until the solid was completely dissolved, the aqueous phase was drained off, and the organic phase was concentrated to 70 ml under vacuum. The suspension was cooled to 0 °C and kept under stirring for 1.5 hours. The resulting solid was filtered off and dried in a static rack dryer under vacuum. 6.7 g of a white solid (60% yield) was obtained.

[0329] Procedure using MCPBA

[0330] 0.5 g of (VII) (where n is 0) was dissolved in 10 ml of THF, 0.34 g of MCPBA (3-chloroperoxybenzoic acid, 77% assay) was added, and the mixture was stirred overnight at room temperature. HPLC control confirmed almost complete conversion. The solution was partitioned between 100 ml of ethyl acetate and 50 ml of 5% aqueous potassium bicarbonate solution. The organic phase was washed with an additional 50 ml of the basic solution and dried under vacuum. The crude product was purified on a silica gel pad using a mixture of ethyl acetate and dichloromethane as the eluent. 0.22 g of (VII) where n = 1 (42% yield) was obtained.

[0331] Example 12

[0332] Oxidation of Intermediate (VI), n = 1 to 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanone (Intermediate (VII), n = 1)

[0333]

[0334] Procedure using DMP

[0335] The alcohol (VI) (where n is 1) (1.0 g, 2.38 mmol) was suspended in acetone (15 ml). The suspension was cooled in an ice bath with stirring at 0 - 5 °C. Then Dess-Martin periodinane (1.4 g, 3.3 mmol) was added in one portion. The reaction was initially exothermic, and after 1 hour, it was allowed to reach room temperature. After 20 hours, the reaction was complete, quenched with 10 mL of 10% aqueous sodium metabisulfite solution, and 30 mL of 15% aqueous potassium carbonate solution was added. The mixture was stirred at 25 °C for 0.5 hour, and the solid was filtered to give the ketone (VII) (where n is 1) in quantitative yield.

[0336] Example 13

[0337] Preparation of 3-(cyclopropylmethoxy)-4-nitrobenzoic acid (Intermediate (III), X = -NO2 and Z = -OH)

[0338]

[0339] (III) was prepared according to the procedure described in Example 18 of WO 2010 / 089107, where X is -NO2 and Z is -OMe. 550 g of (III) (where X is -NO2 and Z is -OMe) was loaded into a reactor, followed by 1.65 L of THF and 2.85 L of 1 M aqueous lithium hydroxide solution. The mixture was heated to 40 °C for 1.5 h and then cooled to room temperature. 4.4 L of ethyl acetate was added, followed by 240 ml of 37% aqueous HCl solution. The aqueous phase was drained off, and the organic phase was washed twice with 2.75 L of water and then concentrated under vacuum at 50 °C. 1.65 L of n-heptane was added at the same temperature, and the suspension was cooled to room temperature. The solid was filtered off and dried in a vacuum tray dryer to give 337 g of (III), where X is -NO2 and Z is -OH (73% yield).

[0340] Example 14

[0341] Preparation of (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethyl ester (Intermediate (IV), n = 0)

[0342]

[0343] Intermediate (III) (where X is -NO2, Z is -OH) (80 g, 0.34 mol, ref.), (II) (where n is 0) (109.1 g, 0.27 mol, 0.9 eq.), EDC.HCl (193.9 g, 1.01 mmol, 3 eq.), DMAP (20.6 g, 0.17 mol, 0.5 eq.) and DMF (400 ml, 5 vol) were mixed together and heated to 75 °C overnight. The solution was partitioned between water and ethyl acetate, and the organic phase was washed with acidic and basic aqueous solutions and concentrated under vacuum. The crude material was crystallized from EtOH (1200 ml) and acetone (100 ml). A white solid was obtained (101 g, 60% yield relative to (VIII)).

[0344] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 2H), 7.97 (d, J = 8.38 Hz, 1H), 7.61 - 7.80 (m, 2H), 7.18 - 7.32 (m, 2H), 7.02 - 7.14 (m, 2H), 6.27 (dd, J = 9.70, 3.97 Hz, 1H), 4.04 - 4.21 (m, 2H), 3.89 - 4.02 (m, 2H), 3.74 (dd, J = 14.11, 9.70 Hz, 1H), 3.45 (dd, J = 13.89, 4.19 Hz, 1H), 1.10 - 1.30 (m, 2H), 0.49 - 0.65 (m, 4H), 0.36 (qd, J = 5.44, 5.29 Hz, 4H).

[0345] Example 15

[0346] Preparation of (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethyl ester (Intermediate (IV), n = 1)

[0347] (III) (where X is -NO2 and Z is -OH) (80 g, 0.34 mol, ref.), (II) (where n is 1) (113.9 g, 0.27 mol, 0.9 eq.), EDC·HCl (193.9 g, 1.01 mmol, 3 eq.), DMAP (20.6 g, 0.17 mol, 0.5 eq.) and DMF (400 ml, 5 vol) were mixed together and heated at 100 °C overnight. The solution was partitioned between water and ethyl acetate, and the organic phase was washed with acidic and basic aqueous solutions and concentrated in vacuo. The crude material was crystallized from EtOH (600 ml), acetone (200 ml) and heptane (200 ml). A white solid was obtained (71 g, 41% yield relative to Intermediate (II) where n is 1).

