Process for preparation of PDE4 inhibitors

Abstract

The present invention relates to a method for preparing a compound having phosphodiesterase (PDE4) inhibitory activity of formula (I). The invention also relates to a process for isolation 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 invention also relates to solvates and crystalline forms of the compounds of formula (I). The synthetic products are suitable for pharmaceutical use, such as for the treatment of respiratory diseases. # imgabs0 #

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 202210366235.7, 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-oxo-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 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.

[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 dermatitis, 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] This method is particularly advantageous compared to known methods because it provides a simpler and safer operation, with improved control over process parameters and reproducibility, a reduced number of synthetic steps and intermediate separations, a higher atom efficiency, a reduced solvent volume, a higher product formation yield and a reduced number of impurities.

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

[0015] The method according to the invention allows the obtention of a thermodynamically stable crystalline form of the compound of formula (I) (where n is 1), which will hereinafter be referred to as form A, 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, crystalline form A of the present invention can be selectively produced, giving it the characteristic peaks and 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 inflammatory or obstructive respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), the method comprising inhaled administration of an effective amount of polymorph A.

[0020] By operating with a suitable solvent, a solvate of the compound of formula (I) (wherein n is 1) is also obtained.

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

[0022] Specifically, the solvate of the compound of formula (I) is obtained from ethanol and can be distinguished based on its characteristic peaks in the 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) (wherein n is 1).

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

[0029] Figure 3 is an XRPD pattern of the ethanol solvate of the compound of formula (I) (wherein 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 polymorph 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 polymorph 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 - NHSO 2 Me and - NO 2 and Z is selected from - OH, chlorine, bromine, linear or branched (C 1 - C 6 ) alkoxy, aryloxy, arylalkoxy, (C 1 - C 6 ) alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 - C 6 ) 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 methanesulfonyl 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), (c2) or (c3):

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

[0050]

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

[0052]

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

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

[0055]

[0056] wherein 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) (wherein 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] wherein R is a straight-chain or branched (C 1 -C 6 ) 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), wherein n has the meaning reported above;

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

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

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

[0066] The term straight-chain or branched (C 1 -C 6 )alkyl represents a straight-chain or branched alkyl group having 1 to 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 (C 1 -C 6 )arylalkyl represents a (C 1 -C 6 )alkyl further substituted by an aryl group.

[0068] The term straight-chain or branched (C 1 -C 6 )alkoxy refers to any alkyl-oxy chain, where the alkyl represents a straight-chain or branched alkyl group having 1 to 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., an 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 to 3 heteroatoms or heteroatom groups selected from N, NH, O, or S. Phenoxy is preferred.

[0070] The term arylalkoxy refers to any (C 1 -C 6 )alkoxy substituted by one or more aryl groups as defined above. Benzyloxy is preferred.

[0071] The term arylalkylcarbonyloxy refers to any (C 1 -C 6 )alkylcarbonyloxy 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) wherein n is 0 or 1, the method comprising, in step (a), reacting a compound of formula (II) wherein n has the meaning reported above with a compound of formula (III) wherein X is NHSO 2 Me 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) wherein n is 0 or 1, the method comprising, in step (a), reacting a compound of formula (II) wherein n has the meaning reported above with a compound of formula (III) wherein X is -NO 2 and Z has the meaning reported above).

[0075] According to a further preferred embodiment, the present invention provides a method for preparing a compound of formula (I) wherein n is 0 or 1, the method comprising reacting a compound of formula (II) obtained according to step (c1) as follows: oxidizing a 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 method for preparing a compound of formula (I) wherein n is 0 or 1, the method comprising reacting a compound of formula (II) obtained according to step (c2) as follows: chromatographically separating a 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 method for preparing a compound of formula (I) wherein n is 0 or 1, the method comprising reacting a compound of formula (II) obtained according to step (c2) as follows: chromatographically separating a 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 method for preparing a compound of formula (I) wherein n is 0 or 1, the method comprising reacting a compound of formula (II) obtained according to step (c3) as follows: reacting an intermediate of formula B”

[0079]

[0080] React with the intermediate of formula D

[0081]

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

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

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

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

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

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

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

[0089] According to step (a) of the present invention, the method provides for preparing a compound of formula (I) or a compound of formula (IV) by reacting a compound of formula (II) with a compound of formula (III) where 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, ethyl 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) where X is -NHSO 2 Me is carried out in ethyl acetate with CDI and DBU.

[0093] In an alternative preferred embodiment, when carrying out the reaction with a compound of formula (III) where X is -NO 2 to produce a 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 a compound of formula (III) where X is -NO 2 in step (a), first reduce the compound of formula (IV) where n has the meaning reported above to the corresponding amino derivative of formula (V), and then appropriately react 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 formic acid is used, 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, 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 ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene and mixtures thereof) and a base, which 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 using an excess 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), first the compound of formula (VI) is oxidized to the corresponding ketone derivative of formula (VII), and then it is enantioselectively reduced to the compound of formula (II).