[0348] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 2H), 7.97 (d, J = 8.38 Hz, 1H), 7.62 - 7.83 (m, 2H), 7.16 - 7.32 (m, 2H), 7.04 - 7.14 (m, 2H), 6.20 (dd, J = 9.26, 4.41 Hz, 1H), 4.11 (dd, J = 7.06, 3.53 Hz, 2H), 3.93 (d, J = 6.62 Hz, 2H), 3.62 (d, J = 9.26 Hz, 1H), 3.32 (d, J = 9.26 Hz, 1H), 1.17 - 1.26 (m, 2H), 0.49 - 0.67 (m, 4H), 0.24 - 0.43 (m, 4H).

[0349] Example 16

[0350] (S)-3-Cyclopropylmethoxy-4-aminobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethyl ester (Intermediate (V), X = NH2 and n = 0) Preparation

[0351]

[0352] Hydrogenation operation

[0353] Charge the reactor with 2.5 g of (IV) (where n is 0), 119 mg of Pd / C catalyst and 25 ml of ethyl acetate. Then seal the reactor and heat to an internal temperature of 40 °C with gentle stirring. Charge the reactor with 4 bar of hydrogen. After 4 hours, the conversion is complete. Remove the catalyst by filtration and distill the solvent under reduced pressure. 2.20 g of the product is recovered (90% yield).

[0354] 1 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 2H), 7.49 - 7.56 (m, 1H), 7.30 - 7.36 (m, 2H), 7.10 - 7.19 (m, 1H), 7.00 - 7.08 (m, 2H), 6.58 - 6.68 (m, 1H), 6.20 - 6.28 (m, 1H), 4.11 (bs, 2H), 3.78 - 3.92 (m, 4H), 3.69 - 3.79 (m, 1H), 3.30 - 3.37 (m, 1H), 1.178 - 1.32 (m, 2H), 0.58 - 0.71 (m, 4H), 0.28 - 0.35 (m, 4H).

[0355] Operation using SnCl2

[0356] Dissolve 2 g of (IV) (where n is 0) in 20 ml of THF, and add 4.34 g of tin(II) chloride dihydrate. Stir the solution overnight at 80 °C. Partition the solution between 100 ml of ethyl acetate and 100 ml of 5% aqueous KHCO3. Filter the mixture to remove the precipitated salts and discard the aqueous phase. Wash the organic phase with additional KHCO3 and brine. Remove the organic solvent under vacuum and isolate (V) (where n is 0) as a yellow oil (1.84 g, 97% yield).

[0357] Example 17

[0358] Preparation of (S)-3-cyclopropylmethoxy-4-aminobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethyl ester (Intermediate (V), n = 1)

[0359]

[0360] Hydrogenation operation

[0361] Charge the reactor with 400 mg of (IV) (where n = 1), 8 mg of 1% Pt / C catalyst and 4 ml of ethyl acetate, seal, and heat to 60 °C with gentle stirring. Charge with 4 bar of hydrogen and continue stirring for 4 hours. Filter the mixture to remove the catalyst and dry under vacuum.

[0362] Operation using SnCl2

[0363] Dissolve 1 g of (IV) (where n = 1) in 10 ml of THF, and add 1.06 g of tin(II) chloride dihydrate. Stir the solution overnight at room temperature. Evaporate the solvent under vacuum and add 10 ml of ethyl acetate and 10 ml of 1 M aqueous NaOH to the crude product. Discard the aqueous phase and wash the organic phase with 10 ml of 10% aqueous NaCl. Remove the organic solvent and suspend the crude product in ether and stir until a solid is obtained; filter it, wash with 4 ml of ether, and dry in a static rack dryer. Obtain a white solid (0.68 g, 71.3%).

[0364] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 2H), 7.40 (dd, J = 8.38, 1.76 Hz, 1H), 7.28 (d, J = 1.76 Hz, 1H), 7.15 - 7.21 (m, 2H), 6.99 - 7.08 (m, 2H), 6.64 (d, J = 8.38 Hz, 1H), 6.14 (dd, J = 9.59, 4.30 Hz, 1H), 5.63 (s, 2H), 3.88 - 3.96 (m, 2H), 3.70 - 3.88 (m, 2H), 3.55 (dd, J = 14.11, 9.92 Hz, 1H), 3.24 - 3.31 (m, 1H), 1.11 - 1.34 (m, 2H), 0.47 - 0.65 (m, 4H), 0.19 - 0.41 (m, 4H).

[0365] Example 18

[0366] (S)-3-Cyclopropylmethoxy-4-methylsulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester (Compound (I), n = 0) Preparation

[0367]

[0368] Dissolve 0.5 g of (V) (where n is 0) (0.84 mmol) in DCM (7 ml) and TEA (0.17 ml, 1.26 mmol), then slowly add methanesulfonyl chloride (0.11 g, 0.93 ml), and stir the solution at room temperature for 20 h. Then quench the reaction with water (20 ml), extract with organic solvent, and wash with 5% aqueous NaCl solution (10 ml). Remove the solvent, and purify the crude product by column chromatography with gradient elution (hexane 100% to hexane / EtOAc 60 / 40) to give the pure product as a colorless oil (yield 30%).

[0369] Example 19

[0370] Oxidize intermediate (IV) (where n is 0) to obtain (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxo-pyridin-4-yl)-ethyl ester (intermediate (IV), n = 1)

[0371]

[0372] Procedure using H2O2 / acetic acid

[0373] Charge 0.5 g of (IV) (where n is 0) into a 50 ml flask containing 3 ml of glacial acetic acid. Heat the solution to 55 °C, then gradually add 1 ml of hydrogen peroxide (35%) and maintain the mixture with stirring at the same temperature for 48 h. Add 5 ml of water, extract the product with ethyl acetate, and remove the organic solvent under reduced pressure to give the product as a yellow oil (yield 74%).

[0374] Using the operation of

[0375] Charge 0.3 g of (IV) (where n is 0) into a 50 ml flask, followed by 2.4 ml of methanol, 1 ml of water and 215 mg of Stir the suspension at 55 °C for 48 h and at 40 °C for 72 h. Remove the methanol under reduced pressure and add 5 ml of ethyl acetate. Extract the aqueous phase with ethyl acetate (3 × 5 ml), dry the organic phase over Na2SO4 and remove the solvent under reduced pressure to give the product as a slightly yellow oil (yield 96%).

[0376] The operation using MCPBA

[0377] Dissolve 0.5 g of (IV) (where n is 0) in 10 ml of THF, add 0.22 g of MCPBA (3-chloroperoxybenzoic acid, 77% assay), and stir the mixture at room temperature overnight. HPLC control confirms almost complete conversion. Partition the solution between 100 ml of ethyl acetate and 50 ml of 5% aqueous potassium bicarbonate. Wash the organic phase with an additional 50 ml of the basic solution and dry under vacuum. Purify the crude product on a silica gel pad using a mixture of ethyl acetate and dichloromethane as the eluent. 0.19 g of (VII) is obtained (37% yield).

[0378] Example 20

[0379] Methanesulfonylate (V) (where n is 1) to obtain (S)-3-cyclopropylmethoxy-4-methanesulfonylaminobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxopyridin-4-yl)ethyl ester (Compound (I), where n is 1)

[0380]

[0381] Dissolve 0.2 g of (V) (where n is 1) (0.33 mmol) in DCM (3 ml) and TEA (0.05 ml, 0.39 mmol), then slowly add methanesulfonyl chloride (0.045 g, 0.07 ml), and stir the solution at room temperature for 20 h. Then quench the reactant with HCl 1N (10 ml), extract with organic solvent, and wash with 5% aqueous NaCl solution (10 ml). Remove the solvent, and purify the crude product by column chromatography with gradient elution (hexane / EtOAc 85 / 15 to EtOAc 100%) to obtain the pure product as a colorless oil (yield 30%).

[0382] Example 21

[0383] Preparation of methyl 3-hydroxy-4-(difluoromethoxy)-benzoate

[0384]

[0385] Dissolve 100 g of 3-hydroxy-4-(difluoromethoxy)-benzaldehyde (0.53 mol) in MeOH (600 ml), add solid (325 g, 1.06 mol) portionwise over 1 h, and stir and warm the solution to 50 - 55 °C for 2 h. Concentrate the solvent in vacuo to 200 ml, and add water (1 L). Stir the resulting heterogeneous solution at 50 - 55 °C, then add toluene (500 ml), and stir the two-phase mixture vigorously. Drain the aqueous phase, and wash the organic phase with water (500 ml). Add activated carbon (10 g), and stir the organic solution for 20 min. Filter it through a pad of diatomaceous earth, concentrate the solvent in vacuo to 2 - 3 volumes, and warm the resulting solution to 80 - 90 °C. Slowly add n-heptane (400 ml). Cool the mixture to 0 °C, and stir the suspension at 0 °C overnight. Filter the solid on a Buchner funnel, and wash with n-heptane (100 ml). Dry the resulting white solid in vacuo at room temperature (yield 70%).

[0386] Example 22

[0387] Preparation of methyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoate

[0388]

[0389] Dissolve 873 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (3.61 mol) in MeOH (4.4 L), then add solid (1.86 Kg, 6.06 mol), and the solution was stirred and warmed to 55 - 60 °C and maintained for 2 hours. The solvent was concentrated in vacuo to 1.6 L and water (7 L) was added. The resulting heterogeneous solution was stirred at 50 - 55 °C, then toluene (3 L) was added, and the two - phase mixture was stirred vigorously. The aqueous phase was drained off, and the organic phase was washed with water (3 L). The solvent was concentrated in vacuo to 2 - 3 volumes, and the resulting solution was warmed to 80 - 90 °C. n - Heptane (5.5 L) was added slowly. The mixture was cooled to - 10 °C, and the suspension was stirred at - 10 °C overnight. The solid was filtered on a Buchner funnel and washed with n - heptane (1 L). The resulting yellow solid was dried in vacuo at room temperature (yield 52%).