[0103] Preferably in the presence of an oxidizing agent (selected from metal oxides such as MnO 2 , hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-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 ane and mixtures thereof) for oxidation.

[0104] Even more preferably, with MnO 2 The reaction is carried out in toluene or with a Swern oxidant in DMSO.

[0105] As described in WO 2010 / 089107, the compound of formula (VI) can be prepared from the intermediate of formula B

[0106]

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

[0108]

[0109] Prepare the compound of formula (VI).

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

[0111]

[0112] into the intermediate of formula B''

[0113]

[0114] React with thionyl chloride, hydrochloric acid, sulfuric acid in methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, with or without other solvents; or react with the relevant alkyl halide 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, 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 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 an oxidant selected from hydrogen peroxide, an organic peracid such as peracetic acid or m-chloroperbenzoic acid or an inorganic peracid such as persulfuric acid or (KHSO 5*1 / 2KHSO 4 *1 / 2K 2 SO 4 ) The oxidizing agent for oxidizing intermediate B can give intermediate B'. More preferably, use The above reaction is carried out in methanol.

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

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

[0119]

[0120] Subsequently, in the presence of a suitable solvent (such as 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 a base, cyclopropyl bromide is alkylated, 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] Then intermediate B'' is converted into 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 ane, 2-methoxyethyl ether, ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof, react with intermediate D in the presence of a base, and the base is preferably selected from lithium diisopropylamide (LDA), butyllithium, hexyllithium, pentyllithium, lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide, potassium tert-butoxide.

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

[0123] Subsequent enantioselective reduction steps are 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 (PPh 3 ) 3 、 [Ru(p - cymene)Cl 2 2 、 [RhCI 2 (Cp*)] 2 or [IrCI 2 (Cp*)] 2 react with chiral ligands 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, C 1 - C 4 sodium alkoxide, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C 1 - C 4 potassium alkoxide, potassium bicarbonate, lithium hydroxide, lithium carbonate, C 1 - C 4 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 RuCl 2 (PPh 3 ) 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 process of the 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) by oxidation to the corresponding derivative of formula (VII) and subsequent reduction and retreatment in the following chromatographic separation method, as previously reported.

[0128] The reduction can be carried out with lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride in a solvent such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, benzene, xylene, THF, dimethylbenzene, The method can be carried out in the range of 1:1 to 2:1, 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof.

[0129] It should be understood that by using a mixture 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, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, The solvent is selected from hydrogen peroxide, an organic peracid such as peracetic acid or m-chloroperbenzoic acid or an inorganic peracid such as persulfuric acid or (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 ) can be oxidized with an oxidizing agent such as .

[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) in which X is -NHSO 2 Me and Z is -OH represent another object of the present invention.

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

[0138] As another example, compounds of formula (III) in which X is -NHSO 2 Me can be prepared from the corresponding derivatives in which X is -NO 2 as follows: reducing the derivatives to amino derivatives and subsequently reacting them with methanesulfonyl halide, substantially as previously reported.

[0139] Similarly, the preparation of compounds of formula (III) in which 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 compounds of formula (III) in which 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 is selected from water alone or water mixed with: methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, di ane and mixtures thereof.

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

[0142] Similarly, the preparation of compounds of formula (III) in which Z is not -OH can be carried out 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 method for preparing further compounds of formula (IX), said compounds bearing additional R 1 and R 2 groups at the positions of the cyclopropylmethyl and difluoromethyl of formula (I) relative to the above compounds of formula (I).

[0144] The compound of formula (IX) can be used for prophylactic purposes or for alleviating the 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 method for preparing a compound of formula (XI)

[0146]

[0147] wherein n is 0 or 1;

[0148] and R 1 and R 2 are independently selected from H, straight-chain or branched (C 1 -C 6 )alkyl, the (C 1 -C 6 )alkyl being optionally substituted with one or more substituents selected from halogen atoms, (C 3 -C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, straight-chain or branched (C 2 -C 6 )alkenyl, aryl(C 2 -C 6 )alkenyl and straight-chain or branched (C 2 -C 6 )alkynyl, the method 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 -NHSO 2 Me and -NO 2 , and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C 1 -C 6 )alkoxy, aryloxy, arylalkoxy, (C 1 -C 6 )alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 -C 6 )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 the compound of formula (XII) is obtained 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] It is obvious from all of the above that the operating conditions of the foregoing steps of the method 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 easily prepared according to known methods.

[0174] In another even more preferred embodiment, when the compound (I) (where n is 0 or 1) is obtained, 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 for separation by crystallization of the 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 preventing and / or treating 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, inhalatory, 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 the inhalatory 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, emulsifying agents, 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 may 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, its toxicological properties and pharmacokinetic properties.

[0185] Advantageously, the compounds of formula (I) (wherein n is 0 or 1) may be administered, for example, in a dosage 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 may be used for prophylactic purposes or for the symptomatic relief 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) may 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 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 preventing or treating 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 disorder being treated, or measurably reduces the likelihood of the development of a 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 selected from metal oxides such as MnO 2 , hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-based oxidizing agent (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 in a solvent of an alkane and its mixture. The reaction is preferably carried out with MnO 2 in toluene or with a Swern oxidant 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 alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether and their mixtures), the intermediate of formula B”

[0200]

[0201] wherein R is a straight-chain or branched (C 1 -C 6 ) alkyl or arylalkyl, is reacted with the 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, 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 their mixtures and a base, react 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.

[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 In the presence of an alkane, 2-methoxyethyl ether, isopropyl acetate, acetonitrile, and mixtures thereof, compound B' can be obtained from compound B using 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 (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 ). More preferably, the above reaction is carried out in methanol.

[0208] Alternatively, intermediate B" can be obtained from intermediate C" 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. 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 using potassium carbonate in dimethylformamide.

[0209] Intermediate C" can be obtained from intermediate C' 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. 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 using sulfuric acid in methanol.

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

[0211] The reducing agent is selected from hydrogen, and in the presence of a preformed or in-situ formed heavy metal chiral complex, a Ru-, Rh- or Ir-complex such as RuCl 2 (PPh 3 ) 3 , [Ru(p-cymene)Cl 2 2 , [RhCI 2 (Cp*)] 2 or [IrCI 2 (Cp*)] 2 is reacted 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, C 1 -C 4 sodium alkoxide, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C 1 -C 4 potassium alkoxide, potassium bicarbonate, lithium hydroxide, lithium carbonate, C 1 -C 4 lithium alkoxide, 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, diethyl 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 by using a complex formed in-situ by reacting RuCl 2 (PPh 3 ) 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, an organic peracid such as peracetic acid or m-chloroperbenzoic acid, or an inorganic peracid such as peroxymonosulfuric acid or (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 ). 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 - 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 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 the separation of large quantities.

[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 to the compound of formula (VI) as follows: oxidation to the corresponding derivative of formula (VII), followed by reduction and reprocessing 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 -NHSO 2 Me, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C 1 -C 6 ) alkoxy, aryloxy, arylalkoxy, (C 1 -C 6 ) alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 -C 6) An alkylcarbonyloxy group, and 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) can be obtained under well-known conditions starting from methyl 3-cyclopropylmethoxy-4-methanesulfonylamino-benzoate (obtained as described in WO2007 / 089107, Example 18) or starting from the relevant ester of 3-hydroxy-4-nitrobenzoic acid according to the same synthetic route, where X is -NHSO 2 Me and Z is as defined above.

[0221] Intermediate (III) (where X is -NHSO 2 Me and Z is as defined above) is converted to (III) (where Z is -OH) by hydrolysis in a base, and the base is preferably selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate; the solvent is selected from water alone or water mixed with the following substances: methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, di ane and mixtures thereof. 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 compound 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 in the presence of a coupling agent such as hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), and DCC (N,N'-dicyclohexylcarbodiimide), or a reagent that can convert a carboxylic acid into an acyl chloride, acyl bromide, activated ester, or mixed anhydride, 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 alkane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, condense intermediate (III) (where X is -NHSO 2 Me and Z is -OH) with intermediate (II) (where n is 0 or 1).

[0223] When the compound of formula (III) is an acyl chloride or acyl bromide or activated ester and 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 -NHSO 2 Me) with (II), intermediate (IV) (where n is 0 or 1) is obtained by the condensation of (III) (where X is -NO 2 ) with (II) (where n is 0 or 1). In a preferred embodiment, the reaction is carried out with EDCI and DMAP in DMF.

[0226] 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, 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 Alkanes, 2-methoxyethyl ether, diethyl 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] 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 Alkanes, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof, to obtain compound (I) (where n is 0 or 1), 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, the solvents 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 Alkanes, 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. The reaction is preferably carried out with n-heptane in ethyl acetate.