[0390] Example 23

[0391] Preparation of 1 - (3 - (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5 - dichloro - 1 - pyridin - 4 - yl)ethanone (Intermediate (VII), n = 0)

[0392]

[0393] Methyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoate (30 g, 0.11 mol) and 3,5 - dichloro - 4 - methyl - pyridine (21.4 g, 0.13 mol) were charged into a 1 L reactor and dissolved in THF (120 ml). The homogeneous solution was cooled to - 10 °C with stirring. A solution of 1 M lithium bis(trimethylsilyl)amide in THF (0.22 mol, 220 ml) was added slowly over 30 minutes. The mixture was stirred at low temperature for 15 - 30 minutes, then quenched with 10% aqueous HCl (250 ml) and warmed to room temperature. Ethyl acetate (300 ml) was added, and the two - phase mixture was stirred vigorously for 15 - 20 minutes. The aqueous phase was re - extracted with ethyl acetate (150 ml). The recombined organic phase was concentrated to 2 volumes. Isopropanol (240 ml) was added, and the solution was concentrated again to 2 - 3 volumes. Isopropanol (150 ml) was added, and the solution was cooled to 0 °C to give a pale yellow solid precipitate. After 3 hours, the solid was filtered on a Buchner funnel and washed with 1 volume of cold isopropanol. The resulting solid was dried in vacuo at room temperature (yield 90.5%).

[0394] Example 24

[0395] Preparation of methyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoate

[0396]

[0397] Procedure using DMF and potassium carbonate

[0398] Dissolve methyl 3-hydroxy-4-(difluoromethoxy)-benzoate (5 g, 22.9 mmol), K2CO3 (4.75 g, 34.4 mmol), NaI (0.34 g, 2.3 mmol) and bromo-methylcyclopropane (3.7 g, 27.5 mmol) in DMF (25 ml), and stir the heterogeneous mixture and warm it at 80 °C for 2 h. Cool the suspension to room temperature and add water (50 ml) with stirring. Cool the heterogeneous mixture to 0 - 5 °C for 60 - 90 min, and filter the solid on a Gooch funnel and wash it with water (50 ml). An orange solid is obtained. Dry it in vacuo at room temperature (yield 95.8%).

[0399] Example 25

[0400] Preparation of methyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoate

[0401]

[0402] Procedure using DMA, potassium carbonate and MeI

[0403] Suspend methyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoate (50 g, 193.6 mmol) and K2CO3 (28.1 g, 203.3 mmol) in DMA (400 ml), and warm the suspension to 75 - 85 °C. Add a solution of MeI (32.97 gr, 232.0 mmol) in DMA (100 ml) dropwise through a dropping funnel over 1 h. At the end of the addition, cool the suspension to 0 - 5 °C, and add water (500 ml) with stirring. Precipitation of a white solid occurs. Stir the heterogeneous cold mixture for 60 - 90 min, and filter the solid on a Gooch funnel and wash it with water (50 ml). The product is obtained as a white solid. Dry it in vacuo at room temperature (yield 98.1%).

[0404] Example 26

[0405] Preparation of methyl 3-hydroxy-4-(difluoromethoxy)-benzoate

[0406]

[0407] In a 50 ml flask, 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzonitrile (0.5 g, 2.7 mmol) was dissolved in MeOH (3 ml), and the homogeneous solution was stirred at room temperature. 91% aqueous H2SO4 solution (1 ml) was added dropwise slowly, and the solution was warmed at 50 °C for 1 week. The solution was cooled to 0 - 5 °C and water (10 ml) was added, and the resulting suspension was stirred at low temperature for 1 hour. The suspension was filtered on a Gooch funnel. The product was obtained as a white solid (yield 78%).

[0408] Example 27

[0409] (R / S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro - 1-oxy-pyridin-4-yl)ethanol (Intermediate (VI), n = 1) Preparation

[0410]

[0411] In a 100 ml round-bottom flask, (VII) (where n is 1) (0.2 g, 0.48 mmol) was added under a nitrogen atmosphere, suspended in MeOH (10 ml) and cooled to 0 - 5 °C. NaBH4 (18.0 mg, 0.48 mmol) was added, and the suspension was stirred for 1.5 hours. The reaction mixture was quenched with H2O (25 ml) and warmed to room temperature. The aqueous solution was extracted twice with ethyl acetate (2 × 15 ml), and the combined organic phases were dried over Na2SO4. The solvent was evaporated under reduced pressure to give a crude solid. It was dissolved in hot toluene (10 ml, 85 - 90 °C), and the solution was cooled to 0 - 5 °C and kept for 2 hours for crystallization. The resulting solid was filtered, washed with 10 ml of toluene and dried in a vacuum desiccator on a stationary rack. 164.5 mg of white solid was obtained (81.6% yield).