[0233] Thus, for example, polymorph 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 the 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 the 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 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 = -NHSO 2 Me, Z = -OH)

[0240]

[0241] (III) is obtained as described in WO 2010 / 08910, Example 18, where X is -NHSO 2Me and Z is -OMe. Charge it (6.0 kg) and 18 L of THF into the reactor. Separately, mix 6.6 kg of 35% w / w sodium hydroxide and 21 L of purified water and transfer into the reactor, and heat the mixture to 65 °C while distilling off all the THF. After the hydrolysis reaction is completed, slowly transfer the alkaline solution 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. Filter the resulting solid and wash with 24 L of water. Reload the wet solid (III) (16.6 kg wet weight) into the reactor together with 60 L of ethyl acetate, then heat to reflux to distill off 30 L of the solvent. Charge 12.6 L of heptane into the reactor and keep the mixture stirred for 15 - 30 minutes. Then cool it to 5 °C and stir for 2 hours. Filter the resulting solid and wash the reactor and the filter cake with 12 L of heptane. Dry the wet solid in a static tray drier under vacuum. 6235 g of a white solid (93.9% yield) is obtained.

[0242] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0243] Example 2

[0244] Preparation of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone (Intermediate (VII), n = 0)

[0245] According to the preparation procedure described in WO 2010 / 089107, Example 1, Intermediate (VI) is obtained, where n is 0.

[0246]

[0247] Alternative procedure for obtaining Intermediate (VII) (n = 0):

[0248] Using MnO 2 procedure

[0249] Dissolve 5 kg of (VI) (where n is 0) in 30 L of toluene in a reactor; add 3.15 kg of activated MnO 2 to the organic mixture and heat the suspension to reflux for 3 hours. Cool the mixture to 50 °C and filter out the MnO 2 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 entire amount of toluene. Load another 20 L of 2-propanol and partially distill the solvent 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).

[0250] Product characterization is described in WO 2009018909, Example 2 (Intermediate 1b).

[0251] Operation of Swern

[0252] 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.SO 3 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% H 2 SO 4 aqueous 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.

[0253] Operation using IBX

[0254] Add (VI) (where n is 0) (1.0 g, 2.5 mmol) 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), and stir the resulting mixture at 25 °C for 1 hour and then heat to 50 °C for 2 hours. After cooling to 25 °C, quench the reactant with 10% aqueous potassium carbonate solution (40 mL) and filter out the solid to obtain ketone (VII) in quantitative yield.

[0255] Using operation of

[0256] At 25 °C, commercially available ("Stabilized IBX", a white powder preparation of IBX composed 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.

[0257] Procedure using DMP

[0258] 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.

[0259] Example 2A

[0260] Preparation of 3,5-dichloro-4-methyl-1-oxypyridine (Intermediate A)

[0261]

[0262] 3,5-Dichloro-4-methylpyridine (0.5 g, 3.08 mmol) and (1.5 g, 4.62 mmol) were 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. The heterogeneous hot solution was then 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 was obtained as a white solid (0.43 g, 78% yield).

[0263] Example 2B

[0264] Preparation of (R / S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethanol (Intermediate (VI), n = 1)

[0265]

[0266] In a 50 ml three-necked flask under a nitrogen atmosphere, Intermediate A (0.4 g, 2.25 mmol) and Intermediate B (0.78 g, 3.22 mmol) were added 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 minutes. After reacting at -35 °C for 60 minutes, the solution was quenched with 25% aqueous NH 4 Cl (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 (10 ml). Then the organic solvent was dried over Na 2 SO 4 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).

[0267] Example 3

[0268] Preparation of (R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethanol (Intermediate (II), n = 0)

[0269]

[0270] 2.40 kg of (VII) (where n is 0) was dissolved in 23 L of toluene in a reactor. The reactor was degassed with nitrogen. Solvias proprietary ligand SL-N004-1 and RuCI2(PPh 3 ) 3Place in a 2 L Schlenk spherical flask and dry, and add degassed toluene (1.2 L). Heat the mixture to 80 °C for 1 hour, 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. Seal the reactor, degas 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 out the carbon and rinse the filter cake with 1.5 L of ethyl acetate. Concentrate the slightly yellow solution to dryness under reduced pressure to yield 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, 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).

[0271] Example 4

[0272] 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)

[0273]

[0274] Using a Chiralpak IC 20μm - 250*76mm column and dichloromethane / ethanol 95 / 5 (v / v) as the mobile phase, the chromatographic separation of 3000 g of (VI) (where n is 0) was carried out in batches. The 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%.

[0275] Example 4A

[0276] (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) Separation

[0277]

[0278] Similarly to Example 4, a chromatographic separation of the solution of the racemate (VI) (where n is 1) can be carried out using a Chiralpak IC 20μm - 250*76mm 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.

[0279] Example 5

[0280] (S)-3-Cyclopropylmethoxy-4-methanesulfonylaminobenzoic acid - 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethyl ester (Compound (I), n = 0) Preparation

[0281]

[0282] 75 g of (III) (where X is -NHSO 2Me 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 NaHCO 3 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).

[0283] Product characterization was described in Example 15 of WO 2010089107.

[0284] Example 6

[0285] (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) Preparation

[0286]

[0287] Using H 2 O 2 / acetic acid operation

[0288] 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% H 2 O 2 , and the mixture was heated to 80 °C for 8 hours. 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% NaHCO 3 aqueous solution until the pH was basic, 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 shelf dryer to give a white solid (65.1 g recovered, 87.1% yield).

[0289] Product characterization was described in Example 17 of WO 2010089107.

[0290] Example 7

[0291] (S)-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)-ethanol (Intermediate (II), n = 1) Preparation

[0292]

[0293]

[0294] Use of H 2 O 2 / acetic acid operation

[0295] 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 keep the mixture stirred at the same temperature 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 keep it stirred 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).

[0296] Product characterization is described in Example 7 of WO 2010089107.

[0297] Use operation

[0298] Charge 456 g (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 ) 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 another 50 g After 1.5 hours, the reaction ends. 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 keep it stirred 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).

[0299] Product characterization is described in Example 7 of WO 2010089107.

[0300] Example 8

[0301] Preparation of (S)-3-(cyclopropylmethoxy)-4-(methylsulfonylamino)benzoic acid 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethyl ester (Compound (I), n = 1)

[0302]

[0303] Charge 100 g of (III) (where X is NHSO 2 Me and Z is -OH) and 1 L of ethyl acetate into a reactor. Add 57 g of carbonyldiimidazole portionwise with stirring at 40 °C, and then stir the mixture for 60 min. Add 123 g of (II) (where n = 1) and 3.7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and heat the mixture to 75 °C for about 4 h. Wash the organic solution with 500 ml of 1 M aqueous HCl, with 500 ml of 5% aqueous NaHCO 3 aqueous solution and with 500 ml of 10% aqueous NaCl. Heat the organic mixture to 70 °C under vacuum and concentrate to 600 ml. Cool the mixture to 50 °C and add 300 ml of n-heptane. Seed the solution, cool to 5 °C and hold with stirring for 1.5 h. Filter off the resulting solid and dry under vacuum. 168 g of a crude solid is obtained (82% yield).

[0304] Product characterization is described in Example 17 of WO 2010089107.

[0305] Example 9

[0306] Preparation of (S)-3-(cyclopropylmethoxy)-4-(methylsulfonylamino)benzoic acid 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxido-pyridin-4-yl)ethyl ester (Compound (I), n is 1) - from ethanol solvation

[0307] Charge a solution of the crude Compound (I) (where n is 1) into a 1 L reactor. Add DCM (90 ml) and EtOH (300 ml), stir the white suspension and warm to reflux until completely dissolved. Distill off the DCM and a white solid starts to precipitate. Further concentrate the ethanol solution to 6 - 7 volumes, distill off a portion of EtOH, and then cool to 0 - 5 °C and stir for 120 min. Filter the resulting solid and wash with 30 ml of EtOH. Dry the wet solid in a static shelf dryer under vacuum. 28.55 g of a white solid is obtained (95% yield).

[0308] The compound of formula (I) obtained as a solvate according to Example 9 (where n is 1) was studied as follows: 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.

[0309] It was characterized as follows: a melting point range of 87 °C - 101 °C was determined by DSC at a scan rate of 10 °C / min;

[0310] An 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.

[0311] Example 10

[0312] Crystalline form A of compound (I) (where n is 1)

[0313] Procedure from ethyl acetate / heptane

[0314] 5 g of crude (I) (where n is 1) was charged 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 held for 2 hours, filtered and dried under vacuum. A white solid, so-called form A (3.6 g, 72% yield) was obtained.

[0315] The compound of formula (I) obtained as form A according to Example 10 (where n is 1) was studied as follows: 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.

[0316] It was characterized as follows: a melting point range of 144 °C - 147 °C was determined by DSC at a scan rate of 10 °C / min;

[0317] X-ray powder diffraction pattern (Bruker D8 Advance with X-ray Diffraction Tube type 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.

[0318] Procedure from isopropyl acetate

[0319] 5 g of crude product (I) (where n is 1) was charged 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.

[0320] Product characterization was described in Example of WO 2010089107.

[0321] Example 11

[0322] 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)

[0323]

[0324] Using H 2 O 2 / acetic acid procedure

[0325] 0.5 g of (VII) (where n is 0) was charged 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).

[0326] Using procedure

[0327] 10 g of (VII) (where n is 0) was charged into a flask together with 11.44 g of 80 ml of methanol and 30 ml of water. 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.

[0328] Procedure using MCPBA

[0329] 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 a further 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.

[0330] Example 12

[0331] 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)

[0332]

[0333] Procedure using DMP

[0334] 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 and 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.