[0412] This application also includes the following specific embodiments:

[0413] 1. A method for preparing a compound of formula (I) wherein n is 0 or 1,

[0414]

[0415] The method comprises:

[0416] a) reacting a compound of formula (II)

[0417]

[0418] wherein n is 0 or 1, with a compound of formula (III)

[0419]

[0420] wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6) alkylcarbonyloxy, to obtain a compound of formula (I), wherein n is 0 or 1, or a compound of formula (IV)

[0421]

[0422] wherein n has the meaning reported above and X is -NO2; and, when a compound of formula (IV) is obtained in step a):

[0423] b) reducing it to the corresponding compound of formula (V)

[0424]

[0425] wherein n is 0 or 1 and reacting it with methanesulfonyl halide to obtain a compound of formula (I), wherein n has the meaning reported above;

[0426] and wherein the compound of formula (II) in step a) is obtained as follows according to either alternative step c1) or c2):

[0427] c1) oxidizing a compound of formula (VI)

[0428]

[0429] wherein n is 0 or 1 to obtain a compound of formula (VII)

[0430]

[0431] wherein n is 0 or 1, and subsequently enantioselectively reducing it to obtain a compound of formula (II), wherein n has the meaning reported above; or

[0432] c2) chromatographically separating a compound of formula (VI), wherein n is 0 or 1, to obtain a compound of formula (II) and a compound of formula (VIII)

[0433]

[0434] wherein n has the meaning reported above;

[0435] and optionally oxidizing the compound of formula (VIII) obtained in step c2) to the corresponding compound of formula (VII), which is subsequently reduced to a compound of formula (VI), wherein n is 0 or 1, and reprocessed in the chromatographic separation method;

[0436] And compounds of all of formulae (I), (II), (IV), (V), (VI), (VII) or (VIII) wherein n is 1 can be obtained by oxidation of the corresponding compounds wherein n is 0.

[0437] 2. The method according to embodiment 1, the method comprising reacting a compound of formula (II) with a compound of formula (III) in step a), wherein X is -NHSO2Me.

[0438] 3. The method according to embodiment 1, the method comprising reacting a compound of formula (II) with a compound of formula (III) in step a), wherein X is -NO2, to obtain a compound of formula (IV), and in step b), reducing (IV) to the corresponding amino derivative of formula (V), and then reacting the amino derivative with methanesulfonyl halide to obtain a compound of formula (I).

[0439] 4. The method according to embodiment 1, the method comprising reacting the compound of formula (II) obtained according to step c1): oxidizing a compound of formula (VI) to a compound of formula (VII), and enantioselectively reducing the latter compound to a compound of formula (II).

[0440] 5. The method according to embodiment 1, the method comprising reacting the compound of formula (II) obtained according to step c2): chromatographically separating a compound of formula (VI) to obtain a compound of formula (II) and a compound of formula (VIII).

[0441] 6. The method according to embodiment 1, the method comprising oxidizing a compound of formula (I) wherein n is 0.

[0442] 7. The method for preparing a compound of formula (I) or a compound of formula (IV) according to any one of embodiments 1-3, the method comprising: in the presence of a coupling agent selected from DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, EDCI, with or without HOBt, with or without an organic base such as TEA, DIPEA, NMM, DBU, DBO, pyridine and DMAP, in a solvent selected from dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di alkane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, reacting a compound of formula (II) with a compound of formula (III) wherein Z is -OH.

[0443] 8. The method according to specific embodiment 1 or 2 is implemented with CDI and DBU in ethyl acetate.

[0444] 9. The method according to specific embodiment 1 or 3 is implemented with EDCI and DMAP in DMF.

[0445] 10. The method according to specific embodiment 1 or 3, wherein the reduction of (IV) in step b) is carried out with a reducing agent selected from hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, stannous chloride, tin, nickel chloride, nickel, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, and sodium dithionite.

[0446] 11. The method according to specific embodiment 10, wherein the reducing agent is selected from hydrogen, cyclohexadiene, ammonium formate, and formic acid, and is carried out in the presence of a catalyst selected from palladium-based, platinum-based, or nickel-based catalysts, or selected from palladium on carbon, palladium sulfide on carbon, palladium on barium sulfate, palladium on calcium carbonate, and platinum on carbon.

[0447] 12. The method according to specific embodiment 10, wherein the reducing agent is formic acid, and is carried out in the presence of ammonia or an amine, preferably triethylamine, in a solvent selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, THF, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, and mixtures thereof.

[0448] 13. The method according to specific embodiment 10 is carried out with hydrogen on 5% palladium on activated carbon powder, model A103038, and sulfided in ethyl acetate.

[0449] 14. The method according to specific embodiment 1 or 3, wherein the reaction of (V) with methanesulfonyl halide is carried out in the presence of one or more solvents and a base, the solvents being selected from toluene, benzene, xylene, tetrahydrofuran, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, and the base is preferably selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA, DIPEA, NMM, DBO, pyridine, and DMAP, and wherein in the case of excessive use of pyridine, other solvents can be avoided.