[0335] Example 13

[0336] 3-(Cyclopropylmethoxy)-4-nitrobenzoic acid (Intermediate (III), X = -NO 2 and Z = -OH) Preparation

[0337]

[0338] Prepare (III) according to the procedure described in Example 18 of WO 2010 / 089107, where X is -NO 2 and Z is -OMe. Load 550 g of (III) (where X is -NO 2 and Z is -OMe) into a reactor, followed by loading 1.65 L of THF and 2.85 L of 1 M aqueous lithium hydroxide solution. Heat the mixture to 40 °C for 1.5 hours, then cool to room temperature. Add 4.4 L of ethyl acetate, followed by adding 240 ml of 37% aqueous HCl solution. Drain the aqueous phase, and wash the organic phase with 2.75 L of water twice, and then concentrate under vacuum at 50 °C. Add 1.65 L of n-heptane at the same temperature, and cool the suspension to room temperature. Filter out the solid and dry it in a vacuum tray dryer to obtain 337 g of (III), where X is -NO 2 and Z is -OH (73% yield).

[0339] Example 14

[0340] (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) Preparation

[0341]

[0342] Mix Intermediate (III) (where X is -NO 2 , Z is -OH) (80 g, 0.34 mol, ref.), (II) (where n is 0) (109.1 g, 0.27 mol, 0.9 equivalent), EDC.HCl (193.9 g, 1.01 mmol, 3 equivalents), DMAP (20.6 g, 0.17 mol, 0.5 equivalent), and DMF (400 ml, 5 vol), and heat to 75 °C overnight. Partition the solution between water and ethyl acetate, wash the organic phase with acidic and basic aqueous solutions, and concentrate under vacuum. Crystallize the crude material with EtOH (1200 ml) and acetone (100 ml). Obtain a white solid (101 g, 60% yield relative to (VIII)).

[0343] 1 1H 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).

[0344] Example 15

[0345] Preparation of (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxo-pyridin-4-yl)-ethyl ester (Intermediate (IV), n = 1)

[0346]

[0347] Mix (III) (where X is -NO 2 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) together and heat to 100 °C overnight. Partition the solution between water and ethyl acetate, wash the organic phase with acidic and basic aqueous solutions and concentrate in vacuo. Crystallize the crude material from EtOH (600 ml), acetone (200 ml) and heptane (200 ml). Obtain a white solid (71 g, 41% yield relative to Intermediate (II) where n is 1).

[0348] 1 H NMR (400 MHz, DMSO-d 6) 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 = NH 2 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 product is recovered (90% yield).

[0354] 1 H 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 SnCl 2

[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% KHCO 3 aqueous solution. Filter the mixture to remove the precipitated salts and drain the aqueous phase. Wash the organic phase with additional KHCO 3 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-oxypyridin-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 SnCl 2 of

[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 NaOH aqueous solution to the crude product. Drain the aqueous phase and wash the organic phase with 10 ml of 10% NaCl aqueous solution. 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] 1 H NMR (400 MHz, DMSO-d 6) 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 hours. Then quench the reactant 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 gradient elution (hexane 100% to hexane / EtOAc 60 / 40) on column chromatography 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] Use H 2 O 2 / acetic acid operation

[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 keep the mixture under 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] Use the operation of

[0375] Charge 0.3 g of (IV) (where n is 0) into a 50 ml flask, then charge 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 Na 2 SO 4 and remove the solvent under reduced pressure to give the product as a pale 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 solution. 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 the 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 diatomaceous earth pad, 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 the 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 to 1,6 L under vacuum 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, and the organic phase was washed with water (3 L). The solvent was concentrated to 2 - 3 volumes under vacuum, 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 Büchner funnel and washed with n-heptane (1 L). The resulting yellow solid was dried under vacuum 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 combined 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 Büchner funnel and washed with 1 volume of cold isopropanol. The resulting solid was dried under vacuum 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), K 2 CO 3 (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 and keep 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 K 2 CO 3 (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) 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. A white solid precipitates. 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% H 2 SO 4 aqueous 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-oxido-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. NaBH 4 (18.0 mg, 0.48 mmol) was added, and the suspension was stirred for 1.5 hours. The reaction mixture was quenched with H 2 O (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 Na 2 SO 4 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 a 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, and reacting with a compound of formula (III)

[0419]

[0420] wherein X is selected from -NHSO 2 Me and -NO 2 , and Z is selected from -OH, chlorine, bromine, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, arylalkoxy, (C 1 -C 6 ) alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 -C 6 ) 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 -NO 2 ; 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 reducing it enantioselectively 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 then reduced to the compound of formula (VI), wherein n is 0 or 1, and reprocessing in a chromatographic separation method;

[0436] and all compounds 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 -NHSO 2 Me.

[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 -NO 2 , 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) as follows: oxidizing the compound of formula (VI) to the compound of formula (VII), and enantioselectively reducing the latter compound to the 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) as follows: chromatographically separating the compound of formula (VI) to obtain the compound of formula (II) and the compound of formula (VIII).

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

[0442] 7. A 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, diethyl 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 embodiment 1 or 2, achieved using CDI and DBU in ethyl acetate.

[0444] 9. The method according to embodiment 1 or 3, achieved using EDCI and DMAP in DMF.

[0445] 10. The method according to embodiment 1 or 3, wherein in step b), the reduction of (IV) 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 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, platinum on carbon.

[0447] 12. The method according to embodiment 10, wherein the reducing agent is formic acid, 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 alkane, 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 embodiment 10, carried out with hydrogen on 5% palladium on activated carbon powder, model A103038, sulfided in ethyl acetate.

[0449] 14. The method according to 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, and the solvents are 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 the oxidation of (VI) to obtain (VII) is carried out in the presence of an oxidant 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 ane and mixtures thereof, and the oxidant is selected from metal oxides such as MnO 2 , hypervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, and dimethyl sulfoxide-based oxidants (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 RuCl 2 (PPh 3 ) 3 , [Ru(p-cymene)Cl 2 2 , [RhCI 2 (Cp*)] 2 or [IrCI 2 (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, C 1 -C 4 sodium alkoxide, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, C 1 -C 4 potassium alkoxide, potassium bicarbonate, lithium hydroxide, lithium carbonate, C 1 -C 4 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 reacting RuCl 2 (PPh 3 ) 3React with the complex formed in situ with the chiral ligand SL-N004-1.

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

[0457]

[0458] 22. Intermediate compound of formula (III), where X is -NHSO 2 Me and Z is -OH

[0459]

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

[0461]

[0462] where n is 0 or 1 and R 1 and R 2 are independently selected from H, straight-chain or branched (C 1 -C 6 ) alkyl, the (C 1 -C 6 ) alkyl is optionally substituted with one or more substituents selected from halogen atoms, (C 3 -C 7 ) cycloalkyl, (C 5 -C 7 ) cycloalkenyl, (C 5 -C 7 ) cycloalkenyl, straight-chain or branched (C 2 -C 6 ) alkenyl, aryl (C 2 -C 6 ) alkenyl and straight-chain or branched (C 2 -C 6 ) alkynyl, and the method comprises:

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

[0464]

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

[0466]

[0467] where X is selected from -NHSO 2 Me and -NO 2 , and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C 1 -C 6)Alkoxy, aryloxy, arylalkyloxy, (C 1 -C 6 )alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 -C 6 )alkylcarbonyloxy, to obtain a compound of formula (XI), where n is 0 or 1, or 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) Reduce it to the corresponding compound of formula (XIII)

[0471]

[0472] wherein R1, R2 and n have the meanings reported above and react it with methanesulfonyl halide to obtain a compound of formula (XI), where 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) Oxidize the compound of formula (XIV)

[0475]

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

[0477]

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

[0479] c2) Chromatographically separate the compound of formula (XIV), where n is 0 or 1, to obtain a compound of formula (X) and a compound of formula (XVI)

[0480]

[0481] where n has the meaning reported above;

[0482] and optionally oxidize 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), where n is 0 or 1 and reprocessed in the following chromatographic separation method;

[0483] And in all compounds of formula (XI), (X), (XII), (XIII), (XIV), (XV) or (XVI) wherein n is 1 can be obtained by oxidizing the corresponding compounds 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 R 1 and R 2 are independently selected from H, linear or branched (C 1 -C 6 ) alkyl, and the (C 1 -C 6 ) alkyl is optionally substituted with one or more substituents selected from halogen atoms, (C 3 -C 7 ) cycloalkyl, (C 5 -C 7 ) cycloalkenyl, (C 5 -C 7 ) cycloalkenyl, linear or branched (C 2 -C 6 ) alkenyl, aryl (C 2 -C 6 ) alkenyl and linear or branched (C 2 -C 6 ) alkynyl.

[0488] 26. The method according to embodiment 1, the method comprising crystallization or comminution 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, 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 crystalline form A according to embodiment 26, the method being carried out in ethyl acetate with n-heptane.

[0490] 28. Use of the method according to embodiment 27 and its combination with a suitable carrier or vehicle for the preparation of a pharmaceutical composition for inhalation.

[0491] 29. A crystal form of a 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 according to 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), the method comprising inhalably administering an effective amount of the crystal form according to embodiment 29 or 30.