[0450] 15. The method according to embodiment 1 or 4, wherein in the presence of an oxidizing agent, the oxidation of (VI) to obtain (VII) is carried out in a solvent selected from water, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, THF, di alkane and mixtures thereof, and the oxidizing agent is selected from metal oxides such as MnO2, hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-based oxidizing agent (Swern) such as sulfur trioxide pyridine complex.

[0451] 16. The method according to embodiment 1 or 4, wherein the enantioselective reduction of (VII) to (II) is carried out with a reducing agent selected from hydrogen in the presence of a preformed or in-situ formed heavy metal chiral complex, and the in-situ formation can occur as follows: reacting a Ru-, Rh- or Ir-complex such as RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCl2(Cp*)]2 or [IrCl2(Cp*)]2 with a chiral ligand such as SL-N004-1 ((S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl] oxazoline), SL-N003-1 ((R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl] oxazoline), (S,S)-Ts-DPEN ((1S,2S)-(-)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine), (S,S)-Ms-DPEN ((1S,2S)-(-)-N-methanesulfonyl-1,2-diphenylethylenediamine), (R)-DAIPEN ((2R)-(-)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), (1R,2S)-1-amino-2-indanol.

[0452] 17. The method according to embodiment 16, wherein the enantioselective reduction is carried out in the presence of a base selected from sodium hydroxide, sodium carbonate, C1-C4 sodium alkoxide, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C1-C4 potassium alkoxide, potassium bicarbonate, lithium hydroxide, lithium carbonate, C1-C4 lithium alkoxide, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, pyridine and 4-dimethylaminopyridine.

[0453] 18. The method according to embodiment 1 or 4, wherein the enantioselective reduction is carried out in the presence of a reducing agent selected from borane chiral complexes such as diisopinocampheylborane (e.g., allyl - diisopinocampheylborane, chloro - diisopinocampheylborane, diisopinocampheyl - methoxyborane) or oxazaborolidine (e.g., 2 - methyl - CBS - oxazaborolidine, 2 - butyl - CBS - oxazaborolidine, o - tolyl - CBS - oxazaborolidine, where CBS represents Corey - Bakshi - Shibata oxazaborolidine catalyst).

[0454] 19. The method according to embodiment 16, wherein the enantioselective reduction is carried out in a solvent selected from water, methanol, ethanol, isopropanol, n - butanol, tert - butanol, dimethylformamide, dimethylacetamide, N - methylpyrrolidone, toluene, benzene, xylene, THF, di ane, 2 - methoxyethyl ether, diethyl ether, isopropyl ether, tert - butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, and mixtures thereof.

[0455] 20. The method according to embodiment 1 or 4, wherein the enantioselective reduction is carried out in toluene and in the presence of an aqueous sodium hydroxide solution, by means of a complex formed in situ by reacting RuCl2(PPh3)3 with a chiral ligand SL - N004 - 1.

[0456] 21. Intermediate compounds of formula (IV) and (V), wherein n is 0 or 1

[0457]

[0458] 22. Intermediate compound of formula (III), wherein X is - NHSO2Me and Z is - OH

[0459]

[0460] 23. A method for preparing a compound of formula (IX)

[0461]

[0462] wherein n is 0 or 1 and R1 and R2 are independently selected from H, straight-chain or branched (C1-C6) alkyl, said (C1-C6) alkyl optionally being substituted with one or more substituents selected from halogen atoms, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C5-C7) cycloalkenyl, straight-chain or branched (C2-C6) alkenyl, aryl(C2-C6) alkenyl and straight-chain or branched (C2-C6) alkynyl, and the method comprises:

[0463] a) reacting a compound of formula (X)

[0464]

[0465] wherein n is 0 or 1, with a compound of formula (III)

[0466]

[0467] wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6) alkylcarbonyloxy, to obtain a compound of formula (XI) wherein n is 0 or 1, or to obtain a compound of formula (XII)

[0468]

[0469] wherein R1, R2 and n have the meanings reported above; and, when a compound of formula (XII) is obtained in step (a):

[0470] b) reducing it to the corresponding compound of formula (XIII)

[0471]

[0472] wherein R1, R2 and n have the meanings reported above, and reacting it with methanesulfonyl halide to obtain a compound of formula (XI) wherein n has the meaning reported above;

[0473] and wherein the compound of formula (X) in step (a) is obtained as follows according to either alternative step (c1) or (c2):

[0474] c1) oxidizing a compound of formula (XIV)

[0475]

[0476] wherein n is 0 or 1, to obtain a compound of formula (XV)

[0477]

[0478] wherein n is 0 or 1, and subsequently enantioselectively reducing it to obtain a compound of formula (X), wherein n has the meaning reported above; or

[0479] c2) chromatographically separating the compound of formula (XIV), wherein n is 0 or 1, to obtain a compound of formula (X) and a compound of formula (XVI)

[0480]

[0481] wherein n has the meaning reported above;

[0482] and optionally oxidizing the compound of formula (XVI) obtained in step (c2) to the corresponding compound of formula (XV), which is subsequently reduced to the compound of formula (XIV), wherein n is 0 or 1 and reprocessed in the following chromatographic separation method;

[0483] and all compounds of formula (XI), (X), (XII), (XIII), (XIV), (XV) or (XVI) wherein n is 1 can be obtained by oxidizing the corresponding compound wherein n is 0.