[0494] 32. A solvate of a 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 comprising:

[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 -NHSO 2 Me and -NO 2 , and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C 1 -C 6 ) alkoxy, aryloxy, arylalkoxy, (C 1 -C 6 ) alkylcarbonyloxy, arylcarbonyloxy and aryl(C 1 -C6 ) an alkylcarbonyloxy group 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 a straight-chain or branched (C 1 -C 6 ) 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’:

[0518]

[0519] in a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, di It reacts with thionyl chloride, hydrochloric acid or sulfuric acid or with the relevant alkyl halides in the presence of a solvent and a base selected from alkanes, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and their mixtures, and the base is 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 specific embodiment 34, wherein the intermediate of formula B’ is converted to 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 peracids, m-chloroperbenzoic acid, persulfuric acid or (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 )

[0524]

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

[0526]

[0527] wherein R is a straight-chain or branched (C 1 -C 6 ) alkyl or arylalkyl, and the method comprises oxidizing intermediate B with (KHSO 5 *1 / 2KHSO 4 *1 / 2K 2 SO 4 ) in the corresponding alkyl alcohol as the solvent

[0528]

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

[0530]

[0531] wherein R is a straight-chain or branched (C 1 -C 6) an alkyl or aralkyl, the method comprising converting intermediate C' by a Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as a solvent

[0532]

[0533] into intermediate C",

[0534]

[0535] subsequently alkylating with cyclopropyl bromide in the presence of a solvent and a base 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 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 readily detectable impurities is less than 1.0 w / w.

[0542] 43. The crystalline form according to embodiment 39, wherein the total amount of readily 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 ane, 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 crystalline form of a compound of formula (I), wherein n is 1, characterized in that it has the following characteristic XRPD peaks: 7.48; 10.15; 12.72; 13.51; 16.18; 18.08; 19.89; 20.2 and 25.82 ± 0.2 degrees / 2θ (CuKα2).

2. The crystalline form according to claim 1, characterized in that it has 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).

3. The crystalline form according to claim 1, wherein the percentage of crystallinity is equal to or higher than 90%.

4. The crystalline form according to claim 1, wherein the percentage of crystallinity is equal to or higher than 95%.

5. The crystalline form according to claim 1, wherein the total amount of readily detectable impurities is less than 1.0 w / w.

6. The crystalline form according to claim 1, wherein the total amount of readily detectable impurities is less than 0.5% w / w.

7. The crystalline form according to claim 1, characterized in that it has the XRPD pattern of the crystalline form from ethyl acetate / n-heptane as shown in Figure 6.

8. The crystalline form according to claim 1, characterized in that it has the XRPD pattern of the crystalline form from isopropyl acetate as shown in Figure 7.

9. The crystalline form according to claim 1, characterized in that it has the Raman spectrum of the crystalline form from ethyl acetate / n-heptane as shown in Figure 5.

10. A method for preparing the crystalline form according to any one of claims 1-9, 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 ane, 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.

11. The method according to claim 10, wherein the solvent is ethyl acetate / heptane or isopropyl acetate.

12. The method according to claim 10, wherein the method comprises heating a suspension of the compound of formula (I) with one or more solvents to a temperature between 50 - 90 °C until the solid is completely dissolved, cooling it between 0 - 5 °C for 1 - 5 hours, filtering and drying.

13. The method according to claim 10, wherein the method comprises heating a suspension of the compound of formula (I) with ethyl acetate to 75 °C, adding n-heptane, and cooling to 5 °C and holding for 2 hours.

14. The method according to claim 10, wherein the method comprises heating a suspension of the compound of formula (I) with isopropyl acetate to reflux until completely dissolved, cooling to 0 °C and stirring for 2 hours.

15. A crystalline form of the compound of formula (I) obtained by the method according to any one of claims 10 - 14.

16. A solvate of a compound of formula (I), wherein n is 1, characterized in that it has the XRPD pattern as shown in Figure 3.

17. A pharmaceutical composition for inhalation or intranasal administration, the pharmaceutical composition comprising the crystalline form according to any one of claims 1 - 9 and 15 or the solvate compound according to claim 16 in combination with a suitable carrier or vehicle.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is in a dosage form selected from the following: tablets, capsules, powders, sustained release formulations, ointments, gels, creams, suppositories, eye drops, transdermal patches, syrups, solutions, suspensions, aerosols, solutions for nebulizers, nasal sprays.

19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is in the dosage form of capsules.

20. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is a dry powder for inhalation.

21. Use of the crystalline form according to any one of claims 1-9 and 15, or the inhaled or intranasally administered pharmaceutical composition according to any one of claims 17-20, or the solvate according to claim 16, in the preparation of a medicament for preventing and / or treating inflammatory or obstructive respiratory diseases.

22. Use of the crystalline form according to any one of claims 1-9 and 15, or the inhaled or intranasally administered pharmaceutical composition according to any one of claims 17-20, or the solvate according to claim 16, in the preparation of a medicament for preventing and / or treating chronic obstructive pulmonary disease or chronic bronchitis.

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