[0484] 24. The method according to embodiment 22, wherein any one of steps a), b), c1) and c2) is carried out according to any one of the foregoing embodiments.

[0485] 25. Intermediate compounds of formula (XII) and (XIII)

[0486]

[0487] wherein n is 0 or 1, and R1 and R2 are independently selected from H, straight-chain or branched (C1-C6) alkyl, said (C1-C6) alkyl optionally being substituted by one or more substituents selected from halogen atoms, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C5-C7) cycloalkenyl, straight-chain or branched (C2-C6) alkenyl, aryl(C2-C6) alkenyl and straight-chain or branched (C2-C6) alkynyl.

[0488] 26. The method according to embodiment 1, the method comprising crystallization or trituration from one or more solvents selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di ane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, aliphatic or aromatic hydrocarbons, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or mixtures thereof.

[0489] 27. The method for preparing Form A as described in embodiment 26, which is carried out with n - heptane in ethyl acetate.

[0490] 28. The method as described in embodiment 27 and its use in combination with a suitable carrier or vehicle for preparing an inhalation pharmaceutical composition.

[0491] 29. A crystal form of the compound of formula (I) wherein n is 1, characterized by the following characteristic XRPD peaks: 7.48; 7.93; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 18.08; 18.53; 18.94; 8.55; 17.79; 19.89; 19.1; 20.2; 21.37; 22.96; 23.63; 24.87; 26.51; 28.09; 28.61 and 25.82 ± 0.2 degrees / 2θ (CuKα2).

[0492] 30. The crystal form as described in embodiment 29, which is used for preventing and / or treating inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0493] 31. A method for preventing and / or treating inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), which comprises inhalably administering an effective amount of the crystal form as described in embodiment 29 or 30.

[0494] 32. A solvate of the compound of formula (I) obtained from ethanol as a solvent.

[0495] 33. A method for preparing a compound of formula (I) wherein n is 0 or 1,

[0496]

[0497] The method comprises:

[0498] a) reacting a compound of formula (II)

[0499]

[0500] wherein n is 0 or 1, with a compound of formula (III)

[0501]

[0502] wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6) alkylcarbonyloxy, to obtain a compound of formula (I), wherein n is 0 or 1, or a compound of formula (IV)

[0503]

[0504] wherein n has the meaning reported above; and, when a compound of formula (IV) is obtained in step a):

[0505] b) reducing it to the corresponding compound of formula (V)

[0506]

[0507] wherein n is 0 or 1 and reacting it with a mesyl halide to obtain a compound of formula (I), wherein n has the meaning reported above;

[0508] and wherein the compound of formula (II) is obtained as follows according to step c3):

[0509] c3) reacting an intermediate of formula B”

[0510]

[0511]

[0512] with an intermediate of formula D

[0513]

[0514] wherein R is straight-chain or branched (C1-C6) alkyl or arylalkyl and n has the meaning reported above, to directly obtain a compound of formula (VII)

[0515]

[0516] and subsequently enantioselectively reducing it to obtain a compound of formula (II), wherein n has the meaning reported above; and wherein all compounds of formula (I), (II), (IV), (V) or (VII), wherein n is 1, can be obtained by oxidizing the corresponding compound wherein n is 0.

[0517] 34. The method according to embodiment 33, wherein the intermediate of formula B” is obtained by converting an intermediate of formula B’ as follows:

[0518]

[0519] in the presence of a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di alkane, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof, and a base, reacting with thionyl chloride, hydrochloric acid or sulfuric acid or with a relevant alkyl halide, said base being selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine.

[0520] 35. The method according to embodiment 34, wherein the intermediate of formula B” is obtained from the intermediate of formula B’ in dimethylformamide or dimethylacetamide in the presence of potassium carbonate.

[0521] 36. A method for preparing intermediate B’

[0522]

[0523] The method comprises oxidizing intermediate B with an oxidizing agent selected from hydrogen peroxide, organic peracid, m-chloroperbenzoic acid, persulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4).

[0524]

[0525] 37. A method for preparing intermediate B”

[0526]

[0527] wherein R is a straight-chain or branched (C1-C6) alkyl or arylalkyl, the method comprising oxidizing intermediate B with (KHSO5*1 / 2KHSO4*1 / 2K2SO4) in the corresponding alkyl alcohol as a solvent.

[0528]

[0529] 38. A method for preparing intermediate B”

[0530]

[0531] wherein R is a straight-chain or branched (C1-C6) alkyl or arylalkyl, the method comprising converting intermediate C’ into intermediate C” by a Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as a solvent.

[0532]

[0533] and then.

[0534]

[0535] Subsequently, it is alkylated with cyclopropyl bromide in the presence of a solvent selected from toluene, benzene, xylene, tetrahydrofuran, di alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene and mixtures thereof and a base selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine and 4-dimethylaminopyridine.

[0536] 39. A crystalline form of the compound of formula (I),

[0537]

[0538] wherein n is 1, characterized by the following characteristic XRPD peaks: 7.48; 7.93; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 18.08; 18.53; 18.94; 8.55; 17.79; 19.89; 19.1; 20.2; 21.37; 22.96; 23.63; 24.87; 26.51; 28.09; 28.61 and 25.82 ± 0.2 degrees / 2θ (CuKα2).

[0539] 40. The crystalline form according to embodiment 39, wherein the percentage of crystallinity is equal to or higher than 90%.

[0540] 41. The crystalline form according to embodiment 39, wherein the percentage of crystallinity is equal to or higher than 95%.

[0541] 42. The crystalline form according to embodiment 39, wherein the total amount of easily detectable impurities is less than 1.0 w / w.

[0542] 43. The crystalline form according to embodiment 39, wherein the total amount of easily detectable impurities is less than 0.5% w / w.

[0543] 44. A method for preparing the crystalline form according to any one of embodiments 39-43, the method comprising crystallizing the compound of formula (I) from one or more solvents selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, di Alkanes, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, aliphatic or aromatic hydrocarbons, pentane, hexane, heptane, cyclohexane, and methylcyclohexane, or mixtures thereof.

[0544] 45. The method according to embodiment 44, wherein the solvent is ethyl acetate / heptane or isopropyl acetate.

[0545] 46. A pharmaceutical composition for inhalation, the pharmaceutical composition comprising the crystalline form according to any one of embodiments 39-43 in combination with a suitable carrier or vehicle.

[0546] 47. Use of the crystalline form according to any one of embodiments 39-43 or the inhalation composition according to embodiment 46 in the manufacture of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases

[0547] 48. Use of the crystalline form according to any one of embodiments 39-43 or the inhalation composition according to embodiment 46 in the manufacture of a medicament for the prevention and / or treatment of asthma, chronic obstructive pulmonary disease or chronic bronchitis.

Claims

1. A method for preparing a compound of formula (I) wherein n is 0 or 1, (I) The method comprises: a) React a compound of formula (II) (II) wherein n is 0 or 1, with a compound of formula (III) (III) wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6) alkoxy, aryloxy, arylalkoxy, (C1-C6) alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6) alkylcarbonyloxy, to obtain a compound of formula (I) wherein n is 0 or 1, or a compound of formula (IV) (IV) wherein n has the meaning reported above; and, when a compound of formula (IV) is obtained in step a): b) Reduce it to the corresponding compound of formula (V) (V) wherein n is 0 or 1 and react it with methanesulfonyl halide to obtain a compound of formula (I) wherein n has the meaning reported above; and wherein the compound of formula (II) is obtained as follows according to step c3): c3) React an intermediate of formula B'' Intermediate B'' with an intermediate of formula D Intermediate D wherein R is straight-chain or branched (C1-C6) alkyl or arylalkyl and n has the meaning reported above, to directly obtain a compound of formula (VII) (VII) and subsequently enantioselectively reduce it to obtain a compound of formula (II) wherein n has the meaning reported above; and wherein all compounds of formula (I), (II), (IV), (V) or (VII) wherein n is 1 can be obtained by oxidizing the corresponding compound wherein n is 0.

2. The method according to claim 1, wherein the intermediate of formula B’’ is obtained by converting the intermediate of formula B’ as follows: Intermediate B’ In a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, with or without other solvents, react with thionyl chloride, hydrochloric acid or sulfuric acid; or in a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di ane, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof in the presence of a base and an alkyl halide, the base being selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine and pyridine.

3. The process according to claim 2, wherein the intermediate of formula B'' is obtained by converting the intermediate of formula B' in dimethylformamide or dimethylacetamide in the presence of potassium carbonate.

4. The method according to claim 3, wherein the method comprises oxidizing the intermediate B with an oxidant selected from hydrogen peroxide, an organic peracid, meta-chloroperbenzoic acid, persulfate or Oxone® (KHSO5*1 / 2KHSO4*1 / 2K2SO4) Intermediate B, Preparation of intermediate B' Intermediate B'.

5. The method according to claim 3, comprising oxidizing the intermediate B by using Oxone® (KHSO5*1 / 2KHSO4*1 / 2K2SO4) in the corresponding alkyl alcohol as solvent Intermediate B, Preparation of intermediate B'' Intermediate B'' wherein R is a linear or branched (C1-C6) alkyl or arylalkyl group.

6. The method according to claim 3, comprising reacting the intermediate C' by Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as solvent. Intermediate C' Transformed into intermediate C'', Intermediate C'' Then, in a mixture selected from toluene, benzene, xylene, tetrahydrofuran, alkylation with cyclopropyl bromide in the presence of a solvent selected from the group consisting of 1,4-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine and 4-dimethylaminopyridine in the presence of a base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine and 4-dimethylaminopyridine, Preparation of intermediate B'' Intermediate B'' Wherein R is a straight-chain or branched (C1-C6) alkyl or aralkyl group.

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